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Propionic Acid Shapes the Multiple Sclerosis Disease Course by an Immunomodulatory Mechanism
Abstract
Short-chain fatty acids are processed from indigestible dietary fibers by gut bacteria and have immunomodulatory properties. Here, we investigate propionic acid (PA) in multiple sclerosis (MS), an autoimmune and neurodegenerative disease. Serum and feces of subjects with MS exhibited significantly reduced PA amounts compared with controls, particularly after the first relapse. In a proof-of-concept study, we supplemented PA to therapy-naive MS patients and as an add-on to MS immunotherapy. After 2 weeks of PA intake, we observed a significant and sustained increase of functionally competent regulatory T (Treg) cells, whereas Th1 and Th17 cells decreased significantly. Post-hoc analyses revealed a reduced annual relapse rate, disability stabilization, and reduced brain atrophy after 3 years of PA intake. Functional microbiome analysis revealed increased expression of Treg-cell-inducing genes in the intestine after PA intake. Furthermore, PA normalized Treg cell mitochondrial function and morphology in MS. Our findings suggest that PA can serve as a potent immunomodulatory supplement to MS drugs.
... Multiple sclerosis patients have been documented to have a decreased biodiversity (Swidsinski et al., 2017;Navarro-López et al., 2022) of microbiome as well as gut dysbiosis (Miyake et al., 2015), or alteration in gut microbiota from homeostatic commensal species. Specifically, there is a reduction in Prevotella (Chen et al., 2016;Berer et al., 2017;Cekanaviciute et al., 2017;Cosorich et al., 2017;Ventura et al., 2019;Duscha et al., 2020;Takewaki et al., 2020), Bacteroidetes, especially in the butyrate producer, Butyricimonas, Clostridia clusters IV and XIV (Miyake et al., 2015;Duscha et al., 2020), Bacteroidaceae family, Faecalibacterium genera (Miyake et al., 2015), and Ruminococcus genera (Takewaki et al., 2020). Several studies have also documented an overrepresentation of gut bacteria such as Streptococcus (Miyake et al., 2015;Cosorich et al., 2017;Takewaki et al., 2020), Methanobrevibacter smithii (Jangi et al., 2016), and Akkermansia genera (Jangi et al., 2016;Berer et al., 2017;Cekanaviciute et al., 2017;Ventura et al., 2019;Duscha et al., 2020;Takewaki et al., 2020) compared to healthy controls. ...
... Multiple sclerosis patients have been documented to have a decreased biodiversity (Swidsinski et al., 2017;Navarro-López et al., 2022) of microbiome as well as gut dysbiosis (Miyake et al., 2015), or alteration in gut microbiota from homeostatic commensal species. Specifically, there is a reduction in Prevotella (Chen et al., 2016;Berer et al., 2017;Cekanaviciute et al., 2017;Cosorich et al., 2017;Ventura et al., 2019;Duscha et al., 2020;Takewaki et al., 2020), Bacteroidetes, especially in the butyrate producer, Butyricimonas, Clostridia clusters IV and XIV (Miyake et al., 2015;Duscha et al., 2020), Bacteroidaceae family, Faecalibacterium genera (Miyake et al., 2015), and Ruminococcus genera (Takewaki et al., 2020). Several studies have also documented an overrepresentation of gut bacteria such as Streptococcus (Miyake et al., 2015;Cosorich et al., 2017;Takewaki et al., 2020), Methanobrevibacter smithii (Jangi et al., 2016), and Akkermansia genera (Jangi et al., 2016;Berer et al., 2017;Cekanaviciute et al., 2017;Ventura et al., 2019;Duscha et al., 2020;Takewaki et al., 2020) compared to healthy controls. ...
... Specifically, there is a reduction in Prevotella (Chen et al., 2016;Berer et al., 2017;Cekanaviciute et al., 2017;Cosorich et al., 2017;Ventura et al., 2019;Duscha et al., 2020;Takewaki et al., 2020), Bacteroidetes, especially in the butyrate producer, Butyricimonas, Clostridia clusters IV and XIV (Miyake et al., 2015;Duscha et al., 2020), Bacteroidaceae family, Faecalibacterium genera (Miyake et al., 2015), and Ruminococcus genera (Takewaki et al., 2020). Several studies have also documented an overrepresentation of gut bacteria such as Streptococcus (Miyake et al., 2015;Cosorich et al., 2017;Takewaki et al., 2020), Methanobrevibacter smithii (Jangi et al., 2016), and Akkermansia genera (Jangi et al., 2016;Berer et al., 2017;Cekanaviciute et al., 2017;Ventura et al., 2019;Duscha et al., 2020;Takewaki et al., 2020) compared to healthy controls. In pediatric MS patients, increased levels of Clostridium, Bilophila, Escherichia, and Shigella have been found along with a decrease in the levels of Eubacterium rectale and Corynebacterium (Tremlett et al., 2016). ...
Since the first model of experimental autoimmune encephalomyelitis (EAE) was introduced almost a century ago, there has been an ongoing scientific debate about the risks and benefits of using EAE as a model of multiple sclerosis (MS). While there are notable limitations of translating EAE studies directly to human patients, EAE continues to be the most widely used model of MS, and EAE studies have contributed to multiple key breakthroughs in our understanding of MS pathogenesis and discovery of MS therapeutics. In addition, insights from EAE have led to a better understanding of modifiable environmental factors that can influence MS initiation and progression. In this review, we discuss how MS patient and EAE studies compare in our learning about the role of gut microbiome, diet, alcohol, probiotics, antibiotics, and fecal microbiome transplant in neuroinflammation. Ultimately, the combination of rigorous EAE animal studies, novel bioinformatic approaches, use of human cell lines, and implementation of well-powered, age- and sex-matched randomized controlled MS patient trials will be essential for improving MS patient outcomes and developing novel MS therapeutics to prevent and revert MS disease progression.
... Among the latter, several studies suggest that intestinal factors modulate MS disease severity [10]. In addition, alterations in the gut microbiota composition [11][12][13][14][15][16], gut-derived products [17][18][19], intestinal permeability [20][21][22], and enteric nervous system functions [23] have been reported in MS patients. The human microbiome encompasses trillions of organisms that inhabit the gut and shape the gut-associated lymphoid tissue. ...
... Notably, Anaerotruncus colihominis (OTU 2694) was depleted in singletreatment housed vancomycin mice ( Fig. 4A-B, S4 A-B). Interestingly, we and others have previously reported increased A. colihominis in MS patients compare to healthy subjects [19,40]. ...
... We found a positive correlation between A. colihominis and EAE severity. Interestingly, we and others have previously reported increased abundance of A. colihominis in MS patients [19,40]. To this date, no human-derived bacteria has been shown to exacerbate EAE. ...
Background
The gut microbiome plays an important role in autoimmunity including multiple sclerosis and its mouse model called experimental autoimmune encephalomyelitis (EAE). Prior studies have demonstrated that the multiple sclerosis gut microbiota can contribute to disease, hence making it a potential therapeutic target. In addition, antibiotic treatment has been shown to ameliorate disease in the EAE mouse model of multiple sclerosis. Yet, to this date, the mechanisms mediating these antibiotic effects are not understood. Furthermore, there is no consensus on the gut-derived bacterial strains that drive neuroinflammation in multiple sclerosis.
Results
Here, we characterized the gut microbiome of untreated and vancomycin-treated EAE mice over time to identify bacteria with neuroimmunomodulatory potential. We observed alterations in the gut microbiota composition following EAE induction. We found that vancomycin treatment ameliorates EAE, and that this protective effect is mediated via the microbiota. Notably, we observed increased abundance of bacteria known to be strong inducers of regulatory T cells, including members of Clostridium clusters XIVa and XVIII in vancomycin-treated mice during the presymptomatic phase of EAE, as well as at disease peak. We identified 50 bacterial taxa that correlate with EAE severity. Interestingly, several of these taxa exist in the human gut, and some of them have been implicated in multiple sclerosis including Anaerotruncus colihominis, a butyrate producer, which had a positive correlation with disease severity. We found that Anaerotruncus colihominis ameliorates EAE, and this is associated with induction of RORγt⁺ regulatory T cells in the mesenteric lymph nodes.
