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The human microbiome and autoimmunity
Abstract
Purpose of review:
To demonstrate how dysbiosis of the human microbiome can drive autoimmune disease.
Recent findings:
Humans are superorganisms. The human body harbors an extensive microbiome, which has been shown to differ in patients with autoimmune diagnoses. Intracellular microbes slow innate immune defenses by dysregulating the vitamin D nuclear receptor, allowing pathogens to accumulate in tissue and blood. Molecular mimicry between pathogen and host causes further dysfunction by interfering with human protein interactions. Autoantibodies may well be created in response to pathogens.
Summary:
The catastrophic failure of human metabolism observed in autoimmune disease results from a common underlying pathogenesis - the successive accumulation of pathogens into the microbiome over time, and the ability of such pathogens to dysregulate gene transcription, translation, and human metabolic processes. Autoimmune diseases are more likely passed in families because of the inheritance of a familial microbiome, rather than Mendelian inheritance of genetic abnormalities. We can stimulate innate immune defenses and allow patients to target pathogens, but cell death results in immunopathology.
... In addition, bacterial translocation markers, including circulatory LPS and intestinal fatty-acid binding protein (I-FABP), were found elevated in suicide attempters, connecting once again neuropathology to gut barrier disruption [55]. As commensal microbiota express proteins identical or similar to those of the human host, their translocation can activate the immune system, triggering pathology [56][57][58][59]. For example, Escherichia coli (E. ...
... For example, Escherichia coli (E. coli) expresses glutamate receptors B and D (GluR-B and GluR-D), which upon translocation, could elicit anti-N-methyl-d-aspartate-receptor (NMDAR) antibodies, immunoglobulins previously associated with suicidal behavior [56,60]. Moreover, Bacteroides species and Pseudomonas fluorescens produce γ-aminobutyric acid (GABA) and GABA-binding proteins, which could elicit anti-GABA antibodies, molecules also connected to suicidal behavior [61,62]. ...
... The microbiome consists of symbiotic microbes that are beneficial to both the human body and microbiota and some, in smaller numbers, of pathogenic microbes that promote diseases. Some of the symbiotic microbes help perform essential functions of the body, such as absorbing nutrients, modulating the immune system, and protecting against pathogenic insults [2]. ...
... The bacteria living with us are mostly beneficial colonizers. In fact, autoimmune diseases such as diabetes, rheumatoid arthritis, muscular dystrophy, multiple sclerosis, and fibromyalgia are associated with microbiome alteration [2]. ...
Despite significant advances in understanding the pathogenetic mechanisms underlying gynaecological cancers, these cancers still remain widespread. Recent research points to a possible link between microbiota and cancer, and the most recent attention is focusing on the relationship between the microbiome, the immune system, and cancer. The microbiome diversity can affect carcinogenesis and the patient’s immune response, modulating the inflammatory cascade and the severity of adverse events. In this review, we presented the recent evidence regarding microbiome alterations in patients with gynaecological tumours to understand if the link that exists between microbiome, immunity, and cancer can guide the prophylactic, diagnostic, and therapeutic management of gynaecological cancers.
... Further, formation of Vitamin D Response Element (VDRE) in the nucleus enhances expression of growth factors, cellular differentiation, immunity and repair. In oral cavity, Vitamin D imbalance causes diseases of auto immune nature including recurrent aphthous stomatitis, Behçet syndrome, Systemic lupus erythematosus, Sjögren syndrome and cancers like squamous cell carcinoma [5,6]. It is therefore evident that modification in VDR influence early cellular proliferation and differentiation but the exact mechanism is still unknown. ...
... The weakened innate defense further causes susceptibility to additional stress on immune system to enhance its chance for survival. In contrary, the immune system overcome the dysregulated response by clearing pathogens through the production of the antimicrobial peptide, cathelicidin which possesses antiviral, antibacterial, and antifungal activity [5,6]. ...
Carcinogenesis is a multifactorial disease which involves
environmental and genetic factors as a predisposing cause that
bring biochemical imbalance resulting in the genomic aberrations
at the cellular levels. Vitamin D (1,25(OH)2D3) mediates pleiotropic
effects on various molecular pathways that is extensively known
in physiologic but elusive in pathological state. Studies suggest that
Vitamin D acts through its receptors like VDR/ RXR to form ligands
which affects transcription of wide spectrum of genes involved in
calcium and phosphate homeostasis as well as cell division and
differentiation. It is these latter actions due to which use of Vitamin
D is gaining attention in cancer cells as an anti-proliferative agent.
Although anti-proliferative role of vitamin D has been realized in the
treatment of psoriasis and in parathyroid cell hyperplasia associated
with secondary hyperparathyroidism, but its role in premalignant and
malignant oral lesions are still in premature state. Immunotherapeutic
modalities focus on the expression of the receptors and its ligands to
assess the prognosis of the disease which depends on the local and
distant spread of neoplastic cells. Though Vitamin D is known to
suppress cancers related to breast, lung, bladder, prostrate, colorectal
and some cancers of oral cavity but chemoresistance and postoperative recurrence are the major challenges to prevent mortality in cancer patients. The present review focuses on the physiologic, epigenetic and molecular interactions of Vitamin D causing lesions affecting the oral cavity.
... It was observed that bacterial diversity was reduced [21] in relation to microbial richness and uniformity, but not in relation to the number of species [19] . This supports studies that reported pro-inflammatory bacteria as responsible for releasing substances which aggravates the level of systemic inflammation [22] related to the intestinal disorder of autoimmune diseases [23][24][25]. ...
... Patients with SLE in activity present specific dysbiosis in microbiota and its related metabolic pathways [21] as a consequence of altered immunological function [3]. Therefore, changes in balanced microbiota composition, i.e. dysbiosis, may play an important role in promoting chronic inflammation in autoimmune diseases [24,25] resulting in exacerbation, rapid progression, and disease worsening [28]. ...
Background
Systemic Lupus Erythematosus (SLE) is an autoimmune disease, characterized by being multi-systemic and, therefore, reaching various organs and affecting mainly young women. Its pathogenesis comprehends many factors, including the interaction between microbiota and immune system. This systematic review assessed the relationship between intestinal microbiota and SLE in activity, highlighting microbiota representative patterns regarding quantity and diversity.
Methods
This study considered researches carried out in patients with SLE, with no restriction of age or gender, which fulfilled the classification criteria of either Systemic Lupus International Collaborating Clinic (SLICC), American College of Rheumatology (ACR) or European League Against Rheumatism (EULAR) and used the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) to classify disease in activity or remission were included. The search was carried out from October, 2020 to January, 2021 using the following databases: Medline via Pubmed, Scopus, and Embase. Five papers were included with a total of 288 participants with SLE.
Results
Regarding microbiota in patients with SLE in activity, there was significant increase in the following genera: Lactobacillus , Streptococcus , Megasphaera , Fusobacterium , Veillonella , Oribacterium , Odoribacter , Blautia , and Campylobacter. On the other hand, decrease in Faecalibacterium and Roseburia genera as well as Ruminococcus gnavus species was observed in remission cases, showing differences between the microbiota profile in SLE in activity and in remission.
Conclusions
Results suggest that dysbiosis may be involved in the disease activity process.
Trial registration
CRD42021229322 .
... Lauder et al., 2016. Indeed, probably all tissues harbour fairly considerable numbers of non-growing microbes even under normal conditions (Bullman et al., 2017;Domingue, Turner & Schlegel, 1974;Domingue, 2010;Domingue & Woody, 1997;Gargano & Hughes, 2014;Mattman, 2001;Proal, Albert & Marshall, 2013Proal, Lindseth & Marshall, 2017). ...
... In particular, those recognising relationships between overt chronic, inflammatory disease and the presence of detectable microbes, can highlight that the blood and tissue microbiome is greatly enhanced in these diseases Arleevskaya et al., 2016;Berstad & Berstad, 2017;Broxmeyer, 2017a,b;Ebringer, 2012;Ebringer & Rashid, 2009;Ebringer, Rashid & Wilson, 2010;Emery et al., 2017;Itzhaki et al., 2016;Kell & Kenny, 2016;Maheshwari & Eslick, 2015;Miklossy, 2011;Miklossy & McGeer, 2016;Pisa et al., 2017;Pretorius et al., 2017a;Pretorius, Bester & Kell, 2016a;Proal et al., 2013Proal et al., , 2014Proal et al., , 2017. We note too that while it is all too easy to dismiss such findings as 'contaminants', those doing so must also explain why the microbes appear at much higher levels only in the 'disease' samples. ...
Since the successful conquest of many acute, communicable (infectious) diseases through the use of vaccines and antibiotics, the currently most prevalent diseases are chronic and progressive in nature, and are all accompanied by inflammation. These diseases include neurodegenerative (e.g. Alzheimer's, Parkinson's), vascular (e.g. atherosclerosis, pre‐eclampsia, type 2 diabetes) and autoimmune (e.g. rheumatoid arthritis and multiple sclerosis) diseases that may appear to have little in common. In fact they all share significant features, in particular chronic inflammation and its attendant inflammatory cytokines. Such effects do not happen without underlying and initially ‘external’ causes, and it is of interest to seek these causes. Taking a systems approach, we argue that these causes include (i) stress‐induced iron dysregulation, and (ii) its ability to awaken dormant, non‐replicating microbes with which the host has become infected. Other external causes may be dietary. Such microbes are capable of shedding small, but functionally significant amounts of highly inflammagenic molecules such as lipopolysaccharide and lipoteichoic acid. Sequelae include significant coagulopathies, not least the recently discovered amyloidogenic clotting of blood, leading to cell death and the release of further inflammagens. The extensive evidence discussed here implies, as was found with ulcers, that almost all chronic, infectious diseases do in fact harbour a microbial component. What differs is simply the microbes and the anatomical location from and at which they exert damage. This analysis offers novel avenues for diagnosis and treatment.
... Similarly, probiotics and pathogenic bacteria have shown to modulate VDR expression in opposite directions, with the former increasing [15], and the latter decreasing [16], its expression. In particular, VDR is subject to the actions of antagonist molecules, in an attempt of pathogens to escape immune surveillance and manipulate host genes to increase their own survival [6,17]. The VDR gene (VDR, 12q12-14) is among the candidate genes that have been extensively studied for associations with IBD. ...
... Probiotics, consisting of ingestible non-pathogenic living microorganisms with the ability to confer some beneficial effects to the host when consumed in adequate amounts as food components [81], have been widely used in clinical trials for the treatment of IBD with variable results [82,83]. It has been recently shown that a properly functioning VDR pathway is required for probiotic protection against colitis [84], a finding that is of importance since VDR expression can be significantly decreased in IBD patients as a consequence of chronic inflammation [85] or dysbiosis [6,17]. VDR KO mice, in fact, did not respond to probiotics such as Lactobacillus rhamnosus strain GG (LGG) and Lactobacillus plantarum (LP) and had worse severity of Salmonella-induced colitis compared to littermates [84]. ...
Increasing evidence supports the concept that the vitamin D axis possesses immunoregulatory functions, with vitamin D receptor (VDR) status representing the major determinant of vitamin D’s pleiotropic effects. Vitamin D promotes the production of anti-microbial peptides, including β-defensins and cathelicidins, the shift towards Th2 immune responses, and regulates autophagy and epithelial barrier integrity. Impairment of vitamin D-mediated pathways are associated with chronic inflammatory conditions, including inflammatory bowel diseases (IBD). Interestingly, inhibition of vitamin D pathways results in dysbiosis of the gut microbiome, which has mechanistically been implicated in the development of IBD. Herein, we explore the role of the vitamin D axis in immune-mediated diseases, with particular emphasis on its interplay with the gut microbiome in the pathogenesis of IBD. The potential clinical implications and therapeutic relevance of this interaction will also be discussed, including optimizing VDR function, both with vitamin D analogues and probiotics, which may represent a complementary approach to current IBD treatments.
... Strachan developed the hygiene hypothesis in 1989 with the notion that viral infections early in life and family size affect the risk of suffering from hay fever and allergic rhinitis (1). Since then, it has been suggested that the increased cleanliness and subsequent lack of proper microbial exposure in early childhood, a common occurrence in Western society, can disrupt the human microbiome causing a lack of indigenous microbes and aberrant immune responses (2)(3)(4). ...
... Similarly, VDR KO mice had more bacteria from the Bacteroidetes and Proteobacteria phyla and fewer bacteria from the Firmicutes and Deferribacteres phyla in the feces compared to wild type (73). Recent evidence has shown that certain pathogenic microorganisms such as Salmonella typhimurium, Borrelia burgdorferi, Cytomegalovirus, Mycobacterium leprae, Aspergillus fumigatus, and Mycobacterium tuberculosis, the Epstein-Barr virus (3,89,102), and HIV (103) block or downregulate VDRs. ...
The hygiene hypothesis postulates that higher levels of cleanliness and improper exposure to microorganisms early in childhood could disturb the intestinal microbiome resulting in abnormal immune responses. Recently, more attention has been put on how a lack of sun exposure and consequently vitamin D deficiency could lead to less immune tolerance and aberrant immune responses. Moreover, vitamin D receptor (VDR) function has been positioned to be a critical aspect of immune response and gut homeostasis. Therefore, this review focuses on the role that the interaction between vitamin D, VDR function, and gut microbiome might have on autoimmune diseases in the context of the hygiene hypothesis. Literature shows that there is a high correlation between vitamin D deficiency, VDR dysfunction, gut microbiota composition, and autoimmune diseases. The biologically active form of vitamin D, 1,25(OH)(2)D-3, serves as the primary ligand for VDRs, which have been shown to play a fundamental role in reducing autoimmune disease symptoms. Although the biological functions of VDR, the effects of its genetic variants, and the effects of epigenetic profiles in its promoter region are largely unknown in humans, studies in murine models are increasingly demonstrating that VDRs play a crucial role in attenuating autoimmune disease symptoms by regulating autophagy and the production of antimicrobial peptides, such cathelicidin and beta-defensin, which are responsible for modifying the intestinal microbiota to a healthier composition. Remarkably, evidence shows that hormonal compounds and byproducts of the microbiota such as secondary bile acids might also activate VDR. Therefore, understanding the interaction between VDR and gut microbiota is of the utmost importance toward understanding the rise in autoimmune diseases in Western countries. We have gained insights on how the VDR functions affects inflammation, autophagy, and microbiota composition that could lead to the development of pathogenesis of autoimmune diseases, while confirming the role vitamin D and VDRs have in the context of hygiene hypothesis.
... In cases where microbe-microbe and host-microbe interactions successfully disable host metabolism, the microbiome may shift towards a state that promotes disease. We have previously termed this process "successive infection" (Proal et al., 2013a). During the successive infectious process, microbes increasingly subvert the immune response by acting in concert as polymicrobial entities. ...
... Individuals with one inflammatory condition are at much greater risk for developing a second and multimorbidity is the norm in older people (Farmer et al., 2016;Proal et al., 2013a). This high incidence of multimorbidity supports the successive infectious model, in which different inflammatory conditions share much of the same underlying pathogenesis and would subsequently be expected to arise concurrently. ...