Conclusions
We identified vancomycin as a potent modulator of the gut-brain axis by promoting the proliferation of bacterial species that induce regulatory T cells. In addition, our findings reveal 50 gut commensals as regulator of the gut-brain axis that can be used to further characterize pathogenic and beneficial host-microbiota interactions in multiple sclerosis patients. Our findings suggest that elevated Anaerotruncus colihominis in multiple sclerosis patients may represent a protective mechanism associated with recovery from the disease.
9r9NT9qYv7iDsLZaQd6sb5Video Abstract
... 27 The ablation of mitochondrial ETC complex III in murine Tregs, by knocking-out Uqcrfs1, encoding for Rieske iron-sulfur poly-peptide 1 (RISP), resulted in Treg loss of function and development of lethal inflammation. Interestingly, recent studies observed that Tregs isolated from patients with MS showed dampening in OXPHOS, with diminished maximal respiration levels compared to healthy controls, 28,29 further displaying a deregulation of mitochondrial genes, 30 indicating defects in mitochondrial function. However, factors contributing to this phenotype are unknown, and if and how metabolic alterations impact the pro-inflammatory signature and function of autoimmune Tregs is poorly understood. ...
... However, these findings need to be validated in larger follow-up studies. Our data go well in line with recent studies that indicated that Tregs of people with MS display a disturbed metabolic phenotype and defects in mitochondrial respiration 28,29 and that autoimmune Tregs show a signature of mitochondrial dysfunction. 30 It is thus tempting to speculate that perturbed mitochondrial function elicited by HS encounter, copying hallmarks of dysfunctional Tregs in autoimmunity, further provides a piece of evidence linking environmental factors and shifts in the ionic microenvironment to the observed deregulation of the immune cell balance. ...
FOXP3+ regulatory T cells (Tregs) are central for peripheral tolerance, and their deregulation is associated with autoimmunity. Dysfunctional autoimmune Tregs display pro-inflammatory features and altered mitochondrial metabolism, but contributing factors remain elusive. High salt (HS) has been identified to alter immune function and to promote autoimmunity. By investigating longitudinal transcriptional changes of human Tregs, we identified that HS induces metabolic reprogramming, recapitulating features of autoimmune Tregs. Mechanistically, extracellular HS raises intracellular Na+, perturbing mitochondrial respiration by interfering with the electron transport chain (ETC). Metabolic disturbance by a temporary HS encounter or complex III blockade rapidly induces a pro-inflammatory signature and FOXP3 downregulation, leading to long-term dysfunction in vitro and in vivo. The HS-induced effect could be reversed by inhibition of mitochondrial Na+/Ca2+ exchanger (NCLX). Our results indicate that salt could contribute to metabolic reprogramming and that short-term HS encounter perturb metabolic fitness and long-term function of human Tregs with important implications for autoimmunity.
... In pediatric multiple sclerosis, both individual and clusters of various gut microbes were associated with longitudinal disease activity, and the known functions and metagenomics predictions of these microbes suggest an important role of butyrate and amino acid biosynthesis pathways [21]. A recent study reported that individuals with multiple sclerosis had lower serum concentrations of propionic acid and that treatment with propionic acid inhibited the development of EAE and promoted the expansion of regulatory T cells by an effect mediated by changes in the gut microbiota [22]. Low serum concentrations of propionic acid or other SCFAs have, however, not been found in all studies of multiple sclerosis [23]. ...
... In the whole multiple sclerosis cohort, we also found that propionate metabolism was different between CNA and CA following deconfounding of microbiome data. Serum concentration of propionic acid is reported to be lower in cases compared to HC in several studies [66], and supplementation of propionate has been shown to alleviate multiple sclerosis symptoms [22]. ...
Background
Multiple sclerosis is a chronic immune-mediated disease of the brain and spinal cord resulting in physical and cognitive impairment in young adults. It is hypothesized that a disrupted bacterial and viral gut microbiota is a part of the pathogenesis mediating disease impact through an altered gut microbiota-brain axis. The aim of this study is to explore the characteristics of gut microbiota in multiple sclerosis and to associate it with disease variables, as the etiology of the disease remains only partially known.
Methods
Here, in a case-control setting involving 148 Danish cases with multiple sclerosis and 148 matched healthy control subjects, we performed shotgun sequencing of fecal microbial DNA and associated bacterial and viral microbiota findings with plasma cytokines, blood cell gene expression profiles, and disease activity.
Results
We found 61 bacterial species that were differentially abundant when comparing all multiple sclerosis cases with healthy controls, among which 31 species were enriched in cases. A cluster of inflammation markers composed of blood leukocytes, CRP, and blood cell gene expression of IL17A and IL6 was positively associated with a cluster of multiple sclerosis-related species. Bacterial species that were more abundant in cases with disease-active treatment-naïve multiple sclerosis were positively linked to a group of plasma cytokines including IL-22, IL-17A, IFN-β, IL-33, and TNF-α. The bacterial species richness of treatment-naïve multiple sclerosis cases was associated with number of relapses over a follow-up period of 2 years. However, in non-disease-active cases, we identified two bacterial species, Faecalibacterium prausnitzii and Gordonibacter urolithinfaciens , whose absolute abundance was enriched. These bacteria are known to produce anti-inflammatory metabolites including butyrate and urolithin. In addition, cases with multiple sclerosis had a higher viral species diversity and a higher abundance of Caudovirales bacteriophages .
Conclusions
Considerable aberrations are present in the gut microbiota of patients with multiple sclerosis that are directly associated with blood biomarkers of inflammation, and in treatment-naïve cases bacterial richness is positively associated with disease activity. Yet, the finding of two symbiotic bacterial species in non-disease-active cases that produce favorable immune-modulating compounds provides a rationale for testing these bacteria as adjunct therapeutics in future clinical trials.
... Fettig and Osborne recently reviewed the cellular effects of SCFAs in the context of neuroinflammation [173]. Reduced SCFAs circulatory concentrations have been described in MS patients [78,[174][175][176]. In mice, the treatment with SCFAs and SCFA-producing bacteria restored the disrupted BBB observed in GF mice compared to conventional mice [22]. ...
... In mice, the treatment with SCFAs and SCFA-producing bacteria restored the disrupted BBB observed in GF mice compared to conventional mice [22]. Furthermore, experimental studies have shown that the treatment with SCFAs reduces EAE severity [61,174,175,177,178]. Additional microbial metabolites, such as indole-3-aldehyde, indole-3 acetic acid, tryptamine, and others, could also promote immunomodulation by serving as aryl hydrocarbon receptor (AHR) ligands (for a review [179]). ...
The gut-associated lymphoid tissue is a primary activation site for immune responses to infection and immunomodulation. Experimental evidence using animal disease models suggests that specific gut microbes significantly regulate inflammation and immunoregulatory pathways. Furthermore, recent clinical findings indicate that gut microbes’ composition, collectively named gut microbiota, is altered under disease state. This review focuses on the functional mechanisms by which gut microbes promote immunomodulatory responses that could be relevant in balancing inflammation associated with autoimmunity in the central nervous system. We also propose therapeutic interventions that target the composition of the gut microbiota as immunomodulatory mechanisms to control neuroinflammation.
... Besides, afterward, it can cause autonomic and cognitive problems, motor, sensory, and visual flaws, and finally paralysis and disruption of the BBB [144][145][146]. Various animal and human studies suggested the participation of gut microbiota in the development of MS [147][148][149]. Animal studies on an experimental autoimmune encephalomyelitis mice model revealed a significant reduction in Lactobacillus phyla, contributing to an impairment of the mice's immune systems [150]. ...
... A low level of SCFAs dysregulates Treg cell functions, leading to insufficient immune tolerance towards endogenous components and enteric microbiota. However, this process can be reversed by SCFAs supplementation (e.g., propionic acid) [147,152]. Furthermore, research results indicated that MS is also connected with intestinal permeability disruption and the altered metabolism of bile acids, causing the dysregulation of the immune and nervous systems. Bile acids can act as CNS inflammatory signalling modulators, e.g., ursodeoxycholic acid can exert microglia inflammatory-inhibiting activity. ...
Herein we gathered updated knowledge regarding the alterations of gut microbiota (dysbiosis) and its correlation with human neurodegenerative and brain-related diseases, e.g., Alzheimer’s and Parkinson’s. This review underlines the importance of gut-derived metabolites and gut metabolic status as the main players in gut-brain crosstalk and their implications on the severity of neural conditions. Scientific evidence indicates that the administration of probiotic bacteria exerts beneficial and protective effects as reduced systemic inflammation, neuroinflammation, and inhibited neurodegeneration. The experimental results performed on animals, but also human clinical trials, show the importance of designing a novel microbiota-based probiotic dietary supplementation with the aim to prevent or ease the symptoms of Alzheimer’s and Parkinson’s diseases or other forms of dementia or neurodegeneration.
... There are up to onethird of metabolites in the blood that can be derived from gut bacteria (Hood, 2012;Wikoff et al., 2009). Indeed, serum levels of bile acids (BAs), short-chain fatty acids (SCFAs) (Duscha et al., 2020;Morrison & Preston, 2016), branch chain amino acids (BCAAs) (Newgard et al., 2009;Pedersen et al., 2016), aromatic amino acids (AAAs) and some vitamins (Alexeev et al., 2018) are partly mediated by the metabolisms of host or gut microbiota, or both (Hofmann, 2009). These metabolites have been identified to be related to host metabolic health and/or disorders, such as obesity and insulin sensitivity (Bar et al., 2020;Liu et al., 2017;Pedersen et al., 2016;Turnbaugh et al., 2006). ...
Gut microbiota plays important roles in host metabolism. Whether and howmuch the gut microbiota in different gut locations contributes to the variationsof host serum metabolites are largely unknown, because it is difficult to obtainmicrobial samples from different gut locations on a large population scale.Here, we quantified the gut microbial compositions using 16S rRNA genesequencing for 1070 samples collected from the ileum, cecum and faeces of544 F6 pigs from a mosaic pig population. Untargeted metabolome measure-ments determined serum metabolome profiles. We found 1671, 12,985 and103,250 significant correlations between circulating serum metabolites andbacterial ASVs in the ileum, cecum, and faeces samples. We detected nineserum metabolites showing significant correlations with gut bacteria in morethan one gut location. However, most metabolite-microbiota pairwise associa-tions were gut location-specific. Targeted metabolome analysis revealed thatCDCA, taurine, L-leucine and N-acetyl-L-alanine can be used as biomarkersto predict porcine fatness. Enriched taxa in fat pigs, for example Prevotellaand Lawsonia intracellularis were positively associated with L-leucine, whileenriched taxa in lean pigs, such as Clostridium butyricum, were negativelyassociated with L-leucine and CDCA, but positively associated with taurineand N-acetyl-L-alanine. These results suggested that the contributions of gutmicrobiota in each gut location to the variations of serum metabolites showedspatial heterogeneity.
... Butyrate can also enhance barrier function and anti-inflammatory activities (26,136,137). Longitudinal data for 97 patients with MS who underwent propionate supplementation for at least 1 year showed a reduced annual relapse rate, disability stabilization, and reduced brain atrophy (116,138). Hence, SCFA supplementation is efficacious in reducing MS clinical severity and inflammation. Compared with HCs, MS patients have been found to harbor significantly lower relative proportions of Bacteroides, Faecalibacterium, Prevotella, Butyricimonas, Paraprevotella, Haemophilus, Slackia, and Anaerostipes. ...
The gut microbiota plays a key role in the function of the host immune system and neuroimmune diseases. Alterations in the composition of the gut microbiota can lead to pathology and altered formation of microbiota-derived components and metabolites. A series of neuroimmune diseases, such as myasthenia gravis (MG), multiple sclerosis (MS), neuromyelitis optica spectrum disorders (NMOSDs), Guillain–Barré syndrome (GBS), and autoimmune encephalitis (AIE), are associated with changes in the gut microbiota. Microecological therapy by improving the gut microbiota is expected to be an effective measure for treating and preventing some neuroimmune diseases. This article reviews the research progress related to the roles of gut microbiota and fecal microbiota transplantation (FMT) in neuroimmune diseases.
... A prominent role in this interplay has been suggested for various SFCAs. It has been proposed that propionate acts directly on neuronal cells and improves the function of mitochondria, thus impeding the progression of multiple sclerosis and brain atrophy in human patients [148,149]. Likewise, acetate has been found to act on microglia cells and restore mitochondrial morphology and activity, are deteriorated by the absence of gut microbiota in mice [150]. ...
Mitochondria are highly dynamic organelles that serve as the primary cellular energy-generating system. Apart from ATP production, they are essential for many biological processes, including calcium homeostasis, lipid biogenesis, ROS regulation and programmed cell death, which collectively render them invaluable for neuronal integrity and function. Emerging evidence indicates that mitochondrial dysfunction and altered mitochondrial dynamics are crucial hallmarks of a wide variety of neurodevelopmental and neurodegenerative conditions. At the same time, the gut microbiome has been implicated in the pathogenesis of several neurodegenerative disorders due to the bidirectional communication between the gut and the central nervous system, known as the gut–brain axis. Here we summarize new insights into the complex interplay between mitochondria, gut microbiota and neurodegeneration, and we refer to animal models that could elucidate the underlying mechanisms, as well as novel interventions to tackle age-related neurodegenerative conditions, based on this intricate network.
... Previous studies have shown that SCFAs modulate cell function by ligation to G protein-coupled free fatty acid receptor (FFAR) 2 and 3 and histone hyperacetylation by inhibiting histone deacetylases (HDAC) class I (5). Orally administered PA has shown antiinflammatory and neuroprotective potential in multiple sclerosis patients by increasing the frequency and activity of regulatory T cells, resulting in a reduction in relapse frequency and reduced brain atrophy (6,7). Furthermore, there is anectotal evidence of a comparable beneficial effect of PA in the PNS, as shown in a case report of a patient with acute motor and sensory axonal neuropathy (8). ...
In inflammatory neuropathies, oxidative stress results in neuronal and Schwann cell (SC) death promoting early neurodegeneration and clinical disability. Treatment with the short-chain fatty acid propionate showed a significant immunoregulatory and neuroprotective effect in multiple sclerosis patients. Similar effects have been described for patients with chronic inflammatory demyelinating polyneuropathy (CIDP). Therefore, Schwann cell’s survival and dorsal root ganglia (DRG) outgrowth were evaluated in vitro after propionate treatment and application of H2O2 or S-nitroso-N-acetyl-D-L-penicillamine (SNAP) to evaluate neuroprotection. In addition, DRG resistance was evaluated by the application of oxidative stress by SNAP ex vivo after in vivo propionate treatment. Propionate treatment secondary to SNAP application on DRG served as a neuroregeneration model. Histone acetylation as well as expression of the free fatty acid receptor (FFAR) 2 and 3, histone deacetylases, neuroregeneration markers, and antioxidative mediators were investigated. β-hydroxybutyrate was used as a second FFAR3 ligand, and pertussis toxin was used as an FFAR3 antagonist. FFAR3, but not FFAR2, expression was evident on SC and DRG. Propionate-mediated activation of FFAR3 and histone 3 hyperacetylation resulted in increased catalase expression and increased resistance to oxidative stress. In addition, propionate treatment resulted in enhanced neuroregeneration with concomitant growth-associated protein 43 expression. We were able to demonstrate an antioxidative and neuroregenerative effect of propionate on SC and DRG mediated by FFAR3-induced histone acetylases expression. Our results describe a pathway to achieve neuroprotection/neuroregeneration relevant for patients with immune-mediated neuropathies.