An extensive microbiome comprised of bacteria, viruses, bacteriophages, and fungi is now understood to persist in nearly every human body site, including tissue and blood. The genomes of these microbes continually interact with the human genome in order to regulate host metabolism. Many components of this microbiome are capable of both commensal and pathogenic activity. They are additionally able to persist in both "acute" and chronic forms. Inflammatory conditions historically studied separately (autoimmune, neurological and malignant) are now repeatedly tied to a common trend: imbalance or dysbiosis of these microbial ecosystems. Population-based studies of the microbiome can shed light on this dysbiosis. However, it is the collective activity of the microbiome that drives inflammatory processes via complex microbe-microbe and host-microbe interactions. Many microbes survive as polymicrobial entities in order to evade the immune response. Pathogens in these communities alter their gene expression in ways that promote community-wide virulence. Other microbes persist inside the cells of the immune system, where they directly interfere with host transcription, translation, and DNA repair mechanisms. The numerous proteins and metabolites expressed by these pathogens further dysregulate human gene expression in a manner that promotes imbalance and immunosuppression. Molecular mimicry, or homology between host and microbial proteins, complicates the nature of this interference. When taken together, these microbe-microbe and host-microbe interactions are capable of driving the large-scale failure of human metabolism characteristic of many different inflammatory conditions.
... Gut microbiome disorders may be one of these factors. There is growing evidence that the gut microbiome interacts with the human immune system and may contribute to the development of autoimmune diseases [5]. Intestinal dysbiosis has also been detected in AIT patients [6]. ...
The gut microbiome may contribute to the development of autoimmune diseases, such as autoimmune thyroiditis (AIT). Diet has a critical impact on the gut microbiome, and it has been shown that a gluten-free diet can negatively affect its composition. A gluten-free diet is popular among patients, and therefore the aim of this study was to check whether it affects thyroid function and gut microbiome composition in AIT. Thirty-one women with AIT complied with a gluten-free diet for 8 weeks. After the first 4 weeks, participants were divided into two groups: the first group received gluten in capsules and the other one—rice starch (placebo). Blood and stool samples were examined before diet (T0), after 4 weeks (T1) and after 8 weeks of diet (T2). The only significant difference in blood parameters was observed between T1 and T2 in the placebo group for the thyroid peroxidase antibody level. After the first 4 weeks, a significant increase in Desulfobacterota, Proteobacteria, Prevotella and Parasutterella and a significant decrease in Actinobacteriota, Coriobacteriaceae and Bifidobacterium were observed. The detected microbiome alterations may indicate increasing inflammation; however, further research is required, and for now, a gluten-free diet should be used cautiously in AIT.
... (8) We are already aware about the debate going on over the 'hygiene hypothesis ' which in simple terms says too much of cleanliness in early childhood, which is quite common these days in urban India and the western world may compromise the proper diversification of microbiome leading to dire long term consequences such as diabetes type 1 (9), obesity, Bronchial Asthma and other auto immune diseases. (3,10) Interestingly there are well written review articles and books showing a two way pathway between the gut microbiome and mental well being. As given in a review article in Gastroenterology (11) there appears to be a close relationship between intestinal microbiota and the central nervous system in normal gastrointestinal function and diseases. ...
The study of human microbiome and its relationship with health and disease is one of the most exciting areas of research in health all over the world, especially after the failure of human genome project to deliver its expected results. Our body is composed of 30 trillion human cells. But it is host to close to 100 trillion bacterial and fungal cells. 70 – 90% of all cells in our body are non human. They reside on every inch of our skin, in our nose, mouth, ears, in our oesophagus, stomach and most abundantly in our gut. They are not a random phenomenon but have co-evolved with us humans over millions of years. Collectively these bacteria weigh about 3 pounds. The more we read about research on microbiome or microbiota, the name given to all these friendly symbiotic partners, the more we get interested in their role in health and disease. According to Martin J. Blaser, director of the Human Microbiome Program, who has also served as the president of Infectious Disease Society of America, in his best seller ‘Missing Microbes' (1), “It is our microbiome that keeps us healthy and parts of it are disappearing. The reason for this disaster is all around us – overuse of antibiotics in humans and animals, caesarean sections and widespread use of sanitizers and antiseptics, to name just a few.”
... There are around six single nucleotide polymorphisms (SNPs) situated for vitamin D pathways [31]. Some of these SNPs are involved in vitamin D transport and hydroxylation (from inert vitamin D to the active form), which sequentially increases the risk of vitamin D deficiency in individuals [32]. People from the Gulf countries may have some of these SNPs. ...
Background:
Vitamin D deficiency has reached pandemic levels in the Middle East and North Africa (MENA) region, even though sunshine is abundant all year round for the cutaneous synthesis of vitamin D through the skin. This study aimed to determine the prevalence of vitamin D deficiency and risk factors associated with serum 25-hydroxy vitamin D (25(OH)D) in children and adolescents aged from 10 to 19 years, as well as the possible associations of vitamin D with calcium, magnesium and phosphate levels.
Methods:
A multi-center, cross-sectional study was conducted between May and August 2019 at the Ministry of Health in the Kingdom of Bahrain. A total of 383 boys and girls were selected from five health centers from five different regions in the Kingdom of Bahrain. Information about sex, age, education level, weight, height, degree of sunlight exposure, and physical activity levels was recorded. A blood sample was taken from each participant to test serum levels of 25(OH)D, calcium, magnesium and phosphate.
Results:
The results revealed that 92.1% of the participants were deficient in vitamin D. A significantly higher percentage of boys (96.2%) were vitamin D deficient (<20 ng/mL) than girls (88.3%) (p value = 0.004). Vitamin D deficiency were more prevalent among overweight (96.8%) and obese (96.2%) participants than normal body weight and wasted participants (p value < 0.001). Being male, overweight, or obese was significantly positively associated with a risk of vitamin D deficiency. Vitamin D deficiency was significantly associated with low serum levels of magnesium. No significant associations were detected between vitamin D deficiency and calcium and phosphate serum levels. However, vitamin D deficiency was significantly associated with low serum level of magnesium (p value = 0.017).
Conclusions:
Our study revealed that vitamin D deficiency was more prevalent among overweight and obese adolescents and mostly boys rather than girls. Magnesium and phosphate were lower in adolescents and children with lower serum 25(OH)D, showing a clear association between these biomarkers and the 25(OH)D.
... Disease-causing microbes' accumulation over time causes changing gene activity and metabolic processes and that result in an abnormal immune response against substances and tissues present in the body. Autoimmune diseases appear to be passed in families by inheriting the family's microbiome not by DNA inheritance [3,4]. ...
Every person has a characteristic “enterotype,” the gut components and the environment. Recently, a strong biological correlation has emerged among the microbiome of the gut, the immune system, cancer development and pharmacological effects of chemotherapy. In this review, we outline the role of gut microbiota in the gastrointestinal tract (GIT) cancers pathogenesis and their implications for enhancing the efficacy of GIT cancer management in clinical practice. We also summarize the molecular pathways linking gut microbiota and GIT cancers and the effectiveness of manipulating microbiota in GIT cancer therapies such as personalized cancer therapy.
... It is thus at least plausible that they share some common aetiologies, as we argue here, and that knowledge of the aetiology of those diseases may give us useful clues for PE. In addition, we and others have recognised the extensive evidence for the role of a dormant blood and/or tissue microbiome in these [131][132][133][134][135][136] and related [137][138][139][140] diseases, coupled in part to the shedding of highly inflammagenic bacterial components such as Gram-negative lipopolysaccharides (LPS) and their Gram-positive cell wall equivalents such as lipoteichoic acids [141]. (We shall often use the term 'LPS' as a 'shorthand', to be illustrative of all of these kinds of highly inflammagenic molecules.) ...
Pre-eclampsia (PE) is a complex, multi-system disorder that remains a leading cause of morbidity and mortality in pregnancy. Four main classes of dysregulation accompany PE, and are widely considered to contribute to its severity. These are abnormal trophoblast invasion of the placenta, anti-angiogenic responses, oxidative stress, and inflammation. What is lacking, however, is an explanation of how these themselves are caused.
We here develop the unifying idea, and the considerable evidence for it, that the originating cause of PE (and of the four classes of dysregulation) is in fact microbial infection, that most such microbes are dormant and hence resist detection by conventional (replication-dependent) microbiology, and that by occasional resuscitation and growth it is they that are responsible for all the observable sequelae, including the continuing, chronic inflammation. In particular, bacterial products such as lipopolysaccharide (LPS), also known as endotoxin, are well known as highly inflammagenic and stimulate an innate (and possibly trained) immune response that exacerbates the inflammation further. The known need of microbes for free iron can explain the iron dysregulation that accompanies PE. We describe the main routes of infection (gut, oral, urinary tract infection) and the regularly observed presence of microbes in placental and other tissues in PE. Every known proteomic biomarker of “pre-eclampsia” that we assessed has in fact also been shown to be raised in response to infection. An infectious component to PE fulfils the Bradford Hill criteria for ascribing a disease to an environmental cause, and suggests a number of treatments, some of which have in fact been shown to be successful.
PE was classically referred to as endotoxaemia or toxaemia of pregnancy, and it is ironic that it seems that LPS and other microbial endotoxins really are involved. Overall, the recognition of an infectious component in the aetiology of PE mirrors that for ulcers and other diseases that were previously considered to lack one.
Insight, innovation, integration
Many descriptors of pre-eclampsia are widely accepted (e.g. abnormal trophoblast invasion, oxidative stress, inflammation and altered immune response, and anti-angiogenic responses). However, without knowing what causes them, they do not explain the syndrome. The Biological Insight of this manuscript is that there is considerable evidence to the effect that each of these phenomena (hence PE) are caused by the resuscitation of dormant bacteria that shed (known and potent) inflammagens such as LPS, often as a consequence of iron availability. PE is thus seen as a milder form of sepsis. The Technological Innovations come from the use of molecular markers (of microbes and omics more generally, as well as novel markers of coagulopathies) to measure this. The Benefit of Integration comes from bringing together a huge number of disparate observations into a unifying theme.
... Evidence linking the biodiversity and makeup of the microbiome to human health is accumulating including studies linking the microbiome (Box 1) to the proper functioning of our immune system [8][9][10][11]. Furthermore, a correlation between our microbiome characteristics and autoimmune disease and allergy has now been established [6,12,13]. It is therefore not surprising that a positive correlation between certain types of allergy and antibiotic use has been observed [4,14,15]. ...
Abstract Antibiotics cause dramatic changes to the human microbiome. The composition of the microbiome has been associated with changes in the immune system and these changes are beginning to be linked to immune diseases. Thus, antibiotics have been implicated as a significant contributor to the continual rise of allergies and autoimmune disease in developed countries. This recognition will hopefully result in the development of post-antibiotic therapies that restore a healthy microbiome and reduce immune system disorders.
... In addition to molecular diagnosis, systemic lupus erythematosus disease activity index (SLEDAI) is used in the assessment of disease severity and response to treatment; manifestations of comorbidities and molecular abnormalities affecting multiple organs of the body often challenges diagnostics at early stages (13). Although complex diseases have shown to be influenced by genetic and environmental forces, the gut microbiome, and recently the oral microbiome, showed direct impact on SLE subjects (14), the complexity of chronic diseases such as SLE is beyond isolated body compartments, and it requires the integration of host-microbial interactions. The heterogeneity of disease presentation and organ involvement contribute to clinical challenges for diagnosis and effective management (15). ...
Background: Systemic lupus erythematosus (SLE) is a potentially fatal complex autoimmune disease, that is characterized by widespread inflammation manifesting tissue damage and comorbidities across the human body including heart, blood vessels, joints, skin, liver, kidneys, and periodontal tissues. The etiology of SLE is partially attributed to a deregulated inflammatory response to microbial dysbiosis and environmental changes. In the mouth, periodontal environment provides an optimal niche for local and systemic inflammation. Our aim was to evaluate the reciprocal impact of periodontal subgingival microbiome on SLE systemic inflammation.
Methods: Ninety-one female subjects were recruited, including healthy (n = 31), SLE-inactive (n = 29), and SLE-active (n = 31). Patients were screened for probing depth, bleeding on probing, clinical attachment level, and classified according to CDC/AAP criteria with or without periodontal dysbiosis. Serum inflammatory cytokines were measured by human cytokine panel and a targeted pathogenic subgingival biofilm panel was examined by DNA-DNA checkerboard from subgingival plaque samples.
Results: The results showed significant upregulation of serum proinflammatory cytokines in individuals with SLE when compared to controls. Stratification of subject's into SLE-inactive (I) and SLE-active (A) phenotypes or periodontitis and non-periodontitis groups provided new insights into SLE pathophysiology. Ten proinflammatory cytokines were upregulated in serum of SLE-I only and one in SLE-A only. Four molecules overlapped in SLE-A and SLE-I. Anti-inflammatory cytokines included IL-4 IL-10, which were upregulated in SLE-I sera (but not SLE-A), controlling clinical phenotypes. Out of 24 significant differential oral microbial abundances found in SLE, 14 unique subgingival bacteria profiles were found to be elevated in SLE. The most severe oral pathogens (Treponema denticola and Tannerella forsythia) showed increase abundances on SLE-A periodontal sites when compared to SLE-I and healthy controls. Inflammation as measured by cytokine-microbial correlations showed that periodontal pathogens dominating the environment increased proinflammatory cytokines systemically.
Conclusions: Altogether, low-grade systemic inflammation that influenced SLE disease activity and severity was correlated to dysbiotic changes of the oral microbiota present in periodontal diseases.
... A number of publications have alluded to the possible involvement of the intestinal and pulmonary microbiota, as well as environmental, lifestyle, and occupational factors, in triggering or exacerbating the development of RA in both humans and in murine models of experimental disease [11,12,20,[30][31][32][33][34][35][36]. However, the potential role of proinflammatory bacterial products, especially endotoxins, reactive with pathogen recognition receptors on cells of the innate immune system, in the immunopathogenesis of RA, remains largely uncertain. ...
Microbial lipopolysaccharides (LPS) have been implicated in the pathogenesis of rheumatoid arthritis (RA), possibly driving a systemic inflammatory response that may trigger the development and/or exacerbation of the disease. To explore the existence of this mechanism in African RA patients, we have measured systemic levels of LPS and its surrogate, LPS-binding protein (LBP), as well as those of intestinal fatty acid-binding protein (I-FABP), pulmonary surfactant protein D (SP-D), and cotinine in serum to identify possible origins of LPS, as well as associations of these biomarkers with rheumatoid factor (RF) and anticitrullinated peptide (aCCP) autoantibodies and the DAS 28-3 clinical disease severity score. A cohort of 40 disease-modifying antirheumatic drug-naïve, black South African RA patients rated by compound disease scores and 20 healthy subjects and 10 patients with chronic obstructive pulmonary disease (COPD) as controls were included in this study. Levels of the various biomarkers and autoantibodies were measured using a combination of ELISA and immunofluorimetric and immunoturbidometric procedures. LPS levels were lowest in the RA group compared to the healthy controls ( p=0.026 ) and COPD patients ( p=0.017 ), while LBP levels were also significantly lower in RA compared to the healthy individuals ( p=0.036 ). Levels of I-FABP and SP-D were comparable between all three groups. Categorisation of RA patients according to tobacco usage revealed the following significant positive correlations: LBP with C-reactive protein ( p=0.0137 ); a trend ( p=0.073 ) towards an association of LBP with the DAS 28-3 disease severity score; RF-IgG antibodies with both LPS and LBP ( p=0.033 and p=0.041 , respectively); aCCP-IgG antibodies with LPS ( p=0.044 ); and aCCP-IgG with RF-IgM autoantibodies ( p=0.0016 ). The findings of this study, several of them novel, imply that tobacco products, as opposed to microbial translocation, represent a potential source of LPS in this study cohort of RA patients, again underscoring the risks posed by tobacco usage for the development and severity of RA.