... Their beneficial effect has also been demonstrated in experimental models such as colitis [25,32,51], experimental autoimmune encephalomyelitis (EAE) [33,52], allergic asthma [53], arthritis [51,54], and prostatitis [55], among others. Thus, this positive effect that has been partly attributed to the induction of Treg cells could be translated into the clinic, and in fact, a few clinical trials have shown some preliminary but encouraging results [56][57][58]. ...
The gut microbiota and its derived metabolites greatly impact the host immune system, both innate and adaptive responses. Gut dysbiosis and altered levels of microbiota-derived metabolites have been described in several immune-related and immune-mediated diseases such as intestinal bowel disease, multiple sclerosis, or colorectal cancer. Gut microbial-derived metabolites are synthesized from dietary compounds ingested by the host or host-produced metabolites, and additionally, some bacterial products can be synthesized de novo. In this review, we focus on the two first metabolites families including short-chain fatty acids, indole metabolites, polyamines, choline-derived compounds, and secondary bile acids. They all have been described as immunoregulatory molecules that specifically affect the adaptive immune system and T helper 17 and regulatory T cells. We discuss the mechanisms of action and the consequences in health and diseases related to these gut microbial-derived metabolites. Finally, we propose that the exogenous administration of these molecules or other compounds that bind to their immunoregulatory receptors in a homologous manner could be considered therapeutic approaches.
... Myeloid cells from the bone marrow become immunosuppressive M2-like TAMs when exposed to oleic acid. Both polyunsaturated and saturated fatty acids work as TLR4 agonists, which can activate NF-kB and JNK, increase the production of TNF-a, and encourage DC maturation [85][86][87][88][89][90][91]. Docosahexaenoic acid (DHA) reduces DC maturation, but eicosapentaenoic and arachidonic acids can also influence T-cell responses, MODC differentiation, and cytokine production. ...
Immune checkpoint inhibitors have ushered in a new era of cancer treatment by increasing the likelihood of long-term survival for patients with metastatic disease and by introducing fresh therapeutic indications in cases where the disease is still in its early stages. Immune checkpoint inhibitors that target the proteins cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) or programmed death-1/programmed death ligand-1 have significantly improved overall survival in patients with certain cancers and are expected to help patients achieve complete long-lasting remissions and cures. Some patients who receive immune checkpoint inhibitors, however, either experience therapeutic failure or eventually develop immunotherapy resistance. Such individuals are common, which necessitates a deeper understanding of how cancer progresses, particularly with regard to nutritional regulation in the tumor microenvironment (TME), which comprises metabolic cross-talk between metabolites and tumor cells as well as intracellular metabolism in immune and cancer cells. Combination of immunotherapy with targeted metabolic regulation might be a focus of future cancer research despite a lack of existing clinical evidence. Here, we reviewed the significance of the tumor microenvironment and discussed the most significant immunological checkpoints that have recently been identified. In addition, metabolic regulation of tumor immunity and immunological checkpoints in the TME, including glycolysis, amino acid metabolism, lipid metabolism, and other metabolic pathways were also incorporated to discuss the possible metabolism-based treatment methods being researched in preclinical and clinical settings. This review will contribute to the identification of a relationship or crosstalk between tumor metabolism and immunotherapy, which will shed significant light on cancer treatment and cancer research.
... Several WGs including barley, highland barley, sorghum, and oats as fermentation substrates retained better propionic acid production capability whether processed by boiling or steaming. This is advisable because propionic acid is beneficial to enhance immune cell function, improve mitochondrial homeostasis, and delay the course of multiple sclerosis (Duscha et al., 2020). ...
Whole grains (WGs) are considered as the representative sources of dietary fiber (DF). Thermal treatments can
change the properties of DF, and potentially affecting the gut microbiota as well as human health. In this study,
DF content and in vitro fermentation characteristics of 9 kinds of WGs (highland barley, barley, buckwheat, proso
millet, quinoa, sorghum, coix seed, foxtail millet, and oats) after boiling and steaming treatments were
compared. It was found that boiling and steaming treatments could both increase DF content in these grains,
except for barley and foxtail millet. Processed WGs could regulate beneficial microbial genus, such as Bifidobacterium, Prevotella, Megamona and Megasphaera. Oats, quinoa, highland barley, and buckwheat after boiling
treatment can produce more total short-chain fatty acids (SCFAs) than steaming treatment (p < 0.05), while
barley, foxtail millet and coix seed showed opposite results. This study can provide data support for the design of
WGs diets and the development of WGs products which are beneficial for gut health.
... Certain clinical studies are looking into the prevention of neurodegenerative conditions through microbiome-targeted strategies utilising microbial metabolites such as SCFAs. Duscha et al. (2020) have shown that two weeks of propionic acid intake leads to a sustained increase of immunoregulatory T (Treg) cells while three years of propionic acid intake positively influenced functional parameters through a reduced relapse rate associated with reduced brain atrophy. In addition, preclinical models have shown that modulation of neuroinflammation and cognitive decline can be achieved through oral supplementation with butyrate (Govindarajan et al., 2011;Matt et al., 2018), however, these findings have yet to be explored in humans. ...
The gut microbiota plays crucial roles in maintaining the health and homeostasis of its host throughout lifespan, including through its ability to impact brain function and regulate behaviour during ageing. Studies have shown that there are disparate rates of biologic ageing despite equivalencies in chronologic age, including in the development of neurodegenerative diseases, which suggests that environmental factors may play an important role in determining health outcomes in ageing. Recent evidence demonstrates that the gut microbiota may be a potential novel target to ameliorate symptoms of brain ageing and promote healthy cognition. This review highlights the current knowledge around the relationships between the gut microbiota and host brain ageing, including potential contributions to age-related neurodegenerative diseases. Furthermore, we assess key areas for which gut microbiota-based strategies may present as opportunities for intervention.
... As a carbon source for the gut microbiota, polysaccharides can promote the growth of gut microbiota, which, in turn, ferment polysaccharides into SCFAs [50] which play an essential role in mucosal integrity and immune response [51]. Propionic acid exerts immunomodulatory properties by inducing regulatory T cell expression [52]. Moreover, fecal isobutyric acid concentration was signi cantly lower in diarrheal calves [53]. ...
Background
Neonatal calf diarrhea (NCD) is still one of the most critical diseases in calf rearing. Studies have shown that Pueraria lobata polysaccharides (PLP) have intense antioxidant and immunomodulatory activity and modulate gut microbiota. This randomized clinical trial aimed to investigate the effect of PLP on fecal score, inflammatory cytokines, antioxidant activity, fecal microbiota and metabolites in diarrheic calves.
Methods
12 neonatal calves (7–8 day ages and 45–55 kg weights) with fecal scores ≥ 2 were determined as diarrhea then orally administered PLP (400mg/kg BW) QD for five consecutive days. 12 age-matched healthy calves with a fecal score ≤ 1 were selected as the control group. Fecal samples and blood samples were collected from the rectum and tail of diarrheic calves (DS) and calves in the control group (HS) on the 0 d; then collected fecal samples and blood samples from diarrheic calves treated with PLP (TS) on the 7 d of the trial. Fecal or blood samples of these calves were analyzed in inflammatory cytokines, antioxidant activity, fecal microbiota and metabolites.
Results
Studies showed that treatment with PLP decreased the fecal score of diarrheal calves, serum concentrations of IL-1β, TNF-α, and malondialdehyde, and also elevated the level of superoxide dismutase. In addition, PLP treatment altered the gut microbiota, significantly increased the relative abundances of beneficial bacteria, including the phyla Bacteroidetes and Actinobacteria, the genus Collinsella, Megamonas and Bifidobacterium; decreased the relative abundances of pathogenetic or diarrhea related bacteria, such as Proteobacteria, Fusobacteria, Clostridium_sensu_stricto_1, and Escherichia_Shigella. Moreover, PLP can increase the fecal concentrations of isobutyric acid, propionic acid, and pantothenate; lower the levels of PC (18:0/18:1(9Z)), arachidonic acid, and docosahexaenoic acid.
Conclusions
PLP perform the therapeutic activity via alleviating intestinal inflammation and regulating gut microbiota, avoiding further dysbiosis to restore the metabolism of gut microbiota, and finally promoting the recovery of diarrhea. The change further mitigated intestinal inflammation and oxidative damage in diarrheal calves.
... In MS patients, another SCFA, propionic acid, was found to be reduced in both serum and feces early in the course of the disease, which was linked to a dysbiotic gut microbiota composition [33]. Supplementation of propionic acid to treatment-naive MS patients restored the balance between Tregs and Th17 after two weeks and improved MS clinically up to three years after supplementation. ...
Autoimmune diseases are complex, multifactorial diseases with a polygenic trait and diverse environmental factors that contribute to triggering and exacerbating each disorder. The human microbiome is increasingly implicated in the multistep pathogenesis of autoimmune diseases. We summarize here the latest developments in the field of how the microbiota interacts with the host on a cellular and molecular level. We review how pathobionts evolve within the gut of autoimmune-prone hosts to translocate to secondary lymphoid tissues. On mucosal sites and in non-gut tissues, pathobionts trigger autoimmune pathways through various mechanisms, including cross-reactivity with autoantigens and secretion of metabolites that alter immune functions. A better understanding of these mechanisms will hasten the development of unconventional therapeutic approaches for autoimmune diseases.
... Changes in gut microbiota composition [64][65][66], bacteria-derived metabolites [67][68][69], intestinal permeability [70,71], and enteric nervous system functions [72] have been repeatedly described in MS patients. Studies on an animal model of MS have shown that the disruption of the intestinal barrier occurs soon after the induction of EAE [73,74]. ...
The gut-brain axis (GBA) refers to the multifactorial interactions between the intestine microflora and the nervous, immune, and endocrine systems, connecting brain activity and gut functions. Alterations of the GBA have been revealed in people with multiple sclerosis (MS), suggesting a potential role in disease pathogenesis and making it a promising therapeutic target. Whilst research in this field is still in its infancy, a number of studies revealed that MS patients are more likely to exhibit modified microbiota, altered levels of short-chain fatty acids, and enhanced intestinal permeability. Both clinical and preclinical trials in patients with MS and animal models revealed that the administration of probiotic bacteria might improve cognitive, motor, and mental behaviors by modulation of GBA molecular pathways. According to the newest data, supplementation with probiotics may be associated with slower disability progression, reduced depressive symptoms, and improvements in general health in patients with MS. Herein, we give an overview of how probiotics supplementation may have a beneficial effect on the course of MS and its animal model. Hence, interference with the composition of the MS patient’s intestinal microbiota may, in the future, be a grip point for the development of diagnostic tools and personalized microbiota-based adjuvant therapy.
... 54 Treatment with autologous Tregs in RRMS is possible and, as far as can be deduced from a small number of participants, appears to be reasonably safe. 55 Agents that indirectly increase the number and function of Tregs, such as propionic acid, 56 are also already being tested in clinical practice. ...
Background and Objectives
Immunomodulatory therapies reduce the relapse rate but only marginally control disability progression in patients with MS. Although serum neurofilament light chain (sNfL) levels correlate best with acute signs of inflammation (e.g., relapses and gadolinium-enhancing [Gd+] lesions), their role in predicting progressive biology and irreversible axonal damage is less clear. We aimed to determine the ability of sNfL to dissect distinct measures of disease severity and predict future (no) evidence of disease activity (EDA/no evidence of disease activity [NEDA]).
Methods
One hundred fifty-three of 221 patients with relapsing-remitting MS initially enrolled in the Neurofilament and longterm outcome in MS cohort at the MS outpatient clinic of the University Medical Center Mainz (Germany) met the inclusion criteria for this prospective observational cohort study with a median follow-up of 6 years (interquartile range 4–7 years). Progressive disease forms were excluded. Inclusion criteria consisted of Expanded Disability Status Scale (EDSS) assessment within 3 months and MRI within 12 months around blood sampling at baseline (y0) and follow-up (y6). EDSS progression at y6 had to be confirmed 12 weeks later. sNfL was measured by single-molecule array, and the following additional variables were recorded: therapy, medical history, and detailed MRI parameters (T2 hyperintense lesions, Gd+ lesions, and new persistent T1 hypointense lesions).
Results
Patients experiencing EDSS progression or new persistent T1 lesions at y6 showed increased sNfL levels at y0 compared with stable patients or patients with inflammatory activity only. As a potential readily accessible marker of neurodegeneration, we incorporated the absence of persistent T1 lesions to the NEDA-3 concept (NEDA-3 T1 : n = 54, 35.3%; EDA T1 : n = 99, 64.7%) and then evaluated a risk score with factors that distinguish patients with and without NEDA-3 T1 status. Adding sNfL to this risk score significantly improved NEDA-3 T1 prediction (0.697 95% CI 0.616–0.770 vs 0.819 95% CI 0.747–0.878, p < 0.001). Patients with sNfL values ≤8.6 pg/mL showed a 76% risk reduction for EDA T1 at y6 (hazard ratio 0.244, 95% CI 0.142–0.419, p < 0.001).
Discussion
sNfL levels associate with severe focal axonal damage as reflected by development of persistent T1 lesions. Baseline sNfL values predicted NEDA-3 T1 status at 6-year follow-up.
... Therefore, past studies have assessed how essential nutrients, including polyunsaturated fatty acids, affect the expression of inflammatory genes [19]. Furthermore, our daily dietary habits may play an essential role in modulating the risk of developing MS [20,21]. The long-chain omega-3 polyunsaturated fatty acids (n-3 PUFAs), α-linolenic acid (ALA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA), mainly present in adipose fish, are promising candidates. ...
The health benefits of omega-3 fatty acid (FA) supplementation on inflammatory gene expression (IGE) and multiple sclerosis (MS) are becoming more evident. However, an overview of the results from randomized controlled trials is lacking. This study aimed to conduct a meta-analysis to evaluate the effect of omega-3 fatty acid intake on MS (based on the criteria of the Expanded Disability Status Scale (EDSS)) and inflammatory gene expression (IGE). A search was conducted of PubMed, EMBASE, and Web of Science for cohort studies published from the inception of the database up to May 2022 that assessed the associations of omega-3 polyunsaturated fatty acids (n-3 PUFAs), docosahexaenoic acid (DHA), α-linolenic acid (ALA), and eicosapentaenoic acid (EPA) with EDSS and inflammatory gene expression (peroxisome proliferator-activated receptor gamma (PPAR-γ), tumor necrosis factor-alpha (TNF-α), interleukin-1 (IL-1), interleukin-6 (IL-6), and interleukin-8 (IL-8)) outcomes. For the highest vs. lowest comparison, the relative risk (RR) estimates with a 95% confidence interval (CI) were pooled using the random-effect model. In total, 13 cohort studies with 1353 participants were included in the meta-analysis during periods of 3 to 144 weeks. A significant inverse relationship was found between DHA and EDSS scores (RR: 1.05; 95% CI: 0.62, 1.48; p < 0.00001). Our results also showed that omega-3 FAs significantly upregulated the gene expression of PPAR-γ (RR: 0.95; 95% CI: 0.52, 1.38; p < 0.03) and downregulated the expression of TNF-α (RR: −0.15; 95% CI: −0.99, 0.70; p < 0.00001) and IL-1 (RR: −0.60; 95% CI: −1.02, −0.18; p < 0.003). There was no clear evidence of publication bias with Egger’s tests for inflammatory gene expression (p = 0.266). Moreover, n-3 PUFAs and EPA were not significantly associated with EDSS scores (p > 0.05). In this meta-analysis of cohort studies, blood omega-3 FA concentrations were inversely related to inflammatory gene expression (IGE) and EDSS score, which indicates that they may hold great potential markers for the diagnosis, prognosis, and management of MS. However, further clinical trials are required to confirm the potential effects of the omega-3 FAs on MS disease management.