... For example, infants with reduced microbial diversity demonstrate a heightened risk of allergic disease in the first 6 years [35]. Moreover, an altered gut microbiome during infancy has been associated with immune-related diseases in adulthood [36]. Therefore, alteration in the gut microbiome, specifically mediated by the feeding method and type of delivery, may contribute to the susceptibility of immune-mediated diseases in adulthood (Fig. 2). ...
Here, we summarized recent advances in laboratory and clinical research on gut microbiome.
The goal is to highlight recent discoveries on the biology and behavioral manifestations of gut
microbiomes under normal and pathologic conditions. With this new scientific knowledge, we wish to
cultivate cross-fertilization of science across multi-disciplines in the hopes of exploiting the gut microbiome
as a key component of human development and its dysbiosis may signal pathological alterations
that can be therapeutically targeted for regenerative medicine. In the end, we identify innovative
research avenues that will merit from collaborations across biomedical disciplines that may facilitate
the development of gut microbiome-based biomarkers and therapeutics. Gut microbiome stands as a
core research area that transcends pediatric and nursing care, cancer biology, neurodegenerative disorders,
cardiac function and diseases, among many other basic science and clinical arenas.
... Humoral responses can result from bacterial infections, wherein antibodies target bacteria. However, antibody responses to particular bacterial strains have also been shown to elicit autoimmunity via molecular mimicry to host antigens (Proal et al., 2013). One example was demonstrated in a seminal study of the contribution of neomycin-induced segmented filamentous bacteria to arthritic ankle thickening in mice (Wu et al., 2010). ...
Vitiligo is impacted by environmental triggers. We studied the contribution of the microbiome in FH mice, in which depigmentation is mediated by tyrosinase-reactive T cells. The mice received oral antibiotics and were monitored for depigmentation. The microbiome was studied in fecal and skin samples using 16S rRNA analysis. The resulting T-cell distributions were evaluated. In untreated mice, pigment loss did not expand to the pelage, whereas mice in the ampicillin group were approximately 1/3 depigmented at 30 weeks. In contrast to models of autoimmunity that are less dependent on IFN-γ, ampicillin but not neomycin treatment correlated with accelerated disease and reduced bacteria in the fecal pellets. Modified cytokine patterns in the tissue and serum suggest a response that transcends the gut. Ampicillin-induced depigmentation was accompanied by gut but not skin dysbiosis, and reduced T cell numbers in both sites. Neomycin induced a redistribution of gut T cells and an accumulation of skin regulatory T cells. This treatment spurred a Bacteroides-dominated population of fecal bacteria. Reduced diversity is prominent particularly after ampicillin treatment, when the gut is dominated by Pseudomonas species. In line with current concepts relating the microbiome and the immune system, we predict that dietary measures might promote skin health and delay vitiligo onset.
... In response to an antigenic challenge, macrophages, dendritic cells, and lymphocytes express the Vitamin D receptor (VDR), thereby becoming targets for the active Vitamin D metabolite, 1,25(OH) 2 D (120). Macrophages and dendritic cells also express the CYP27B1 that synthesizes 1,25(OH) 2 D leading to intra and paracrine responses such as stimulates enhancing the phagocytotic responses of macrophages and production of antimicrobial proteins such as cathelicidin (49,121,122). Active Vitamin D also modulates adaptive immunity. At the level of the APCs (like DCs), 1,25(OH) 2 D inhibits the surface expression of MHC-II-complexed antigen. ...
Vitamin D is a fat soluble secosteroid that is primarily synthesized in the skin upon exposure to Ultraviolet B (UVB) sun rays. Vitamin D is essential for the growth and development of bones and helps in reducing inflammation by strengthening muscles and the immune system. Despite the endless supply of sunlight in the Gulf Cooperation Council (GCC) countries which includes United Arab Emirates, Qatar, Kuwait, Bahrain, Saudi Arabia, and Oman, Vitamin D deficiency in the (GCC) general population at various age groups remains alarmingly high. In parallel runs the increasing prevalence of acute and chronic illnesses including, autoimmune diseases, cancer, type 1 diabetes mellitus, cardiovascular disease and Inflammatory bowel disease in the adult as well as the pediatric population of these countries. The exact association between Vitamin D deficiency and chronic disease conditions remains unclear; however, studies have focused on the mechanism of Vitamin D regulation by assessing the role of the Vitamin D associated genes/proteins such as VDR (Vitamin D receptor), VDBP (Vitamin D Binding protein), CYP27B1 as these are integral parts of the Vitamin D signaling pathway. VDR is known to regulate the expression of more than 200 genes across a wide array of tissues in the human body and may play a role in controlling the Vitamin D levels. Moreover, reduced Vitamin D level and downregulation of VDR have been linked to gut dysbiosis, highlighting an intriguing role for the gut microbiome in the Vitamin D metabolism. However, this role is not fully described yet. In this review, we aim to expand our understanding of the causes of Vitamin D deficiency in the GCC countries and explore the potential relationship between the genetic predisposition, Vitamin D levels, immune system and the gut microbiome composition. Trying to unravel this complex interaction may aid in understanding the mechanism by which Vitamin D contributes to various disease conditions and will pave the way toward new therapeutics treatments for Vitamin D deficiency and its associated outcomes.
... In addition to molecular diagnosis, systemic lupus erythematosus disease activity index (SLEDAI) is used in the assessment of disease severity and response to treatment; manifestations of comorbidities and molecular abnormalities affecting multiple organs of the body often challenges diagnostics at early stages (13). Although complex diseases have shown to be influenced by genetic and environmental forces, the gut microbiome, and recently the oral microbiome, showed direct impact on SLE subjects (14), the complexity of chronic diseases such as SLE is beyond isolated body compartments, and it requires the integration of host-microbial interactions. The heterogeneity of disease presentation and organ involvement contribute to clinical challenges for diagnosis and effective management (15). ...
Systemic lupus erythematosus (SLE) is a potentially fatal complex autoimmune disease, that is characterized by widespread inflammation manifesting tissue damage and comorbidities across the human body including heart, blood vessels, joints, skin, liver, kidneys, and periodontal tissues. The etiology of SLE is partially attributed to a deregulated inflammatory response to microbial dysbiosis and environmental changes. In the mouth, the periodontal environment provides an optimal niche to assay local dynamic microbial ecological changes in health and disease important to systemic inflammation in SLE subjects. Our aim was to evaluate the reciprocal impact of periodontal subgingival microbiota on SLE systemic inflammation. Ninety-one female subjects were recruited, including healthy (n=31), SLE-inactive (n=29), and SLE-active (n=31). Patients were screened for probing depth (PD), bleeding on probing (BOP), clinical attachment level (CAL), and classified with or without periodontal dysbiosis, periodontitis. Serum inflammatory cytokines were measured by human cytokine panel and subgingival biofilm was examined by DNA-DNA checkerboard. The results showed significant upregulation of proinflammatory cytokines in individuals with SLE when compared to controls. Stratification of the subjects into SLE-inactive (I) and SLE-active (A) phenotypes or periodontitis and non-periodontitis groups provided new insights into SLE pathophysiology. While low-grade inflammation was found in SLE-I subjects, a potent anti-inflammatory cytokine, IL-10 was found to control clinical phenotypes. Out of twenty-four significant differential oral microbial abundances found in SLE, fourteen unique subgingival bacteria profiles were found to be elevated in SLE. Pathogens from periodontal disease sites (Treponema denticola and Tannerella forsythia) showed increase abundance in SLEA subjects when compared to controls. Cytokine-microbial correlations showed that periodontal pathogens dominating the environment increased proinflammatory cytokines systemically. Deeper clinical attachment loss and periodontal pathogens were found in SLE subjects, especially on SLEI, likely due to long-term chronic and low-grade inflammation. Altogether, local periodontal pathogen enrichment was positively associated with high systemic inflammatory profiles, relevant to the overall health and SLE disease pathogenesis.
... For example, the microbiome at 2 months of age has been shown to be predictive of a child's interleukin expression levels at 2 years of age (3). Indeed, children with altered microbiome development show an increased incidence of immune-mediated disorders in adulthood (4)(5)(6)(7). This implies that perturbations or abnormal assembly during this early life interval may have lifelong health consequences. ...
Preterm infants are at greater risk of microbial insult than full-term infants, including reduced exposure to maternal vaginal and enteric microbes, higher rates of formula feeding, invasive procedures, and administration of antibiotics and medications that alter gastrointestinal pH. This investigation of the VLBW infant microbiome over the course of the neonatal intensive care unit (NICU) stay, and at ages 2 and 4 years, showed that the only clinical variables associated with significant differences in taxon abundance were weight gain during NICU stay ( Klebsiella and Staphylococcus ) and antibiotic administration ( Streptococcus and Bifidobacterium ). At 2 and 4 years of age, the microbiota of these VLBW infants became similar to the mothers’ microbiota. The number of microbial taxa shared between the infant or toddler and the mother varied, with least the overlap between infants and mothers. Overall, there was a significant association between the diversity and structure of the microbial community and infant weight and length gain in an at-risk childhood population.
... Studies of the human genome must also account for the full extent of microbial DNA and RNA in human tissue and blood. If a genomic assembler fails to account for this contamination, chances of a false positive single nucleotide polymorphism (SNP) increase significantly during analysis (191). Contamination with even a small amount of microbial DNA/RNA-just one or two base pairs of difference-is enough to cause significant statistical errors in this fashion. ...
The illness ME/CFS has been repeatedly tied to infectious agents such as Epstein Barr Virus. Expanding research on the human microbiome now allows ME/CFS-associated pathogens to be studied as interacting members of human microbiome communities. Humans harbor these vast ecosystems of bacteria, viruses and fungi in nearly all tissue and blood. Most well-studied inflammatory conditions are tied to dysbiosis or imbalance of the human microbiome. While gut microbiome dysbiosis has been identified in ME/CFS, microbes and viruses outside the gut can also contribute to the illness. Pathobionts, and their associated proteins/metabolites, often control human metabolism and gene expression in a manner that pushes the body toward a state of illness. Intracellular pathogens, including many associated with ME/CFS, drive microbiome dysbiosis by directly interfering with human transcription, translation, and DNA repair processes. Molecular mimicry between host and pathogen proteins/metabolites further complicates this interference. Other human pathogens disable mitochondria or dysregulate host nervous system signaling. Antibodies and/or clonal T cells identified in patients with ME/CFS are likely activated in response to these persistent microbiome pathogens. Different human pathogens have evolved similar survival mechanisms to disable the host immune response and host metabolic pathways. The metabolic dysfunction driven by these organisms can result in similar clusters of inflammatory symptoms. ME/CFS may be driven by this pathogen-induced dysfunction, with the nature of dysbiosis and symptom presentation varying based on a patient's unique infectious and environmental history. Under such conditions, patients would benefit from treatments that support the human immune system in an effort to reverse the infectious disease process.
... For example, functional amyloid from Klebsiella pneumoniae can depolymerise from its fibrillary state to release oligomers which induce cytotoxicity equal to that caused by pathological Aβ in AD (Shahnawaz and Soto, 2012). The molecular mimicry theory (Ebringer and Rashid, 2009;Proal et al., 2013Proal et al., , 2017 includes microbial curli fibers 2 and Aβ as a protein-protein interaction which could result in cross-seeding, even if these proteins are essentially unalike (Friedland, 2015;. These extrinsic curli proteins act as pathogen-associated molecular patterns with increased β-pleated sheet structures, and can cross-react with antibodies to Aβ plaques (Miklossy, 2016). ...
Alzheimer’s disease and other similar dementias are debilitating neurodegenerative disorders whose etiology and pathogenesis remain largely unknown, even after decades of research. With the anticipated increase in prevalence of Alzheimer’s type dementias among the more susceptible aging population, the need for disease-modifying treatments is urgent. While various hypotheses have been put forward over the last few decades, we suggest that Alzheimer’s type dementias are triggered by external environmental factors, co-expressing in individuals with specific genetic susceptibilities. These external stressors are defined in the Iron Dysregulation and Dormant Microbes (IDDM) hypothesis, previously put forward. This hypothesis is consistent with current literature in which serum ferritin levels of individuals diagnosed with Alzheimer’s disease are significantly higher compared those of age- and gender-matched controls. While iron dysregulation contributes to oxidative stress, it also causes microbial reactivation and virulence of the so-called dormant blood (and tissue) microbiome. Dysbiosis (changes in the microbiome) or previous infections can contribute to the dormant blood microbiome (atopobiosis¹), and also directly promotes systemic inflammation via the amyloidogenic formation and shedding of potent inflammagens such as lipopolysaccharides. The simultaneous iron dysregulation and microbial aberrations affect the hematological system, promoting fibrin amylodiogenesis, and pathological clotting. Systemic inflammation and oxidative stress can contribute to blood brain barrier permeability and the ensuing neuro-inflammation, characteristic of Alzheimer’s type dementias. While large inter-individual variability exists, especially concerning disease pathogenesis, the IDDM hypothesis acknowledges primary causative factors which can be targeted for early diagnosis and/or for prevention of disease progression.
... Classic symptoms of CD have been shown to poorly correspond with histopathological findings and are insufficient indicators of CD. Given that hundreds of protein interactions define a chronic disease, not a defect in any single pathway, a wheat-related disorder can present with a variety of symptoms due to its profound impact on the microbiome, and its systemic inflammatory and immunogenic impacts on the body [93]. These cases illustrate that "any symptom" in the body may be caused by a sensitivity to an environmental trigger (in this case gluten), initiating an inflammatory cascade. ...
The consumption of wheat-based products is high in most West- ern countries (e.g. Europe, United States) and is increasing in East- ern countries as a consequence of a shift toward a Western lifestyle. Historically, Wheat-Related Disorders (WRD) referred only to wheat allergy and celiac disease. In recent years, a growing number of sub- jects worldwide have reported intestinal and extraintestinal symp- toms, without the diagnostic features of celiac disease or wheat al- lergy. In these subjects, symptoms of a wheat-related disorder may originate from non-celiac gluten sensitivity, the non-gluten antibody target protein serpins, purinins, α-amylase/protease inhibitors, glob- ulins, farinins, wheat exorphin sensitivity, wheat germ agglutinin sen- sitivity, wheat amylase-trypsin inhibitor sensitivity, and/or FODMAP (fermentable oligo-, di-, mono- saccharides and polyols) sensitivity. This article reviews the pertinent literature and presents three pediat- ric cases of wheat-related disorders that present with varied clinical presentations: liver failure, type 1 diabetes mellitus and a conjuncti- val tumor believed to be Kaposi’s sarcoma. All conditions responded rapidly to a wheat-free diet. A wheat-related disorder (with or without
celiac disease) may affect any organ or system including cardio- vascular disease, neurological diseases, connective tissue diseas- es, allergies, in ammatory bowel disease, nephritis and others. While there is increasing awareness that wheat-related disorders can manifest with extra-intestinal symptoms, clinicians still rely too heavily on the presence of gastrointestinal symptoms to suspect a wheat-related disorder. These three cases showed wheat-related pathogenesis affecting diverse organs, such as the liver, pancre- as, or eye, without marked gastrointestinal symptoms. Therefore, in patients with unexplained symptoms, who do not improve with stan- dard therapies, it may be prudent to screen for serological indicators of a WRD. Clinical awareness of the diversity of presentations of a WRD may lead to earlier suspicion, investigation and a reduction in co-morbidity.