... In line, it is to be noted that "gut barrier dysfunction" and "leaky-gut" are often used in an interchangeable manner, however only the formed is associated with disease condition. Others have reported that the level of gut bacteria generated faecal propionate is related to gut microbial composition in multiple sclerosis patients, and dietary supplementation of propionate triggers expansion of regulatory T cells (Treg) and attenuates neurological symptoms in mice (Duscha et al. 2020), indicating the immunoregulatory role of commensal microbe-derived metabolites. ...
The abundance of gut commensals has historically been associated with health-promoting effects despite the fact that the definition of good or bad microbiota remains condition-specific. The beneficial or pathogenic nature of microbiota is generally dictated by the dimensions of host-microbiota and microbe-microbe interactions. With the increasing popularity of gut micro-biota in human health and disease, emerging evidence suggests opportunistic infections promoted by those gut bacteria that are generally considered beneficial. Therefore, the current review deals with the opportunistic nature of the gut commensals and aims to summarise the concepts behind the occasional commensal-to-pathogenic transformation of the gut microbes. Specifically, relevant clinical and experimental studies have been discussed on the overgrowth and bacteraemia caused by commensals. Three key processes and their underlying mechanisms have been summarised to be responsible for the opportunistic nature of commensals, viz. improved colonisation fitness that is dictated by commensal-pathogen interactions and availability of preferred nutrients; pathoadaptive mutations that can trigger the commensal-to-pathogen transformation; and evasion of host immune response as a survival and proliferation strategy of the microbes. Collectively, this review provides an updated concept summary on the underlying mechanisms of disease causative events driven by gut commensal bacteria. ARTICLE HISTORY
... Furthermore, PA normalizes Treg cell mitochondrial function and morphology in MS (128). In other autoimmune diseases, propionate also increases Treg cell numbers while reducing Th17-cell numbers, improving the prognosis of the disease (129)(130)(131). ...
Rheumatoid arthritis (RA) is an autoimmune disease characterized by joint destruction, synovitis, and pannus formation. Gut microbiota dysbiosis may exert direct pathogenic effects on gut homeostasis. It may trigger the host’s innate immune system and activate the “gut–joint axis”, which exacerbates the RA. However, although the importance of the gut microbiota in the development and progression of RA is widely recognized, the mechanisms regulating the interactions between the gut microbiota and the host immune system remain incompletely defined. In this review, we discuss the role of gut microbiota-derived biological mediators, such as short-chain fatty acids, bile acids, and tryptophan metabolites, in maintaining intestinal barrier integrity, immune balance and bone destruction in RA patients as the bridge of the gut–joint axis.
... Propionate has also been shown to modulate the activity of immune cells, including increased production of IL-10 by Tregs, which leads to inhibition of Th17 cells (Fig. 2). In the context of Multiple sclerosis, patients receiving propionate daily (1000 mg) for 14 days reported alleviation of clinical symptoms and a reduced risk of disease progression if taken continuously over a year 250 . ...
The gut microbiome lies at the intersection between the environment and the host, with the ability to modify host responses to disease-relevant exposures and stimuli. This is evident in how enteric microbes interact with the immune system, e.g., supporting immune maturation in early life, affecting drug efficacy via modulation of immune responses, or influencing development of immune cell populations and their mediators. Many factors modulate gut ecosystem dynamics during daily life and we are just beginning to realise the therapeutic and prophylactic potential of microbiome-based interventions. These approaches vary in application, goal, and mechanisms of action. Some modify the entire community, such as nutritional approaches or faecal microbiota transplantation, while others, such as phage therapy, probiotics, and prebiotics, target specific taxa or strains. In this review, we assessed the experimental evidence for microbiome-based interventions, with a particular focus on their clinical relevance, ecological effects, and modulation of the immune system.
... A recent differential analysis of distinct SCFAs revealed acetate to be a key regulator of microglial metabolism and phagocytosis [151]. In the context of multiple sclerosis, the SCFA propionate was shown to induce regulatory Treg activation, whereas pro-inflammatory Th1 and Th17 responses were diminished [153]. Moreover, bacterial metabolites of dietary tryptophan signal via the aryl hydrocarbon receptor to reduce microglial inflammatory activation of astrocytes [154]. ...
Inflammatory bowel disease (IBD) comprises Crohn’s disease (CD) and ulcerative colitis (UC) and is associated with neuropsychiatric symptoms like anxiety and depression. Both conditions strongly worsen IBD disease burden. In the present review, we summarize the current understanding of the pathogenesis of depression and anxiety in IBD. We present a stepwise cascade along a gut–immune–brain axis initiated by evasion of chronic intestinal inflammation to pass the epithelial and vascular barrier in the gut and cause systemic inflammation. We then summarize different anatomical transmission routes of gut-derived peripheral inflammation into the central nervous system (CNS) and highlight the current knowledge on neuroinflammatory changes in the CNS of preclinical IBD mouse models with a focus on microglia, the brain-resident macrophages. Subsequently, we discuss how neuroinflammation in IBD can alter neuronal circuitry to trigger symptoms like depression and anxiety. Finally, the role of intestinal microbiota in the gut–immune–brain axis in IBD will be reviewed. A more comprehensive understanding of the interaction between the gastrointestinal tract, the immune system and the CNS accounting for the similarities and differences between UC and CD will pave the path for improved prediction and treatment of neuropsychiatric comorbidities in IBD and other inflammatory diseases.
Autoimmune diseases such as ankylosing spondylitis (AS) can be driven by emerging neoantigens that disrupt immune tolerance. Here, we developed a workflow to profile posttranslational modifications involved in neoantigen formation. Using mass spectrometry, we identified a panel of cysteine residues differentially modified by carboxyethylation that required 3-hydroxypropionic acid to generate neoantigens in patients with AS. The lysosomal degradation of integrin αIIb [ITGA2B (CD41)] carboxyethylated at Cys96 (ITGA2B-ceC96) generated carboxyethylated peptides that were presented by HLA-DRB1*04 to stimulate CD4 ⁺ T cell responses and induce autoantibody production. Immunization of HLA-DR4 transgenic mice with the ITGA2B-ceC96 peptide promoted colitis and vertebral bone erosion. Thus, metabolite-induced cysteine carboxyethylation can give rise to pathogenic neoantigens that lead to autoreactive CD4 ⁺ T cell responses and autoantibody production in autoimmune diseases.
Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by progressive polyarthritis that leads to cartilage and bone damage. Pre-clinical RA is a prolonged state before clinical arthritis and RA develop, in which autoantibodies (antibodies against citrullinated proteins, rheumatoid factors) can be present due to the breakdown of immunologic self-tolerance. As early treatment initiation before the onset of polyarthritis may achieve sustained remission, optimize clinical outcomes, and even prevent RA progression, the pre-clinical RA stage is showing the prospect to be the window of opportunity for RA treatment. Growing evidence has shown the role of the gut microbiota in inducing systemic inflammation and polyarthritis via multiple mechanisms, which may involve molecular mimicry, impaired intestinal barrier function, gut microbiota-derived metabolites mediated immune regulation, modulation of the gut microbiota's effect on immune cells, intestinal epithelial cells autophagy, and the interaction between the microbiome and human leukocyte antigen alleles as well as microRNAs. Since gut microbiota alterations in pre-clinical RA have been reported, potential therapies for modifying the gut microbiota in pre-clinical RA, including natural products, antibiotic therapy, fecal microbiota transplantation, probiotics, microRNAs therapy, vitamin D supplementation, autophagy inducer-based treatment, prebiotics, and diet, holds great promise for the successful treatment and even prevention of RA via altering ongoing inflammation. In this review, we summarized current studies that include pathogenesis of gut microbiota in RA progression and promising therapeutic strategies to provide novel ideas for the management of pre-clinical RA and possibly preventing arthritis progression.
The hallmarks of Parkinson's disease (PD) include the loss of dopaminergic neurons and formation of Lewy bodies, whereas multiple sclerosis (MS) is an autoimmune disorder with damaged myelin sheaths and axonal loss. Despite their distinct etiologies, mounting evidence in recent years suggests that neuroinflammation, oxidative stress, and infiltration of the blood-brain barrier (BBB) all play crucial roles in both diseases. It is also recognized that therapeutic advances against one neurodegenerative disorder are likely useful in targeting the other. As current drugs in clinical settings exhibit low efficacy and toxic side effects with long-term usages, the use of natural products (NPs) as treatment modalities has attracted growing attention. This mini-review summarizes the applications of natural compounds to targeting diverse cellular processes inherent in PD and MS, with the emphasis placed on their neuroprotective and immune-regulating potentials in cellular and animal models. By reviewing the many similarities between PD and MS and NPs according to their functions, it becomes evident that some NPs studied for one disease are likely repurposable for the other. A review from this perspective can provide insights into the search for and utilization of NPs in treating the similar cellular processes common in major neurodegenerative diseases.
Synbiotic 2000, a pre + probiotic, reduced comorbid autistic traits and emotion dysregulation in attention deficit hyperactivity disorder (ADHD) patients. Immune activity and bacteria-derived short-chain fatty acids (SCFAs) are microbiota–gut–brain axis mediators. The aim was to investigate Synbiotic 2000 effects on plasma levels of immune activity markers and SCFAs in children and adults with ADHD. ADHD patients (n = 182) completed the 9-week intervention with Synbiotic 2000 or placebo and 156 provided blood samples. Healthy adult controls (n = 57) provided baseline samples. At baseline, adults with ADHD had higher pro-inflammatory sICAM-1 and sVCAM-1 and lower SCFA levels than controls. Children with ADHD had higher baseline sICAM-1, sVCAM-1, IL-12/IL-23p40, IL-2Rα, and lower formic, acetic, and propionic acid levels than adults with ADHD. sICAM-1, sVCAM-1, and propionic acid levels were more abnormal in children on medication. Synbiotic 2000, compared to placebo, reduced IL-12/IL-23p40 and sICAM-1 and increased propionic acid levels in children on medication. SCFAs correlated negatively with sICAM-1 and sVCAM-1. Preliminary human aortic smooth-muscle-cell experiments indicated that SCFAs protected against IL-1β-induced ICAM-1 expression. These findings suggest that treatment with Synbiotic 2000 reduces IL12/IL-23p40 and sICAM-1 and increases propionic acid levels in children with ADHD. Propionic acid, together with formic and acetic acid, may contribute to the lowering of the higher-than-normal sICAM-1 levels.
Immune tolerance deletes or suppresses autoreactive lymphocytes and is established at multiple levels during the development, activation and effector phases of T and B cells. These mechanisms are cell-intrinsically programmed and critical in preventing autoimmune diseases. We have witnessed the existence of another type of immune tolerance mechanism that is shaped by lifestyle choices, such as diet, microbiome and microbial metabolites. Short-chain fatty acids (SCFAs) are the most abundant microbial metabolites in the colonic lumen and are mainly produced by the microbial fermentation of prebiotics, such as dietary fiber. This review focuses on the preventive and immunomodulatory effects of SCFAs on autoimmunity. The tissue- and disease-specific effects of dietary fiber, SCFAs and SCFA-producing microbes on major types of autoimmune diseases, including type I diabetes, multiple sclerosis, rheumatoid arthritis and lupus, are discussed. Additionally, their key regulatory mechanisms for lymphocyte development, tissue barrier function, host metabolism, immunity, autoantibody production, and inflammatory effector and regulatory lymphocytes are discussed. The shared and differential effects of SCFAs on different types and stages of autoimmune diseases are discussed.
Regulatory T cells (Treg) maintain immune homeostasis due to their anti-inflammatory functions. They can be generated either centrally in the thymus or in peripheral organs. Metabolites such as short chain fatty acids produced by intestinal microbiota can induce peripheral Treg differentiation, by activating G-protein-coupled-receptors like GPR109A. In this study, we identified a novel role for GPR109A on thymic Treg development. We found that Gpr109a-/- mice had increased Treg under basal conditions in multiple organs compared to wild type mice (WT). GPR109A was not expressed on T cells but on medullary thymic epithelial cells (mTECs), as revealed by single cell RNA sequencing in both mice and humans and confirmed by flow cytometry in mice. mTECs isolated from Gpr109a-/- mice had higher expression of autoimmune regulator (AIRE), the key regulator of Treg development, while the subset of mTECs that did not express Gpr109a displayed increased Aire expression and enhanced signalling related to mTEC functionality as well. Increased thymic Treg in Gpr109a-/- mice was associated with protection from experimental autoimmune encephalomyelitis, with ameliorated clinical signs and reduced inflammation. This work identifies a novel role for GPR109A and by extension, the gut microbiota, on thymic Treg development via its regulation of mTECs.
With the emphasis on intestinal health, probiotics have exploded into a vast market potential. However, new scientific evidence points out that the beneficial health benefits of probiotics are not necessarily directly related to viable bacteria. However, the metabolites or bacterial components of the live bacteria are the driving force behind health promotion. Therefore, scientists gradually noticed that the beneficial effects of probiotics are based on bacteria itself, metabolites, or cell lysates, and these factors are officially named “postbiotics” by the ISAPP. Postbiotic components are diverse and outperform live probiotics in terms of technology, safety, and cost due to their good absorption, metabolism, and organismal distribution. Postbiotics have been shown to have bioactivities such as antimicrobial, antioxidant, anti-inflammatory, anti-proliferative, and immunomodulation. Moreover, numerous studies have revealed the significant potential of postbiotics for disease treatment. This paper first presents the production and classification of postbiotics with examples from lactic acid bacteria (LAB), followed by the mechanisms of action with the most recent pre-clinical and clinical studies and the wide range of non-clinical and clinical applications of postbiotics. Furthermore, the current and future prospects of the postbiotic market with commercial available products are discussed. Finally, we comment on the knowledge gaps and future clinical applications with several examples.
Although metabolic rewiring of Treg cells constitutes a hallmark in autoimmune diseases, extrinsic and intrinsic mechanisms that imprint on this re-programming remain poorly understood. In this issue of Cell Metabolism, Côrte-Real and colleagues demonstrate that high salt exposure disturbs the mitochondrial respiration in Treg cells, promoting a pro-inflammatory phenotype, loss of function, and associated breakdown of self-tolerance.
It has now been established that a perturbation in gut microbiome composition exists in multiple sclerosis (MS) and its interplay with the immune system and brain could potentially contribute to the development of the disease and influence its course. The effects of the gut microbiota on the disease may be mediated by direct interactions between bacteria and immune cells or through interactions of products of bacterial metabolism with immune and CNS cells. In this review article we summarize the ways in which the gut microbiome of people with MS differs from controls and how bacterial metabolites can potentially play a role in MS pathogenesis, and examine approaches to alter the composition of the gut microbiota potentially alleviating gut dysbiosis and impacting the course of MS.
Traditional fermented foods harbor microbes that transform raw food components, improving their nutritional, shelf life, organoleptic, and health-promoting characteristics. Fermented foods are an important conduit of contact between bioactive components that act like antigens and the human body system. Versatile microbes in traditional fermented foods are associated with many health-promoting end-products, including dietary fatty acids and inherent fermenting microbial cells. Evidence shows that dietary fatty acid components regulate genes in a hormonally dependent manner, either directly via specific binding to nuclear receptors or indirectly by changing regulatory transcription factors. Fatty acids are implicated in anti-inflammatory, anti-obesogenic, immunoreg-ulatory, cardioprotective, etc., activities. Challenges with scaling the production of traditional fermented foods stem from losing effective consortiums of microbial groups and the production of differential end-products. Industrialists scaling the production of traditional fermented foods must overcome safety and consistency challenges. They need to combine processes that lessen the advent of public health issues and introduce omics technologies that identify and maintain effective consortium groups, prune genes that code for toxic products, and inculcate microbes with additional beneficial characteristics. Incorporating omics in production will avail the benefits of traditional fermented foods to a larger population that craves them outside their native areas.