... HGT in the human gut is intense, and the material for genetic exchange can come from various sources such as microorganisms, viruses, ingested probiotics, fermented and processed food products or industrial additives, plants, livestock, proximity to companion animals, and synthetic biology products. In the human microbiome, the microbial enzymatic machinery, especially involved in posttranslational activity, may modify naïve proteins to immunogenic ones (72,73,99,165,166). Bacterial or viral infections (167)(168)(169)(170) could also impact the fine tuning of the intestinal homeostasis. ...
... The gut microbiome influences human metabolic and other functions (O'Hara and Shanahan, 2006). Dysbiosis can increase the risk of diseases such as obesity (Turnbaugh et al., 2006), diabetes (Qin et al., 2012), various inflammatory bowel diseases (Gevers et al., 2014), and autoimmune diseases (Proal et al., 2013). Fecal microbiota transplantation from healthy individual to patient could become a therapeutic method for treatment of some diseases (Khoruts et al., 2010). ...
Biobanks are infrastructures for large-scale biology innovation. Governance of biobanks can be usefully informed by studies of publication trends, for example, on the types of biosamples employed in scientific publications. We examined trends in each of the serum, plasma, peripheral blood mononuclear cell (PBMC), buffy coat, tissue, and gut microbiome biosample-related scientific publications over the past 40 years, using data between 1977 and 2016 from the Scopus database. We found that the number of tissue-related publications was the highest in each year of our analysis than other biosamples, but was generally less than the sum of serum- and plasma-related publications. Importantly, the microbiome publications increased greatly starting in the 2010s, and currently overtook the number of publications on PBMC and buffy coat. Among serum-, plasma-, and tissue-related publications, the number of protein- and RNA-related publications was generally higher than cell-free DNA-, DNA-, and metabolite-related publications for the past 40 years. Mass spectrometry- and next-generation sequencing-related publications have increased dramatically since the 2000s and 2010s, respectively. Microbiome- and metabolite-related biosamples can help diversify future biosample collections, while tissue collections appear to maintain their importance in scientific publications. We also report here our observations on the countries that use biosample research (e.g., China, United Kingdom, United States, and others). These publication trends by the type of biosamples illuminate roadmaps by which biobanks might establish and diversify their biosample collections in the future. In addition, we note that biobanks need to secure biosamples appropriate for integrated analysis of multi-omics research data.
... HGT in the human gut is intense, and the material for genetic exchange can come from various sources such as microorganisms, viruses, ingested probiotics, fermented and processed food products or industrial additives, plants, livestock, proximity to companion animals, and synthetic biology products. In the human microbiome, the microbial enzymatic machinery, especially involved in posttranslational activity, may modify naïve proteins to immunogenic ones (72,73,99,165,166). Bacterial or viral infections (167)(168)(169)(170) could also impact the fine tuning of the intestinal homeostasis. ...
Many essential functions of the human body are dependent on the symbiotic microbiota, which is present at especially high numbers and diversity in the gut. This intricate host–microbe relationship is a result of the long-term coevolution between the two. While the inheritance of mutational changes in the host evolution is almost exclusively vertical, the main mechanism of bacterial evolution is horizontal gene exchange. The gut conditions, with stable temperature, continuous food supply, constant physicochemical conditions, extremely high concentration of microbial cells and phages, and plenty of opportunities for conjugation on the surfaces of food particles and host tissues, represent one of the most favorable ecological niches for horizontal gene exchange. Thus, the gut microbial system genetically is very dynamic and capable of rapid response, at the genetic level, to selection, for example, by antibiotics. There are many other factors to which the microbiota may dynamically respond including lifestyle, therapy, diet, refined food, food additives, consumption of pre- and probiotics, and many others. The impact of the changing selective pressures on gut microbiota, however, is poorly understood. Presumably, the gut microbiome responds to these changes by genetic restructuring of gut populations, driven mainly via horizontal gene exchange. Thus, our main goal is to reveal the role played by horizontal gene exchange in the changing landscape of the gastrointestinal microbiome and potential effect of these changes on human health in general and autoimmune diseases in particular.
... No diabetes tipo I e em outras doenças com fisiopatologia autoimune, perfis específicos de microbioma funcionam como gatilho e deflagram respostas autoimunes e autoinflamatórias. Essa resposta culmina, no caso do diabetes tipo I, por exemplo, com a destruição das células beta no pâncreas (10)(11)(12)(13)(14) . Alguns tipos de câncer, como o colorretal, o de mama e o de endométrio, têm sido associados à presença no intestino e até no próprio tecido neoplásico de algumas bactérias dos gêneros Fusobacterium, Atopobium, Gluconacetobacter e Hydrogenophaga (15,16) . ...
In this article the definition, main characteristics, and potential pathological and therapeutic implications of the human microbiome are briefly discussed.
... Furthermore, susceptibility to dysbiosis may result from individual genetic variation in microbial recognition and host response, a phenomenon known as genetic dysbiosis [90]. Although the relationship between the pathways for multifactorial disorders is complicated, the fact that many are united through the role of misregulated inflammation in their etiology and progression raises the intriguing possibility that either co-morbid and multi-morbid disease in some patients [91], or that alterations in the gut microbiota, may directly lead to the development of one condition that subsequently triggers further disorders [92]. For example, gut dysbiosis may lead to weight gain, which in turn may lead to obesity which can result in the development of type-2 diabetes mellitus and high blood pressure (metabolic syndrome). ...
Introduction: Management of co- and multi-morbidity continues to represent a major clinical challenge. There remains a lack of understanding of how multiple pathologies or conditions co-evolve or interact and importantly how treatments should be combined to effectively improve outcomes. This review highlights the challenges presented to the clinical community in managing co- and multi-morbidity.
Areas covered: The review focuses on frequently co-existing chronic conditions characterised by prolonged inflammation; these conditions include chronic obstructive pulmonary disease, rheumatoid arthritis, cardiovascular disease and certain forms of cancer. Literature searches were performed to retrieve relevant articles, particularly those published in the last 10–15 years. Within the review, current management strategies and opportunities for improvements are discussed. Problems with current clinical trial designs are described and the need emphasized for novel treatments and diagnostics for exemplar co- and multi-morbidities. We provide an overview of how precision medicine approaches could offer opportunities to treat multiple inflammation-driven disorders in a more comprehensive fashion.
Expert commentary: This section emphasizes the need for further research on individual gene-environment interactions, with the view that environmental risk factors could offer a viable route to prevention of multi-morbidities.
... Similar to retinoic acid, D3 inhibits the induction of the Th1-mediated immunity response in favor of the Th2 phenotype, through enhancing the production of IL-4 and decreasing IFNγ. The Th17 cell response is also mitigated by vitamin D through the inhibition of IL-6 and IL-23 production, leading to the promotion of the Treg cell phenotype through expansion of Foxp3 [51,52]. ...
The host’s genetic make-up is the primary factor in determining the composition of one’s adult microbiota. Other contributing factors include mother’s health in utero, the method of delivery during birth, if one is either breast fed or fed formula, the use of antibiotics during early childhood and types of foods consumed prior to, and during, weaning. The adult microbiota is not a static entity, however, and can be modified through many different environmental factors, and the composition will also change with age. Many of the previously discussed contributions to SLE are associated with alterations in the microbiota. Obese patients have an increased Firmicutes to Bacterioidetes ratio, with members of Firmicutes leading to increased energy harvest from dietary nutrients [113]. The “western diet” is associated with alterations in the gut microbiota as well. Children from a rural village in the West African country of Burkina Faso had increased microbial richness and greater Prevotella with decreased Bacteroides levels compared to European children. The microbiota of the Burkina Faso children also produced more short chain fatty acids than the intestinal microbiota of the European children [114]. These findings of agrarian societies with increased Prevotella and decreased Bacteroides have been supported in studies comparing rural South Americans and people from Bangladesh to people living in industrialized regions [115]. The source of dietary fat can impact microbiota composition as well, as mice fed diets with a fat source from either milk-fat, lard, safflower oil or a low-fat diet, all resulted in distinct phylogenetic profiles [116, 117].
Rheumatoid arthritis (RA) is a chronic autoimmune condition frequently found in rheumatological patients that sometimes raises diagnosis and management problems. The pathogenesis of the disease is complex and involves the activation of many cells and intracellular signaling pathways, ultimately leading to the activation of the innate and acquired immune system and producing extensive tissue damage. Along with joint involvement, RA can have numerous extra-articular manifestations (EAMs), among which lung damage, especially interstitial lung disease (ILD), negatively influences the evolution and survival of these patients. Although there are more and more RA-ILD cases, the pathogenesis is incompletely understood. In terms of genetic predisposition, external environmental factors act and subsequently determine the activation of immune system cells such as macrophages, neutrophils, B and T lymphocytes, fibroblasts, and dendritic cells. These, in turn, show the ability to secrete molecules with a proinflammatory role (cytokines, chemokines, growth factors) that will produce important visceral injuries, including pulmonary changes. Currently, there is new evidence that supports the initiation of the systemic immune response at the level of pulmonary mucosa where the citrullination process occurs, whereby the autoantibodies subsequently migrate from the lung to the synovial membrane. The aim of this paper is to provide current data regarding the pathogenesis of RA-associated ILD, starting from environmental triggers and reaching the cellular, humoral, and molecular changes involved in the onset of the disease.
Long COVID disproportionately affects premenopausal women, but relatively few studies have examined Long COVID's impact on female reproductive health. We conduct a review of the literature documenting the female reproductive health impacts of Long COVID which may include disruptions to the menstrual cycle, gonadal function, ovarian sufficiency, menopause, and fertility, as well as symptom exacerbation around menstruation. Given limited research, we also review the reproductive health impacts of overlapping and associated illnesses including myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), postural orthostatic tachycardia syndrome (POTS), connective tissue disorders like Ehlers-Danlos syndrome (EDS), and endometriosis, as these illnesses may help to elucidate reproductive health conditions in Long COVID. These associated illnesses, whose patients are 70%–80% women, have increased rates of dysmenorrhea, amenorrhea, oligomenorrhea, dyspareunia, endometriosis, infertility, vulvodynia, intermenstrual bleeding, ovarian cysts, uterine fibroids and bleeding, pelvic congestion syndrome, gynecological surgeries, and adverse pregnancy complications such as preeclampsia, maternal mortality, and premature birth. Additionally, in Long COVID and associated illnesses, symptoms can be impacted by the menstrual cycle, pregnancy, and menopause. We propose priorities for future research and reproductive healthcare in Long COVID based on a review of the literature. These include screening Long COVID patients for comorbid and associated conditions; studying the impacts of the menstrual cycle, pregnancy, and menopause on symptoms and illness progression; uncovering the role of sex differences and sex hormones in Long COVID and associated illnesses; and addressing historical research and healthcare inequities that have contributed to detrimental knowledge gaps for this patient population.
Multi-omics approaches hold promise to facilitate the understanding of underlying mechanisms and facilitate diagnosis and management of many autoimmune conditions. Despite a lot of hype based mainly on reports from oncology, the progress of multi-omic approaches in autoimmunity is still limited. Critical steps required to successfully apply multi-omics to autoimmune diseases include data collection, data handling and analysis. This chapter aims to provide a high-level overview on the concepts of multi-omics and how they could be applied to autoimmune research and patient management. In addition, a few selected examples are provided.
Irritable bowel syndrome (IBS) is a common functional gastrointestinal disease in children and has the clinical manifestations of recurrent abdominal pain with the changes in defecation frequency or stool form. Many studies have shown that children with IBS have a significantly lower vitamin D level than the healthy population, and vitamin D supplementation can significantly improve the clinical symptoms and quality of life of the children, suggesting that vitamin D supplementation may play a role in the treatment of IBS. This article reviews the association between vitamin D and IBS in children and elaborates on the possible mechanism of action of vitamin D.
The chief and largely terminal element of normal blood clotting is considered to involve the polymerisation of the mainly α-helical fibrinogen to fibrin, with a binding mechanism involving ‘knobs and holes’ but with otherwise littl change in protein secondary structure. We recognise, however, that extremely unusual mutations, or mechanical stressing, can cause fibrinogen to adopt a conformation containing extensive β-sheets. Similarly, prions can change morphology from a largely alpha-helical to a largely β-sheet conformation, and the latter catalyses both the transition and the self-organising polymerisation of the β-sheet structures. Many other proteins can do this, where it is known as amyloidogenesis. When fibrin is formed in samples from patients harbouring different diseases it can have widely varying diameters and morphologies. We here develop the idea, and summarise the evidence, that in many cases the anomalous fibrin fibre formation seen in such diseases actually amounts to amyloidogenesis. In particular, fibrin can interact withthe amyloid-β (Aβ) protein that is misfolded in Alzheimer's disease. Seeing these unusual fibrin morphologies as true amyloids explains a great deal about fibrin(ogen) biology that was previously opaque, and provides novel strategies for treating such coagulopathies. The literature on blood clotting can usefully both inform and be informed by that on prions and on the many other widely recognised (β)-amyloid proteins.
“Novel but physiologically important factors that affect fibrinolysis have seldom been discovered and characterized in recent years” [1]
Introduction
Human microbiome refers to the entire habitat, including the microorganisms, their genomes and the surrounding environmental conditions of the microbial ecosystem. When the equilibrium between microbial habitats and host is disturbed ‘dysbiosis’ is caused. The oral microbiome has been implicated in the manifestation of many intra- and extra-oral diseases. Lately, there is an intense effort to investigate and specify the relationship between microbial complexes, especially that of oral cavity and intestine, and autoimmunity.
Aim
To review the current literature about the possible role of oral microbiome in the pathogenesis of autoimmune diseases.
Methods
We searched for published articles in English indexed in Pubmed, Medline, ResearchGate and Google Scholar using a search strategy that included terms for oral microbiome, autoimmune diseases, dysbiosis and next generation sequencung.
Results
an important number of articles were gathered and used for the description of the possible impact of dysbiosis of oral microbiome in the pathogenesis of Sjögren’s syndrome, systemic lupus erythematosus, rheumatoid arthritis, Behcet’s disease, Crohn’s disease and psoriasis
Conclusion
This review article draws attention to the relationship of oral microbiome with the triggering of a number of autoimmune diseases. Although this specific topic has been previously reviewed, herein, the authors provide recent literature regarding the full list of nosological entities related to oral microbiome, point out the interaction between microbiome and sex hormones regarding their role in autoimmunity and mention novel, promising therapeutic approaches against systemic autoimmune diseases. Furthermore, a question arises: Is it possible that oral microbiome is associated to oral bullous autoimmune diseases?
A role for B cells in autoimmune diseases is now clearly established both in mouse models and humans by successful treatment of multiple sclerosis and rheumatoid arthritis with anti‐CD20 monoclonal antibodies that eliminate B cells. However, the underlying mechanisms by which B cells promote the development of autoimmune diseases remain poorly understood. Here, we review evidence that patients with autoimmune disease suffer from defects in early B‐cell tolerance checkpoints and therefore fail to counterselect developing autoreactive B cells. These B‐cell tolerance defects are primary to autoimmune diseases and may result from altered B‐cell receptor signaling and dysregulated T‐cell/regulatory T‐cell compartment. As a consequence, large numbers of autoreactive naive B cells accumulate in the blood of patients with autoimmune diseases and may promote autoimmunity through the presentation of self‐antigen to T cells. In addition, new evidence suggests that this reservoir of autoreactive naive B cells contains clones that may develop into CD27−CD21−/lo B cells associated with increased disease severity and plasma cells secreting potentially pathogenic autoantibodies after the acquisition of somatic hypermutations that improve affinity for self‐antigens.
Microorganisms resident in our bodies participate in a variety of regulatory and pathogenic processes. Here, we describe how etiological pathways implicated in Alzheimer's disease (AD) may be regulated or disturbed by symbiotic microbial activity. Furthermore, the composition of symbiotic microbes has changed dramatically across human history alongside the rise of agriculturalism, industrialization, and globalization. We postulate that each of these lifestyle transitions engendered progressive depletion of microbial diversity and enhancement of virulence, thereby enhancing AD risk pathways. It is likely that the human life span extended into the eighth decade tens of thousands of years ago, yet little is known about premodern geriatric epidemiology. We propose that microbiota of the gut, oral cavity, nasal cavity, and brain may modulate AD pathogenesis, and that changes in the microbial composition of these body regions across history suggest escalation of AD risk. Dysbiosis may promote immunoregulatory dysfunction due to inadequate education of the immune system, chronic inflammation, and epithelial barrier permeability. Subsequently, proinflammatory agents—and occasionally microbes—may infiltrate the brain and promote AD pathogenic processes. APOE genotypes appear to moderate the effect of dysbiosis on AD risk. Elucidating the effect of symbiotic microbiota on AD pathogenesis could contribute to basic and translational research.
Linkages between human innate immune capacity, the environment in which we live, and the development of clinical tolerance versus a spectrum of disease phenotypes are a major focus of inflammatory disease research. While extensive epidemiologic evidence indicates key roles for the microbiome and other environmental factors, the underlying mechanisms that explain how these stimuli lead to a given clinical phenotype remain speculative. Here we review strategies for characterizing human cytokine production ex vivo in response to innate immune receptor stimulation with defined ligands. Human cytokine and chemokine biomarker data provides a tool to test hypotheses on the relationship between innate immune capacity in vivo and expression of current or future clinical phenotypes. The most important limitations of experimental strategies that have been used to date are reviewed. Detailed experimental protocols are provided for characterization of pattern recognition receptor (PRR)-driven stimulation with a panel of bacterial (TLR4, TLR5) and viral (TLR3, TLR7/8, RIG-I/MDA5) ligands to assess the role played by human pro-inflammatory, anti-inflammatory, Th1-like, and Th2-like responses. The importance of characterizing human innate immune phenotypes extends beyond discovery-based research to development of improved strategies for prevention or inhibition of chronic inflammatory diseases, improved design of immunization programs, and more effective cancer immunotherapy.
Intestinal dysbiosis is implicated in Systemic Lupus Erythematosus (SLE). However, the evidence of gut microbiome changes in SLE is limited, and the association of changed gut microbiome with the activity of SLE, as well as its functional relevance with SLE still remains unknown. Here, we sequenced 16S rRNA amplicon on fecal samples from 40 SLE patients (19 active patients, 21 remissive patients), 20 disease controls (Rheumatoid Arthritis (RA) patients), and 22 healthy controls (HCs), and investigated the association of functional categories with taxonomic composition by Phylogenetic Investigation of Communities by Reconstruction of Unobserved States (PICRUSt). We demonstrated SLE patients, particularly the active patients, had significant dysbiosis in gut microbiota with reduced bacterial diversity and biased community constitutions. Amongst the disordered microbiota, the genera Streptococcus, Campylobacter, Veillonella, the species anginosus and dispar, were positively correlated with lupus activity, while the genus Bifidobacterium was negatively associated with the disease activity. PICRUSt analysis showed metabolic pathways were different between SLE and HCs, and also between active and remissive SLE patients. Moreover, we revealed that a random forest model could distinguish SLE from RA and HCs (area under the curve (AUC) = 0.792), and another random forest model could well predict the activity of SLE patients (AUC = 0.811). In summary, SLE patients, especially the active patients, show an apparent dysbiosis in gut microbiota and its related metabolic pathways. Amongst the disordered microflora, four genera and two species are associated with lupus activity. Furthermore, the random forest models are able to diagnose SLE and predict disease activity.
A granuloma is a physical pathological structure that manifests when the host mounts an immune response to fend off pathogens/infections, immunological aberrations, irritants, inflammations and other foreign particles. It is an amalgamation of immune cells (lymphocytes, phagocytes (mostly macrophages and their derivatives) plasma cells, neutrophils and eosinophils), pathogens or foreign particles or irritants, fibroblasts, epithelioid cells and multi-nucleated giant cells. This well-organized dynamic structure form after an ingested pathogen or particle finds its way into tissues. The host will then mount a response to prevent the pathogen from replicating or the foreign particle from propagating inflammation. Multiple granulomas can form upon infection/invasion in a single host. The ensemble of these structures dictates the state of disease manifestation and end points, such as rapid, fulminant infections, chronic persistent states (both symptomatic and asymptomatic) or sterilization where the infection gets cleared and cure is established. Studying granuloma formation and how it shapes immune responses is an enigma, mainly because they develop at remote locations, which makes the acquisition of relevant biological readouts a nightmare. Therefore, researchers are resorting to the use of computational inference techniques as a gateway to gain more insights. Mathematical and computational modeling approaches have been used to elucidate the mechanisms driving granuloma formation, function of granulomas, and disease progression in these granulomatous diseases. However, the use of mathematical modeling to elaborately explain non-tuberculosis infections is still primal. The goals of this review are i) to review existing modeling studies describing the initiation, progression and development of different granulomatous diseases, and ii) to suggest how existing modeling approaches can be exploited to understand the immunobiology of granulomatous non-TB infections.
The advent of novel therapeutics for rheumatoid arthritis (RA) has transformed articular improvement and systemic outcomes, but the number of respiratory infections has been increasing in the past decade. Important causes for the elevated susceptibility to bacterial and fungal respiratory infections are mainly due to immune dysregulation of RA, pulmonary comorbidities, and immunosuppressive treatments such as corticosteroids, methotrexate, and biological agents. Pneumonia is the most common infection, and fungal infection is also frequently seen in patients with RA. Respiratory infections in patients with RA are considered important factors that affect not only patient survival but also the development of RA itself. Thus, it is essential for clinicians to have sufficient knowledge of the characteristics of respiratory infections in these settings of RA. Because controlling respiratory infections improves the survival of patients with RA, proper diagnosis and prompt treatment of respiratory infections in these patients are necessary throughout their treatment period.
Objective:
To determine if prenatal, pregnancy, or postpartum-related environmental factors are associated with multiple sclerosis (MS) risk in children.
Methods:
This is a case-control study of children with MS or clinically isolated syndrome and healthy controls enrolled at 16 clinics participating in the US Network of Pediatric MS Centers. Parents completed a comprehensive environmental questionnaire, including the capture of pregnancy and perinatal factors. Case status was confirmed by a panel of 3 pediatric MS specialists. Multivariable logistic regression analyses were used to determine association of these environmental factors with case status, adjusting for age, sex, race, ethnicity, US birth region, and socioeconomic status.
Results:
Questionnaire responses were available for 265 eligible cases (median age 15.7 years, 62% girls) and 412 healthy controls (median age 14.6, 54% girls). In the primary multivariable analysis, maternal illness during pregnancy was associated with 2.3-fold increase in odds to have MS (95% confidence interval [CI] 1.20-4.21, P = .01) and cesarean delivery with 60% reduction (95% CI 0.20-0.82, P = .01). In a model adjusted for these variables, maternal age and BMI, tobacco smoke exposure, and breastfeeding were not associated with odds to have MS. In the secondary analyses, after adjustment for age, sex, race, ethnicity, and socioeconomic status, having a father who worked in a gardening-related occupation (odds ratio [OR] 2.18, 95% CI 1.14-4.16, P = .02) or any use in household of pesticide-related products (OR 1.73, 95% CI 1.06-2.81, P = .03) were both associated with increased odds to have pediatric MS.
Conclusion:
Cesarean delivery and maternal health during pregnancy may influence risk for pediatric-onset MS. We report a new possible association of pesticide-related environmental exposures with pediatric MS that warrants further investigation and replication.
A strategy to understand the microbial components of the human genetic and metabolic landscape and how they contribute to normal physiology and predisposition to disease.
Background
The inflammatory bowel diseases (IBD) Crohn's disease and ulcerative colitis result from alterations in intestinal microbes and the immune system. However, the precise dysfunctions of microbial metabolism in the gastrointestinal microbiome during IBD remain unclear. We analyzed the microbiota of intestinal biopsies and stool samples from 231 IBD and healthy subjects by 16S gene pyrosequencing and followed up a subset using shotgun metagenomics. Gene and pathway composition were assessed, based on 16S data from phylogenetically-related reference genomes, and associated using sparse multivariate linear modeling with medications, environmental factors, and IBD status.
Results
Firmicutes and Enterobacteriaceae abundances were associated with disease status as expected, but also with treatment and subject characteristics. Microbial function, though, was more consistently perturbed than composition, with 12% of analyzed pathways changed compared with 2% of genera. We identified major shifts in oxidative stress pathways, as well as decreased carbohydrate metabolism and amino acid biosynthesis in favor of nutrient transport and uptake. The microbiome of ileal Crohn's disease was notable for increases in virulence and secretion pathways.
Conclusions
This inferred functional metagenomic information provides the first insights into community-wide microbial processes and pathways that underpin IBD pathogenesis.
Background
Multimorbidity is increasingly recognized as a major public health challenge of modern societies. However, knowledge about the size of the population suffering from multimorbidity and the type of multimorbidity is scarce. The objective of this study was to present an overview of the prevalence of multimorbidity and comorbidity of chronic diseases in the Dutch population and to explore disease clustering and common comorbidities.
Methods
We used 7 years data (2002–2008) of a large Dutch representative network of general practices (212,902 patients). Multimorbidity was defined as having two or more out of 29 chronic diseases. The prevalence of multimorbidity was calculated for the total population and by sex and age group. For 10 prevalent diseases among patients of 55 years and older (N = 52,014) logistic regressions analyses were used to study disease clustering and descriptive analyses to explore common comorbid diseases.
Results
Multimorbidity of chronic diseases was found among 13% of the Dutch population and in 37% of those older than 55 years. Among patients over 55 years with a specific chronic disease more than two-thirds also had one or more other chronic diseases. Most disease pairs occurred more frequently than would be expected if diseases had been independent. Comorbidity was not limited to specific combinations of diseases; about 70% of those with a disease had one or more extra chronic diseases recorded which were not included in the top five of most common diseases.
Conclusion
Multimorbidity is common at all ages though increasing with age, with over two-thirds of those with chronic diseases and aged 55 years and older being recorded with multimorbidity. Comorbidity encompassed many different combinations of chronic diseases. Given the ageing population, multimorbidity and its consequences should be taken into account in the organization of care in order to avoid fragmented care, in medical research and healthcare policy.
Rationale:
Aspergillus fumigatus (A. fumigatus) in cystic fibrosis (CF) is increasingly recognized. Although allergic bronchopulmonary aspergillosis (ABPA) leads to deterioration of pulmonary function, the effect of A. fumigatus colonization in the absence of ABPA remains unclear.
Objectives:
To address this, we examined individuals with CF with A. fumigatus who were ABPA negative to identify the effects of itraconazole therapy on Aspergillus-induced lung inflammation.
Methods:
The effect of A. fumigatus on nuclear vitamin D receptor (VDR) expression was investigated using qRT-PCR and Western blotting. IL-5 and IL-13 levels were quantified by ELISA. The effect of itraconazole was assessed by a combination of high-resolution computed tomography, lung function test, and microbiological analysis.
Measurements and main results:
We demonstrate that A. fumigatus down-regulates VDR in macrophages and airway epithelial cells and that the fungal metabolite gliotoxin (Gt) is the main causative agent. Gt overcame the positive effect of 1,25-OH vitamin D(3) on VDR expression in vitro, resulting in increased IL-5 and IL-13 production. In vivo, A. fumigatus positivity was associated with increased Gt in CF bronchoalveolar lavage fluid and increased bronchoalveolar lavage fluid levels of IL-5 and IL-13. After airway eradication of A. fumigatus with itraconazole, we observed decreased Gt, IL-5 and IL-13, improved respiratory symptoms, and diminished high-resolution computed tomography mosaic pattern consistent with sustained pulmonary function.
Conclusions:
This study provides a rationale for the therapeutic effect of itraconazole and implied that the therapeutic potential of vitamin D supplementation in preventing ABPA is only feasible with concurrent elimination of A. fumigatus to permit VDR expression and its positive functional consequences.
Background:
Dysfunctional immune responses characterize sarcoidosis, but the status of cathelicidin, a potent immunoregulatory and antimicrobial molecule, has not been established in clinical disease activity.
Methods:
Alveolar macrophage cathelicidin expression was determined in biopsy-proven sarcoidosis patients classified clinically as 'severe' (requiring systemic treatment) or 'non-severe' (never requiring treatment). Bronchoalveolar lavage (BAL) cells from sarcoidosis patients and healthy controls were analyzed for mRNA expression of cathelicidin, vitamin D receptor (VDR) and the VDR coactivator steroid receptor coactivator-3 (SRC3) by quantitative PCR. Cathelicidin-derived peptide LL-37 was determined by immunocytochemistry. Serum calcidiol (25-hydroxyvitamin D2; vitD2) and calcitriol (1,25-dihydroxyvitamin D3; vitD3) were quantified.
Results:
The results indicated reduced BAL cell expression of cathelicidin and SRC3 in severe but not non-severe sarcoidosis compared to controls. Serum levels of biologically active vitD3 in both severe and non-severe patients were within the control range even though vitD2 levels in both groups were below the recommended level (30 ng/ml). Sarcoidosis and control alveolar macrophages were studied in vitro to determine cathelicidin responses to vitD3 and tumor necrosis factor-α (TNFα), a vitD3 antagonist elevated in active sarcoidosis. Alveolar macrophage cathelicidin was stimulated by vitD3 but repressed by TNFα, which also repressed SRC3.
Conclusions:
These findings suggest that TNFα-mediated repression of SRC3 contributes to alveolar macrophage cathelicidin deficiency in severe sarcoidosis despite healthy vitD3 levels. Deficiency of cathelicidin, a multifunctional regulator of immune cells and proinflammatory cytokines, may impede resolution of inflammation in the lungs of patients with severe sarcoidosis.
Some of the most successful pathogens of human, such as Mycobacterium tuberculosis (Mtb), HIV, and Leishmania donovani not only establish chronic infections but also remain a grave global threat. These pathogens have developed innovative strategies to evade immune responses such as antigenic shift and drift, interference with antigen processing/presentation, subversion of phagocytosis, induction of immune regulatory pathways, and manipulation of the costimulatory molecules. Costimulatory molecules expressed on the surface of various cells play a decisive role in the initiation and sustenance of immunity. Exploitation of the "code of conduct" of costimulation pathways provides evolutionary incentive to the pathogens and thereby abates the functioning of the immune system. Here we review how Mtb, HIV, Leishmania sp., and other pathogens manipulate costimulatory molecules to establish chronic infection. Impairment by pathogens in the signaling events delivered by costimulatory molecules may be responsible for defective T-cell responses; consequently organisms grow unhindered in the host cells. This review summarizes the convergent devices that pathogens employ to tune and tame the immune system using costimulatory molecules. Studying host-pathogen interaction in context with costimulatory signals may unveil the molecular mechanism that will help in understanding the survival/death of the pathogens. We emphasize that the very same pathways can potentially be exploited to develop immunotherapeutic strategies to eliminate intracellular pathogens.
The prevailing theory of autoimmune disease, that the body creates autoantibodies that attack “self,” was developed during
an era when culture-based methods vastly underestimated the number of microbes capable of persisting in and on Homo sapiens. Thanks to the advent of culture-independent tools, the human body is now known to harbor billions of microbes whose collective
genomes work in concert with the human genome. Thus, the human genome can no longer be studied in isolation. Some of these
microbes persist by slowing the activity of the vitamin D receptor nuclear receptor, affecting the expression of endogenous
antimicrobials and other key components of the innate immune system. It seems that bacteria that cause autoimmune disease
accumulate over a lifetime, with individuals picking up pathogens with greater ease over time, as the immune response becomes
increasingly compromised. Any one autoimmune disease is likely due to many different microbes within the metagenomic microbiota.
This helps explain the high levels of comorbidity observed among patients with autoimmune conditions. What are commonly believed
to be autoantibodies may instead be created in response to this metagenomic microbiota when the adaptive immune system is
forced to deal with disintegration of infected cells. Similarly, haplotypes associated with autoimmune conditions vary widely
among individuals and populations. They are more suggestive of a regional infectious model rather than a model in which an
illness is caused by inherited variation of HLA haplotypes
Studies of the human microbiome have revealed that even healthy individuals differ remarkably in the microbes that occupy habitats such as the gut, skin and vagina. Much of this diversity remains unexplained, although diet, environment, host genetics and early microbial exposure have all been implicated. Accordingly, to characterize the ecology of human-associated microbial communities, the Human Microbiome Project has analysed the largest cohort and set of distinct, clinically relevant body habitats so far. We found the diversity and abundance of each habitat's signature microbes to vary widely even among healthy subjects, with strong niche specialization both within and among individuals. The project encountered an estimated 81-99% of the genera, enzyme families and community configurations occupied by the healthy Western microbiome. Metagenomic carriage of metabolic pathways was stable among individuals despite variation in community structure, and ethnic/racial background proved to be one of the strongest associations of both pathways and microbes with clinical metadata. These results thus delineate the range of structural and functional configurations normal in the microbial communities of a healthy population, enabling future characterization of the epidemiology, ecology and translational applications of the human microbiome.
Numerous aspects of the relationship between bacteria and human have been investigated. One aspect that has recently received attention is sequence overlap at the proteomic level. However, there has not yet been a study that comprehensively characterizes the level of sequence overlap between bacteria and human, especially as it relates to bacterial characteristics like pathogenicity, G-C content, and proteome size. In this study, we began by performing a general characterization of the range of bacteria-human similarity at the proteomic level, and identified characteristics of the most- and least-similar bacterial species. We then examined the relationship between proteomic similarity and numerous other variables. While pathogens and nonpathogens had comparable similarity to the human proteome, pathogens causing chronic infections were found to be more similar to the human proteome than those causing acute infections. Although no general correspondence between a bacterium's proteome size and its similarity to the human proteome was noted, no bacteria with small proteomes had high similarity to the human proteome. Finally, we discovered an interesting relationship between similarity and a bacterium's G-C content. While the relationship between bacteria and human has been studied from many angles, their proteomic similarity still needs to be examined in more detail. This paper sheds further light on this relationship, particularly with respect to immunity and pathogenicity.
Information on dietary supplements, medications, and other xenobiotics in epidemiologic surveys is usually obtained from questionnaires and is subject to recall and reporting biases. The authors used metabolite data obtained from hydrogen-1 (or proton) nuclear magnetic resonance ((1)H NMR) analysis of human urine specimens from the International Study of Macro-/Micro-Nutrients and Blood Pressure (INTERMAP Study) to validate self-reported analgesic use. Metabolic profiling of two 24-hour urine specimens per individual was carried out for 4,630 participants aged 40-59 years from 17 population samples in Japan, China, the United Kingdom, and the United States (data collection, 1996-1999). (1)H NMR-detected acetaminophen and ibuprofen use was low (∼4%) among East Asian population samples and higher (>16%) in Western population samples. In a comparison of self-reported acetaminophen and ibuprofen use with (1)H NMR-detected acetaminophen and ibuprofen metabolites among 496 participants from Chicago, Illinois, and Belfast, Northern Ireland, the overall rate of concordance was 81%-84%; the rate of underreporting was 15%-17%; and the rate of underdetection was approximately 1%. Comparison of self-reported unspecified analgesic use with (1)H NMR-detected acetaminophen and ibuprofen metabolites among 2,660 Western INTERMAP participants revealed similar levels of concordance and underreporting. Screening for urinary metabolites of acetaminophen and ibuprofen improved the accuracy of exposure information. This approach has the potential to reduce recall bias and other biases in epidemiologic studies for a range of substances, including pharmaceuticals, dietary supplements, and foods.
Neurologic Post Treatment Lyme disease (nPTLS) and Chronic Fatigue (CFS) are syndromes of unknown etiology. They share features of fatigue and cognitive dysfunction, making it difficult to differentiate them. Unresolved is whether nPTLS is a subset of CFS.
Pooled cerebrospinal fluid (CSF) samples from nPTLS patients, CFS patients, and healthy volunteers were comprehensively analyzed using high-resolution mass spectrometry (MS), coupled with immunoaffinity depletion methods to reduce protein-masking by abundant proteins. Individual patient and healthy control CSF samples were analyzed directly employing a MS-based label-free quantitative proteomics approach. We found that both groups, and individuals within the groups, could be distinguished from each other and normals based on their specific CSF proteins (p<0.01). CFS (n = 43) had 2,783 non-redundant proteins, nPTLS (n = 25) contained 2,768 proteins, and healthy normals had 2,630 proteins. Preliminary pathway analysis demonstrated that the data could be useful for hypothesis generation on the pathogenetic mechanisms underlying these two related syndromes.
nPTLS and CFS have distinguishing CSF protein complements. Each condition has a number of CSF proteins that can be useful in providing candidates for future validation studies and insights on the respective mechanisms of pathogenesis. Distinguishing nPTLS and CFS permits more focused study of each condition, and can lead to novel diagnostics and therapeutic interventions.
Viruses are the most abundant known infectious agents on the planet and are significant drivers of diversity in a variety of ecosystems. Although there have been numerous studies of viral communities, few have focused on viruses within the indigenous human microbiota. We analyzed 2 267 695 virome reads from viral particles and compared them with 263 516 bacterial 16S rRNA gene sequences from the saliva of five healthy human subjects over a 2- to 3-month period, in order to improve our understanding of the role viruses have in the complex oral ecosystem. Our data reveal viral communities in human saliva dominated by bacteriophages whose constituents are temporally distinct. The preponderance of shared homologs between the salivary viral communities in two unrelated subjects in the same household suggests that environmental factors are determinants of community membership. When comparing salivary viromes to those from human stool and the respiratory tract, each group was distinct, further indicating that habitat is of substantial importance in shaping human viromes. Compared with coexisting bacteria, there was concordance among certain predicted host-virus pairings such as Veillonella and Streptococcus, whereas there was discordance among others such as Actinomyces. We identified 122 728 virulence factor homologs, suggesting that salivary viruses may serve as reservoirs for pathogenic gene function in the oral environment. That the vast majority of human oral viruses are bacteriophages whose putative gene function signifies some have a prominent role in lysogeny, suggests these viruses may have an important role in helping shape the microbial diversity in the human oral cavity.
In order to ensure their function(s) in the cell, proteins are organized in machineries, underlaid by a complex network of interactions. Identifying protein interactions is thus crucial to our understanding of cell functioning. Technical advances in molecular biology and genomic technology now allow for the systematic study of the interactions occurring in a given organism. This review first presents the techniques readily available to microbiologists for studying protein-protein interactions in bacteria, as well as their usability for high-throughput studies. Two types of techniques need to be considered: (1) the isolation of protein complexes from the organism of interest by affinity purification, and subsequent identification of the complex partners by mass spectrometry and (2) two-hybrid techniques, in general based on the production of two recombinant proteins whose interaction has to be tested in a reporter cell. Next, we summarize the bacterial interactomes already published. Finally, the strengths and pitfalls of the techniques are discussed, together with the potential prospect of interactome studies in bacteria.
Although the vaginal microflora (VMF) has been well studied, information on the fluctuation of the different bacterial species throughout the menstrual cycle and the information on events preceding the presence of disturbed VMF is still very limited. Documenting the dynamics of the VMF during the menstrual cycle might provide better insights. In this study, we assessed the presence of different Lactobacillus species in relation to the BV associated species during the menstrual cycle, assessed the influence of the menstrual cycle on the different categories of vaginal microflora and assessed possible causes, such as menstruation and sexual intercourse, of VMF disturbance. To our knowledge, this is the first longitudinal study in which swabs and Gram stains were available for each day of two consecutive menstrual cycles, whereby 8 grades of VMF were distinguished by Gram stain analysis, and whereby the swabs were cultured every 7(th) day and identification of the bacterial isolates was carried out with a molecular technique.
Self-collected vaginal swabs were obtained daily from 17 non pregnant, menarchal volunteers, and used for daily Gram staining and weekly culture. Bacterial isolates were identified with tDNA-PCR and 16 S rRNA gene sequencing.
Nine women presented with predominantly normal VMF and the 8 others had predominantly disturbed VMF. The overall VMF of each volunteer was characteristic and rather stable. Menses and antimicrobials were the major disturbing factors of the VMF. Disturbances were always accompanied by a rise in Gram positive cocci, which also appeared to be a significant group within the VMF in general.
We observed a huge interindividual variability of predominantly stable VMF types. The importance of Gram positive cocci in VMF is underestimated. L. crispatus was the species that was most negatively affected by the menses, whereas the presence of the other lactobacilli was less variable.
The Genomes OnLine Database (GOLD, http://www.genomesonline.org/) is a comprehensive resource for centralized monitoring of genome and metagenome projects worldwide. Both complete and ongoing
projects, along with their associated metadata, can be accessed in GOLD through precomputed tables and a search page. As of
September 2011, GOLD, now on version 4.0, contains information for 11 472 sequencing projects, of which 2907 have been completed
and their sequence data has been deposited in a public repository. Out of these complete projects, 1918 are finished and 989
are permanent drafts. Moreover, GOLD contains information for 340 metagenome studies associated with 1927 metagenome samples.
GOLD continues to expand, moving toward the goal of providing the most comprehensive repository of metadata information related
to the projects and their organisms/environments in accordance with the Minimum Information about any (x) Sequence specification
and beyond.
Horizontal gene transfer (HGT), the acquisition of genetic material from non-parental lineages, is known to be important in bacterial evolution. In particular, HGT provides rapid access to genetic innovations, allowing traits such as virulence, antibiotic resistance and xenobiotic metabolism to spread through the human microbiome. Recent anecdotal studies providing snapshots of active gene flow on the human body have highlighted the need to determine the frequency of such recent transfers and the forces that govern these events. Here we report the discovery and characterization of a vast, human-associated network of gene exchange, large enough to directly compare the principal forces shaping HGT. We show that this network of 10,770 unique, recently transferred (more than 99% nucleotide identity) genes found in 2,235 full bacterial genomes, is shaped principally by ecology rather than geography or phylogeny, with most gene exchange occurring between isolates from ecologically similar, but geographically separated, environments. For example, we observe 25-fold more HGT between human-associated bacteria than among ecologically diverse non-human isolates (P = 3.0 × 10(-270)). We show that within the human microbiome this ecological architecture continues across multiple spatial scales, functional classes and ecological niches with transfer further enriched among bacteria that inhabit the same body site, have the same oxygen tolerance or have the same ability to cause disease. This structure offers a window into the molecular traits that define ecological niches, insight that we use to uncover sources of antibiotic resistance and identify genes associated with the pathology of meningitis and other diseases.
For psoriasis, an idiopathic inflammatory disorder of the skin, the microbial biota has not been defined using cultivation-independent methods. We used broad-range 16S rDNA PCR for archaea and bacteria to examine the microbiota of normal and psoriatic skin. From 6 patients, 19 cutaneous samples (13 from diseased skin and 6 from normal skin) were obtained. Extracted DNA was subjected to the broad range PCR, and 1,925 cloned products were compared with 2,038 products previously reported from healthy persons. Using 98% sequence identity as a species boundary, 1,841 (95.6%) clones were similar to known bacterial 16S rDNA, representing 6 phyla, 86 genera, or 189 species-level operational taxonomic unit (SLOTU); 84 (4.4%) clones with <98% identity probably represented novel species. The most abundant and diverse phylum populating the psoriatic lesions was Firmicutes (46.2%), significantly (P<0.001) overrepresented, compared to the samples from uninvolved skin of the patients (39.0%) and healthy persons (24.4%). In contrast, Actinobacteria, the most prevalent and diverse phylum in normal skin samples from both healthy persons (47.6%) and the patients (47.8%), was significantly (P<0.01) underrepresented in the psoriatic lesion samples (37.3%). Representation of Propionibacterium species were lower in the psoriatic lesions (2.9+/-5.5%) than from normal persons (21.1+/-18.2%; P<0.001), whereas normal skin from the psoriatic patients showed intermediate levels (12.3+/-21.6%). We conclude that psoriasis is associated with substantial alteration in the composition and representation of the cutaneous bacterial biota.
Rhinovirus (RV), a single-stranded RNA picornavirus, is the most frequent cause of asthma exacerbations. We previously demonstrated in human bronchial epithelial cells that melanoma differentiation-associated gene (MDA)-5 and the adaptor protein for Toll-like receptor (TLR)-3 are each required for maximal RV1B-induced interferon (IFN) responses. However, in vivo, the overall airway response to viral infection likely represents a coordinated response integrating both antiviral and pro-inflammatory pathways. We examined the airway responses of MDA5- and TLR3-deficient mice to infection with RV1B, a minor group virus which replicates in mouse lungs. MDA5 null mice showed a delayed type I IFN and attenuated type III IFN response to RV1B infection, leading to a transient increase in viral titer. TLR3 null mice showed normal IFN responses and unchanged viral titers. Further, RV-infected MDA5 and TLR3 null mice showed reduced lung inflammatory responses and reduced airways responsiveness. Finally, RV-infected MDA5 null mice with allergic airways disease showed lower viral titers despite deficient IFN responses, and allergic MDA5 and TLR3 null mice each showed decreased RV-induced airway inflammatory and contractile responses. These results suggest that, in the context of RV infection, binding of viral dsRNA to MDA5 and TLR3 initiates pro-inflammatory signaling pathways leading to airways inflammation and hyperresponsiveness.
Understanding the normal temporal variation in the human microbiome is critical to developing treatments for putative microbiome-related afflictions such as obesity, Crohn’s disease, inflammatory bowel disease and malnutrition. Sequencing and computational technologies, however, have been a limiting factor in performing dense time series analysis of the human microbiome. Here, we present the largest human microbiota time series analysis to date, covering two individuals at four body sites over 396 timepoints.
We find that despite stable differences between body sites and individuals, there is pronounced variability in an individual’s microbiota across months, weeks and even days. Additionally, only a small fraction of the total taxa found within a single body site appear to be present across all time points, suggesting that no core temporal microbiome exists at high abundance (although some microbes may be present but drop below the detection threshold). Many more taxa appear to be persistent but non-permanent community members.
DNA sequencing and computational advances described here provide the ability to go beyond infrequent snapshots of our human-associated microbial ecology to high-resolution assessments of temporal variations over protracted periods, within and between body habitats and individuals. This capacity will allow us to define normal variation and pathologic states, and assess responses to therapeutic interventions.
The hypothesis that mimicry between a self and a microbial peptide antigen is strictly related to autoimmune pathology remains a debated concept in autoimmunity research. Clear evidence for a causal link between molecular mimicry and autoimmunity is still lacking. In recent studies we have demonstrated that viruses and bacteria share amino acid sequences with the human proteome at such a high extent that the molecular mimicry hypothesis becomes questionable as a causal factor in autoimmunity. Expanding upon our analysis, here we detail the bacterial peptide overlapping to the human proteome at the penta-, hexa-, hepta- and octapeptide levels by exact peptide matching analysis and demonstrate that there does not exist a single human protein that does not harbor a bacterial pentapeptide or hexapeptide motif. This finding suggests that molecular mimicry between a self and a microbial peptide antigen cannot be assumed as a basis for autoimmune pathologies. Moreover, the data are discussed in relation to the microbial immune escape phenomenon and the possible vaccine-related autoimmune effects.
High-throughput sequencing technologies have strongly impacted microbiology, providing a rapid and cost-effective way of generating draft genomes and exploring microbial diversity. However, sequences obtained from impure nucleic acid preparations may contain DNA from sources other than the sample. Those sequence contaminations are a serious concern to the quality of the data used for downstream analysis, causing misassembly of sequence contigs and erroneous conclusions. Therefore, the removal of sequence contaminants is a necessary and required step for all sequencing projects. We developed DeconSeq, a robust framework for the rapid, automated identification and removal of sequence contamination in longer-read datasets (150 bp mean read length). DeconSeq is publicly available as standalone and web-based versions. The results can be exported for subsequent analysis, and the databases used for the web-based version are automatically updated on a regular basis. DeconSeq categorizes possible contamination sequences, eliminates redundant hits with higher similarity to non-contaminant genomes, and provides graphical visualizations of the alignment results and classifications. Using DeconSeq, we conducted an analysis of possible human DNA contamination in 202 previously published microbial and viral metagenomes and found possible contamination in 145 (72%) metagenomes with as high as 64% contaminating sequences. This new framework allows scientists to automatically detect and efficiently remove unwanted sequence contamination from their datasets while eliminating critical limitations of current methods. DeconSeq's web interface is simple and user-friendly. The standalone version allows offline analysis and integration into existing data processing pipelines. DeconSeq's results reveal whether the sequencing experiment has succeeded, whether the correct sample was sequenced, and whether the sample contains any sequence contamination from DNA preparation or host. In addition, the analysis of 202 metagenomes demonstrated significant contamination of the non-human associated metagenomes, suggesting that this method is appropriate for screening all metagenomes. DeconSeq is available at http://deconseq.sourceforge.net/.
Microbes are increasingly being implicated in autoimmune disease. This calls for a re-evaluation of how these chronic inflammatory illnesses are routinely treated. The standard of care for autoimmune disease remains the use of medications that slow the immune response, while treatments aimed at eradicating microbes seek the exact opposite-stimulation of the innate immune response. Immunostimulation is complicated by a cascade of sequelae, including exacerbated inflammation, which occurs in response to microbial death. Over the past 8 years, we have collaborated with American and international clinical professionals to research a model-based treatment for inflammatory disease. This intervention, designed to stimulate the innate immune response, has required a reevaluation of disease progression and amelioration. Paramount is the inherent conflict between palliation and microbicidal efficacy. Increased microbicidal activity was experienced as immunopathology-a temporary worsening of symptoms. Further studies are needed, but they will require careful planning to manage this immunopathology.
Several studies have shown that gut bacteria have a role in diabetes in murine models. Specific bacteria have been correlated with the onset of diabetes in a rat model. However, it is unknown whether human intestinal microbes have a role in the development of autoimmunity that often leads to type 1 diabetes (T1D), an autoimmune disorder in which insulin-secreting pancreatic islet cells are destroyed. High-throughput, culture-independent approaches identified bacteria that correlate with the development of T1D-associated autoimmunity in young children who are at high genetic risk for this disorder. The level of bacterial diversity diminishes overtime in these autoimmune subjects relative to that of age-matched, genotype-matched, nonautoimmune individuals. A single species, Bacteroides ovatus, comprised nearly 24% of the total increase in the phylum Bacteroidetes in cases compared with controls. Conversely, another species in controls, represented by the human firmicute strain CO19, represented nearly 20% of the increase in Firmicutes compared with cases overtime. Three lines of evidence are presented that support the notion that, as healthy infants approach the toddler stage, their microbiomes become healthier and more stable, whereas, children who are destined for autoimmunity develop a microbiome that is less diverse and stable. Hence, the autoimmune microbiome for T1D may be distinctly different from that found in healthy children. These data also suggest bacterial markers for the early diagnosis of T1D. In addition, bacteria that negatively correlated with the autoimmune state may prove to be useful in the prevention of autoimmunity development in high-risk children.
To understand the impact of gut microbes on human health and well-being it is crucial to assess their genetic potential. Here we describe the Illumina-based metagenomic sequencing, assembly and characterization of 3.3 million non-redundant microbial genes, derived from 576.7 gigabases of sequence, from faecal samples of 124 European individuals. The gene set, approximately 150 times larger than the human gene complement, contains an overwhelming majority of the prevalent (more frequent) microbial genes of the cohort and probably includes a large proportion of the prevalent human intestinal microbial genes. The genes are largely shared among individuals of the cohort. Over 99% of the genes are bacterial, indicating that the entire cohort harbours between 1,000 and 1,150 prevalent bacterial species and each individual at least 160 such species, which are also largely shared. We define and describe the minimal gut metagenome and the minimal gut bacterial genome in terms of functions present in all individuals and most bacteria, respectively.
Recent evidence suggests that there is a link between metabolic diseases and bacterial populations in the gut. The aim of this study was to assess the differences between the composition of the intestinal microbiota in humans with type 2 diabetes and non-diabetic persons as control.
The study included 36 male adults with a broad range of age and body-mass indices (BMIs), among which 18 subjects were diagnosed with diabetes type 2. The fecal bacterial composition was investigated by real-time quantitative PCR (qPCR) and in a subgroup of subjects (N = 20) by tag-encoded amplicon pyrosequencing of the V4 region of the 16S rRNA gene. The proportions of phylum Firmicutes and class Clostridia were significantly reduced in the diabetic group compared to the control group (P = 0.03). Furthermore, the ratios of Bacteroidetes to Firmicutes as well as the ratios of Bacteroides-Prevotella group to C. coccoides-E. rectale group correlated positively and significantly with plasma glucose concentration (P = 0.04) but not with BMIs. Similarly, class Betaproteobacteria was highly enriched in diabetic compared to non-diabetic persons (P = 0.02) and positively correlated with plasma glucose (P = 0.04).
The results of this study indicate that type 2 diabetes in humans is associated with compositional changes in intestinal microbiota. The level of glucose tolerance should be considered when linking microbiota with metabolic diseases such as obesity and developing strategies to control metabolic diseases by modifying the gut microbiota.
Vitamin D signaling through its nuclear vitamin D receptor has emerged as a key regulator of innate immunity in humans. Here
we show that hormonal vitamin D, 1,25-dihydroxyvitamin D3, robustly stimulates expression of pattern recognition receptor NOD2/CARD15/IBD1 gene and protein in primary human monocytic
and epithelial cells. The vitamin D receptor signals through distal enhancers in the NOD2 gene, whose function was validated by chromatin immunoprecipitation and chromatin conformation capture assays. A key downstream
signaling consequence of NOD2 activation by agonist muramyl dipeptide is stimulation of NF-κB transcription factor function,
which induces expression of the gene encoding antimicrobial peptide defensin β2 (DEFB2/HBD2). Pretreatment with 1,25-dihydroxyvitamin
D3 synergistically induced NF-κB function and expression of genes encoding DEFB2/HBD2 and antimicrobial peptide cathelicidin
in the presence of muramyl dipeptide. Importantly, this synergistic response was also seen in macrophages from a donor wild
type for NOD2 but was absent in macrophages from patients with Crohn disease homozygous for non-functional NOD2 variants.
These studies provide strong molecular links between vitamin D deficiency and the genetics of Crohn disease, a chronic incurable
inflammatory bowel condition, as Crohn's pathogenesis is associated with attenuated NOD2 or DEFB2/HBD2 function.
The new generation of massively parallel DNA sequencers, combined with the challenge of whole human genome resequencing, result in the need for rapid and accurate alignment of billions of short DNA sequence reads to a large reference genome. Speed is obviously of great importance, but equally important is maintaining alignment accuracy of short reads, in the 25-100 base range, in the presence of errors and true biological variation.
We introduce a new algorithm specifically optimized for this task, as well as a freely available implementation, BFAST, which can align data produced by any of current sequencing platforms, allows for user-customizable levels of speed and accuracy, supports paired end data, and provides for efficient parallel and multi-threaded computation on a computer cluster. The new method is based on creating flexible, efficient whole genome indexes to rapidly map reads to candidate alignment locations, with arbitrary multiple independent indexes allowed to achieve robustness against read errors and sequence variants. The final local alignment uses a Smith-Waterman method, with gaps to support the detection of small indels.
We compare BFAST to a selection of large-scale alignment tools -- BLAT, MAQ, SHRiMP, and SOAP -- in terms of both speed and accuracy, using simulated and real-world datasets. We show BFAST can achieve substantially greater sensitivity of alignment in the context of errors and true variants, especially insertions and deletions, and minimize false mappings, while maintaining adequate speed compared to other current methods. We show BFAST can align the amount of data needed to fully resequence a human genome, one billion reads, with high sensitivity and accuracy, on a modest computer cluster in less than 24 hours. BFAST is available at (http://bfast.sourceforge.net).
The goal of the International HapMap Project is to determine the common patterns of DNA sequence variation in the human genome and to make this information freely available in the public domain. An international consortium is developing a map of these patterns across the genome by determining the genotypes of one million or more sequence variants, their frequencies and the degree of association between them, in DNA samples from populations with ancestry from parts of Africa, Asia and Europe. The HapMap will allow the discovery of sequence variants that affect common disease, will facilitate development of diagnostic tools, and will enhance our ability to choose targets for therapeutic intervention.
Infection of human B cells with Epstein - Barr virus (EBV) induces metabolic activation, morphological transformation, cell proliferation and eventual immortalization.
To identify the nuclear receptors, which are the cellular interaction partners of EBNAs, that will help to elucidate the mechanism of B cell transformation. METHODs: We have compared the nuclear receptor profile in the naïve and EBV-transformed B-lymphocytes, using TaqMan LDA microfluidic card technology.
Out of 48 nuclear receptor, 17 showed differential expression at the mRNA level. The expression of 5 genes was elevated in EBV-transformed cells, whereas 12 genes were downregulated in lymphoblastoid cells (LCLs). 7 genes were studied at the protein level; 2 genes were up regulated (Nr2F2 and RARA) and 4 genes were down regulated (ERB, NUR77, PPARG, and VDR) in LCLs.
The nuclear receptor profiling on EBV infected B cells showed alterations of nuclear receptors expression at both mRNA and protein levels compared with non infected peripheral blood cells. Further analysis on a possible role of each nuclear receptor in EBV induced cell transformation should be performed.
The Close and Personal Biome
Fortunately, our skin is readily accessible for ecological studies of the microbial communities that influence health and disease states. Grice et al. (p. 1190 ) present a metagenomic survey of body sites from 10 healthy human individuals sampled over time. Although, altogether 18 phyla were discovered, only a few predominated. The most diverse communities were found on the forearm and the least behind the ear, but between people the microorganisms living behind the knees, in the elbow, and behind the ear were most similar. This finding might have some bearing on the common occurrence of atopic dermatitis in these zones, although no similar relationship was discerned between skin microbial flora and psoriasis.
It is widely believed that innate immune responses to Borrelia burgdorferi (Bb) are primarily triggered by the spirochete's outer membrane lipoproteins signaling through cell surface TLR1/2. We recently challenged this notion by demonstrating that phagocytosis of live Bb by peripheral blood mononuclear cells (PBMCs) elicited greater production of proinflammatory cytokines than did equivalent bacterial lysates. Using whole genome microarrays, we show herein that, compared to lysates, live spirochetes elicited a more intense and much broader transcriptional response involving genes associated with diverse cellular processes; among these were IFN-beta and a number of interferon-stimulated genes (ISGs), which are not known to result from TLR2 signaling. Using isolated monocytes, we demonstrated that cell activation signals elicited by live Bb result from cell surface interactions and uptake and degradation of organisms within phagosomes. As with PBCMs, live Bb induced markedly greater transcription and secretion of TNF-alpha, IL-6, IL-10 and IL-1beta in monocytes than did lysates. Secreted IL-18, which, like IL-1beta, also requires cleavage by activated caspase-1, was generated only in response to live Bb. Pro-inflammatory cytokine production by TLR2-deficient murine macrophages was only moderately diminished in response to live Bb but was drastically impaired against lysates; TLR2 deficiency had no significant effect on uptake and degradation of spirochetes. As with PBMCs, live Bb was a much more potent inducer of IFN-beta and ISGs in isolated monocytes than were lysates or a synthetic TLR2 agonist. Collectively, our results indicate that the enhanced innate immune responses of monocytes following phagocytosis of live Bb have both TLR2-dependent and -independent components and that the latter induce transcription of type I IFNs and ISGs.
Infected siblings, mothers, and fathers have all been suggested to be major sources for Helicobacter pylori acquisition among children, but few studies have addressed the potential role of various family members simultaneously.
A systematic review was performed on studies investigating intrafamilial transmission of childhood H. pylori infection. Within the Ulm Birth Cohort Study, which consists of 1,066 healthy newborns, born between November 2000 and November 2001 and followed up to age 4, and their siblings and parents, the independent role of the infection status of parents and siblings in transmission of H. pylori among children at age 4 was assessed.
Among four studies reporting infected mothers and siblings as independent risk factors for childhood H. pylori infection, odds ratios (ORs) for childhood infection given an infected sibling decreased meaningfully after adjustment for maternal infection status. Within the Ulm Birth Cohort Study, the prevalence of infection was 3.0% among index children at age 4. In bivariate analyses, maternal, paternal, and sibling infection were all strongly and significantly related to infection of the child. However, after multivariate adjustment, only maternal infection persisted as the single strong and significant risk factor (OR 13.0, 95% confidence interval 3.0-55.2).
These patterns suggest that mutual control for H. pylori status of other family members is crucial for estimating the role of mothers, fathers, and siblings in the transmission of childhood H. pylori infection. In populations with low H. pylori prevalence the infected mother is likely to be the main source for childhood H. pylori infection.
The 'Human Immunodeficiency Virus Type 1 (HIV-1), Human Protein Interaction Database', available through the National Library of Medicine at www.ncbi.nlm.nih.gov/RefSeq/HIVInteractions, was created to catalog all interactions between HIV-1 and human proteins published in the peer-reviewed literature. The database serves the scientific community exploring the discovery of novel HIV vaccine candidates and therapeutic targets. To facilitate this discovery approach, the following information for each HIV-1 human protein interaction is provided and can be retrieved without restriction by web-based downloads and ftp protocols: Reference Sequence (RefSeq) protein accession numbers, Entrez Gene identification numbers, brief descriptions of the interactions, searchable keywords for interactions and PubMed identification numbers (PMIDs) of journal articles describing the interactions. Currently, 2589 unique HIV-1 to human protein interactions and 5135 brief descriptions of the interactions, with a total of 14,312 PMID references to the original articles reporting the interactions, are stored in this growing database. In addition, all protein-protein interactions documented in the database are integrated into Entrez Gene records and listed in the 'HIV-1 protein interactions' section of Entrez Gene reports. The database is also tightly linked to other databases through Entrez Gene, enabling users to search for an abundance of information related to HIV pathogenesis and replication.
Preterm delivery causes substantial neonatal mortality and morbidity. Unrecognized intra-amniotic infections caused by cultivation-resistant microbes may play a role. Molecular methods can detect, characterize and quantify microbes independently of traditional culture techniques. However, molecular studies that define the diversity and abundance of microbes invading the amniotic cavity, and evaluate their clinical significance within a causal framework, are lacking.
In parallel with culture, we used broad-range end-point and real-time PCR assays to amplify, identify and quantify ribosomal DNA (rDNA) of bacteria, fungi and archaea from amniotic fluid of 166 women in preterm labor with intact membranes. We sequenced up to 24 rRNA clones per positive specimen and assigned taxonomic designations to approximately the species level. Microbial prevalence, diversity and abundance were correlated with host inflammation and with gestational and neonatal outcomes. Study subjects who delivered at term served as controls. The combined use of molecular and culture methods revealed a greater prevalence (15% of subjects) and diversity (18 taxa) of microbes in amniotic fluid than did culture alone (9.6% of subjects; 11 taxa). The taxa detected only by PCR included a related group of fastidious bacteria, comprised of Sneathia sanguinegens, Leptotrichia amnionii and an unassigned, uncultivated, and previously-uncharacterized bacterium; one or more members of this group were detected in 25% of positive specimens. A positive PCR was associated with histologic chorioamnionitis (adjusted odds ratio [OR] 20; 95% CI, 2.4 to 172), and funisitis (adjusted OR 18; 95% CI, 3.1 to 99). The positive predictive value of PCR for preterm delivery was 100 percent. A temporal association between a positive PCR and delivery was supported by a shortened amniocentesis-to-delivery interval (adjusted hazard ratio 4.6; 95% CI, 2.2 to 9.5). A dose-response association was demonstrated between bacterial rDNA abundance and gestational age at delivery (r(2) = 0.42; P<0.002).
The amniotic cavity of women in preterm labor harbors DNA from a greater diversity of microbes than previously suspected, including as-yet uncultivated, previously-uncharacterized taxa. The strength, temporality and gradient with which these microbial sequence types are associated with preterm delivery support a causal relationship.
To understand the impact of gut microbes on human health and well-being it is crucial to assess their genetic potential. Here we describe the Illumina-based metagenomic sequencing, assembly and characterization of 3.3 million non-redundant microbial genes, derived from 576.7 gigabases of sequence, from faecal samples of 124 European individuals. The gene set, approximately 150 times larger than the human gene complement, contains an overwhelming majority of the prevalent (more frequent) microbial genes of the cohort and probably includes a large proportion of the prevalent human intestinal microbial genes. The genes are largely shared among individuals of the cohort. Over 99% of the genes are bacterial, indicating that the entire cohort harbours between 1,000 and 1,150 prevalent bacterial species and each individual at least 160 such species, which are also largely shared. We define and describe the minimal gut metagenome and the minimal gut bacterial genome in terms of functions present in all individuals and most bacteria, respectively.
The goal of the International HapMap Project is to determine the common patterns of DNA sequence variation in the human genome and to make this information freely available in the public domain. An international consortium is developing a map of these patterns across the genome by determining the genotypes of one million or more sequence variants, their frequencies and the degree of association between them, in DNA samples from populations with ancestry from parts of Africa, Asia and Europe. The HapMap will allow the discovery of sequence variants that affect common disease, will facilitate development of diagnostic tools, and will enhance our ability to choose targets for therapeutic intervention.
Cystic fibrosis (CF) is an autosomal recessive disease caused by mutations in the gene encoding the CF transmembrane conductance regulator. Disruption of electrolyte homeostasis at mucosal surfaces leads to severe lung, pancreatic, intestinal, hepatic, and reproductive abnormalities. Loss of lung function as a result of chronic lung disease is the primary cause of death from CF. Using high-throughput sequencing to survey microbes in the sputum of 16 CF patients and 9 control individuals, we identified diverse microbial communities in the healthy samples, contravening conventional wisdom that healthy airways are not significantly colonized. Comparing these communities with those from the CF patients revealed significant differences in microbial ecology, including differential representation of uncultivated phylotypes. Despite patient-specific differences, our analysis revealed a focal microbial profile characteristic of CF. The profile differentiated case and control groups even when classically recognized CF pathogens were excluded. As a control, lung explant tissues were also processed from a group of patients with pulmonary disease. The findings in lung tissue corroborated the presence of taxa identified in the sputum samples. Comparing the sequencing results with clinical data indicated that diminished microbial diversity is associated with severity of pulmonary inflammation within our adult CF cohort.
First they sequenced it. Now they have surveyed its hinterlands.
Sequencing DNA from single cells has opened new windows onto the microbial world. It is becoming routine to sequence bacterial species directly from environmental samples or clinical specimens without the need to develop cultivation methods. Recent technical improvements often allow nearly complete genome assembly from these otherwise inaccessible species. New bioinformatics methods are also improving genome assembly from single cells. The use of single-cell sequencing in combination with metagenomic analysis is also emerging as a powerful new strategy to analyse bacterial communities. Here, the technical developments that have enabled single-cell sequencing, as well as some of the most exciting applications of this approach from the past few years, are reviewed.
Early studies on vitamin D showed promise that various forms of the “vitamin” may be protective against chronic disease, yet systematic reviews and longer-term studies have failed to confirm these findings. A number of studies have suggested that patients with autoimmune diagnoses are deficient in 25-hydroxyvitamin D (25-D) and that consuming greater quantities of vitamin D, which further elevates 25 D levels, alleviates autoimmune disease symptoms. Some years ago, molecular biology identified 25 D as a secosteroid. Secosteroids would typically be expected to depress inflammation, which is in line with the reports of symptomatic improvement. The simplistic first-order mass-action model used to guide the early vitamin studies is now giving way to a more complex description of action. When active, the Vitamin D nuclear receptor (VDR) affects transcription of at least 913 genes and impacts processes ranging from calcium metabolism to expression of key antimicrobial peptides. Additionally, recent research on the Human Microbiome shows that bacteria are far more pervasive than previously thought, increasing the possibility that autoimmune disease is bacterial in origin. Emerging molecular evidence suggests that symptomatic improvements among those administered vitamin D is the result of 25-D's ability to temper bacterial-induced inflammation by slowing VDR activity. While this results in short-term palliation, persistent pathogens that may influence disease progression, proliferate over the long-term.
Leprosy provides a model to investigate mechanisms of immune regulation in humans, given that the disease forms a spectrum of clinical presentations that correlate with host immune responses. Here we identified 13 miRNAs that were differentially expressed in the lesions of subjects with progressive lepromatous (L-lep) versus the self-limited tuberculoid (T-lep) disease. Bioinformatic analysis revealed a significant enrichment of L-lep-specific miRNAs that preferentially target key immune genes downregulated in L-lep versus T-lep lesions. The most differentially expressed miRNA in L-lep lesions, hsa-mir-21, was upregulated in Mycobacterium leprae-infected monocytes. By directly downregulating Toll-like receptor 2/1 heterodimer (TLR2/1)-induced CYP27B1 and IL1B expression as well as indirectly upregulating interleukin-10 (IL-10), hsa-mir-21 inhibited expression of the genes encoding two vitamin D-dependent antimicrobial peptides, CAMP and DEFB4A. Conversely, knockdown of hsa-mir-21 in M. leprae-infected monocytes enhanced expression of CAMP and DEFB4A and restored TLR2/1-mediated antimicrobial activity against M. leprae. Therefore, the ability of M. leprae to upregulate hsa-mir-21 targets multiple genes associated with the immunologically localized disease form, providing an effective mechanism to escape from the vitamin D-dependent antimicrobial pathway.
Interest in the role of the microbiome in human health has burgeoned over the past decade with the advent of new technologies for interrogating complex microbial communities. The large-scale dynamics of the microbiome can be described by many of the tools and observations used in the study of population ecology. Deciphering the metagenome and its aggregate genetic information can also be used to understand the functional properties of the microbial community. Both the microbiome and metagenome probably have important functions in health and disease; their exploration is a frontier in human genetics.
Mammals are complex assemblages of mammalian and bacterial cells organized into functional organs, tissues, and cellular communities. Human biology can no longer concern itself only with human cells: Microbiomes at different body sites and functional metagenomics must be considered part of systems biology. The emergence of metagenomics has resulted in the generation of vast data sets of microbial genes and pathways present in different body habitats. The profound differences between microbiomes in various body sites reveal how metagenomes contribute to tissue and organ function. As next-generation DNA-sequencing methods provide whole-metagenome data in addition to gene-expression profiling, metaproteomics, and metabonomics, differences in microbial composition and function are being linked to health and disease states in different organs and tissues. Global parameters of microbial communities may provide valuable information regarding human health status and disease predisposition. More detailed knowledge of the human microbiome will yield next-generation diagnostics and therapeutics for various acute, chronic, localized, and systemic human diseases.
Molecular understanding of disease processes can be accelerated if all interactions between the host and pathogen are known. The unavailability of experimental methods for large-scale detection of interactions across host and pathogen organisms hinders this process. Here we apply a simple method to predict protein-protein interactions across a host and pathogen organisms. We use homology detection approaches against the protein-protein interaction databases, DIP and iPfam in order to predict interacting proteins in a host-pathogen pair. In the present work, we first applied this approach to the test cases involving the pairs phage T4 -Escherichia coli and phage lambda -E. coli and show that previously known interactions could be recognized using our approach. We further apply this approach to predict interactions between human and three pathogens E. coli, Salmonella enterica typhimurium and Yersinia pestis. We identified several novel interactions involving proteins of host or pathogen that could be thought of as highly relevant to the disease process. Serendipitously, many interactions involve hypothetical proteins of yet unknown function. Hypothetical proteins are predicted from computational analysis of genome sequences with no laboratory analysis on their functions yet available. The predicted interactions involving such proteins could provide hints to their functions.
The term 'antimicrobial peptides' refers to a large number of peptides first characterized on the basis of their antibiotic and antifungal activities. In addition to their role as endogenous antibiotics, antimicrobial peptides, also called host defense peptides, participate in multiple aspects of immunity (inflammation, wound repair, and regulation of the adaptive immune system) as well as in maintaining homeostasis. The possibility of utilizing these multifunctional molecules to effectively combat the ever-growing group of antibiotic-resistant pathogens has intensified research aimed at improving their antibiotic activity and therapeutic potential, without the burden of an exacerbated inflammatory response, but conserving their immunomodulatory potential. In this minireview, we focus on the contribution of small cationic antimicrobial peptides - particularly human cathelicidins and defensins - to the immune response and disease, highlighting recent advances in our understanding of the roles of these multifunctional molecules.
Researchers have noted that the incidence of autoimmune diseases, such as Hashimoto's thyroiditis, is markedly higher in women than in men, but to date the reason for this disparity has been unclear. The vitamin D nuclear receptor (VDR) is expressed in the human cycling endometrium. Because the VDR controls expression of the cathelicidin and beta-defensin antimicrobial peptides (AmPs), dysregulation of the receptor greatly compromises the innate immune response. Increasing evidence indicates the presence of a chronic, intraphagocytic, metagenomic microbiota in patients with autoimmune disease that may survive by dysregulating the VDR. VDR dysregulation, in turn, prevents the breakdown of the active vitamin D metabolite 1,25-hydroxyvitamin D (1,25-D) by CYP24. In silico data suggest that when 1,25-D rises above its normal range, it binds the alpha/beta thyroid receptors, the glucocorticoid receptor (GCR), and the androgen receptor (AR), displacing their native ligands and causing an array of hormonal imbalances. If T3 is displaced from alpha-thyroid, thyroiditis may result. Because the VDR, GCR, and AR also express multiple families of AmPs, expression of these natural antibiotics further wanes in response to dysregulation by 1,25-D. The end result is a system-wide drop in AmP expression that may allow pathogens to spread with greater ease. Because women have an extra site of VDR expression in the endometrium, the drop in AmP expression associated with nuclear receptor dysregulation may disproportionately affect them. This would cause women to accumulate higher bacterial loads than their male counterparts, particularly during early pregnancy when 1,25-D levels rise by 40%.
Bacterial 16S ribosomal RNA genes (rDNA) were detected in blood samples from two healthy individuals by PCR under conditions involving 30 cycles that did not produce any visible products from negative control saline. Even from control samples, PCR involving 35-40 cycles yielded visible bands. Major clones detected in the blood samples, but not in control, were the Aquabacterium subgroup, Stenotrophomonas subgroup, Budvicia subgroup, Serratia subgroup, Bacillus subgroup and Flavobacteria subgroup. No clone was located within the bacteroides-clostridium-lactobacillus cluster, which is indigenous to gastrointestinal flora.