Age-related gastrointestinal decline contributes to whole-organism frailty and mortality. Genistein is known to have beneficial effects on age-related diseases, but its precise role in homeostasis of the aging gut remains to be elucidated. Here, wild-type aging mice and Zmpste24-/- progeroid mice were used to investigate the role of genistein in lifespan and homeostasis of the aging gut in mammals. A series of longitudinal, clinically relevant measurements were performed to evaluate the effect of genistein on healthspan. It was found that dietary genistein promoted a healthier and longer life and was associated with a decrease in the levels of systemic inflammatory cytokines in aging mice. Furthermore, dietary genistein ameliorated gut dysfunctions, such as intestinal inflammation, leaky gut, and impaired epithelial regeneration. A distinct genistein-mediated alteration in gut microbiota was observed by increasing Lachnospira abundance and short-chain fatty acid (SCFA) production. Further fecal microbiota transplantation and dirty cage sharing experiments indicated that the gut microbiota from genistein-fed mice rejuvenated the aging gut and extended the lifespan of progeroid mice. It was demonstrated that genistein-associated SCFAs alleviated tumor necrosis factor alpha-induced intestinal organoid damage. Moreover, genistein-associated propionate promoted regulatory T cell-derived interleukin 10 production, which alleviated macrophage-derived inflammation. This study provided the first data, to the authors' knowledge, indicating that dietary genistein modulates homeostasis in the aging gut and extends the healthspan and lifespan of aging mammals. Moreover, the existence of a link between genistein and the gut microbiota provides a rationale for dietary interventions against age-associated frailty.
Background:
The gut microbiome is involved in autoimmunity. Data about its composition in chronic inflammatory demyelinating polyneuropathy (CIDP), the most common autoimmune disorder of peripheral nerves, are currently lacking.
Methods:
In this monocentric exploratory pilot study, stool samples were prospectively collected from 16 CIDP patients (mean age 58 ± 10 years, 25 % female) before and one week after administration of intravenous immunoglobulin (IVIg). Gut microbiota were analyzed via bacterial 16S rRNA gene sequencing and compared to 15 age-matched healthy subjects (mean age 59 ± 15 years, 66 % female).
Results:
Gut microbiota of CIDP patients showed an increased alpha-diversity (p=0.005) and enrichment of Firmicutes, such as Blautia (p=0.0004), Eubacterium hallii (p=0.0004), or Ruminococcus torques (p=0.03), and of Actinobacteriota (p=0.03) compared to healthy subjects. IVIg administration did not alter the gut microbiome composition in CIDP in a short-term observation (p=0.95).
Conclusions:
The gut microbiome in IVIg-treated CIDP shows distinct features with increased bacterial diversity and enrichment of short-chain fatty acid (SCFA) producing Firmicutes. IVIg had no short-term impact on the gut microbiome in CIDP patients. As small cohort size is a main limitation of this exploratory pilot study, future studies also including therapy-naïve patients are warranted to verify our findings and to explore the impact of a long-term IVIg treatment on the gut microbiome in CIDP.
Neurodegenerative diseases, in particular for Alzheimer's disease (AD), Parkinson's disease (PD) and Multiple sclerosis (MS), are a category of diseases with progressive loss of neuronal structure or function (encompassing neuronal death) leading to neuronal dysfunction, whereas the underlying pathogenesis remains to be clarified. As the microbiological ecosystem of the intestinal microbiome serves as the second genome of the human body, it is strongly implicated as an essential element in the initiation and/or progression of neurodegenerative diseases. Nevertheless, the precise underlying principles of how the intestinal microflora impact on neurodegenerative diseases via gut-brain axis by modulating the immune function are still poorly characterized. Consequently, an overview of initiating the development of neurodegenerative diseases and the contribution of intestinal microflora on immune function is discussed in this review.
Food allergy has caused lots of global public health issues, particularly in developed countries. Presently, gut microbiota has been widely studied on allergy, while the role of dysbiosis in food allergy remains unknown. Scientists found that changes in gut microbial compositions and functions are strongly associated with a dramatic increase in the prevalence of food allergy. Altering microbial composition is crucial in modulating food antigens’ immunogenicity. Thus, the potential roles of probiotics, prebiotics, synbiotics, and postbiotics in affecting gut bacteria communities and the immune system, as innovative strategies against food allergy, begins to attract high attention of scientists. This review briefly summarized the mechanisms of food allergy and discussed the role of the gut microbiota and the use of probiotics, prebiotics, synbiotics, and postbiotics as novel therapies for the prevention and treatment of food allergy. The perspective studies on the development of novel immunotherapy in food allergy were also described. A better understanding of these mechanisms will facilitate the development of preventive and therapeutic strategies for food allergy.
Th17/Treg imbalance is closely related to the occurrence and development of multiple sclerosis (MS), and the transdifferentiation of Th17 cells into Treg cells may contribute to the resolution of inflammation, presenting a therapeutic strategy for MS. To modulate this phenotypic shift in situ, we report a “Trojan horse”‐like hybrid system, nanocapsule‐coupled Th17 cells, for MS treatment. Following intravenous injection into MS mice, the hybrid system efficiently transmigrated across the blood‐brain barrier (BBB) and homed to the inflamed MS niche. Aminooxy‐acetic acid (AOA), a transdifferentiation inducer, was locally released upon the production of ROS and in turn taken up by Th17 cells. We demonstrated that the Trojan horse hybrid system enabled in situ phenotypic transdifferentiation of Th17 cells into anti‐inflammatory Treg cells. This phenotypic conversion led to a domino‐like immune response that was conducive to MS therapy. Overall, this work highlights a new pathway for accurate modulation of the phenotypes of adoptively transferred cells in situ, from proinflammatory to anti‐inflammatory for MS therapy, and may be broadly applicable for patients suffering from other autoimmune diseases. This article is protected by copyright. All rights reserved
Multiple sclerosis (MS) is an autoimmune and demyelinating disease of the central nervous system that results from complex interactions between genetic and environmental determinants. Patients with MS exhibit a high risk of depression, however, the exact pathomechanisms remain largely unknown. It is becoming widely accepted that the gut–brain axis (GBA) disorders may exert an influence on neuroinflammation and psychiatric symptoms, including so‐called MS‐related depression. The element suggested as a bridge between intestinal disorders, depression, and MS is an inflammatory response with the central role of the NLR family pyrin domain containing 3 (NLRP3) inflammasome. The pro‐inflammatory activity of effector cytokines of the NLRP3 inflammasome forms the hypothesis that it is actively involved in the development of inflammatory and autoimmune diseases. Despite extensive reviews considering the possible origins of MS‐related depression, its complex pathophysiology prevents any easy determination of its underlying mechanisms. This paper aims to discuss molecular mechanisms related to the GBA axis that can mediate dysbiosis, intestinal barrier dysfunction, disruption of blood–brain barrier integrity, neuroinflammation, and subsequent manifestation of MS‐related major depressive disorder. Overview of the crosstalk between the gut and the brain affecting MS‐related depression
IntroductionNeonatal calf diarrhea (NCD) is still one of the most critical diseases in calf rearing. Studies have shown that Pueraria lobata polysaccharides (PLP) have intense antioxidant and immunomodulatory activity and modulate gut microbiota. This randomized clinical trial aimed to determine the effect of PLP on the neonatal calf with diarrhea.Methods
In this study, we recorded the fecal score of experimental calves, and calves with fecal scores ≥ 2 were determined as diarrhea and assessed their serum concentrations of inflammatory cytokines and oxidative damage-related indices. Fecal microbiota and metabolomics of diarrheal calves were further investigated.ResultsResults showed that treatment with PLP decreased the fecal score of diarrheal calves, serum concentrations of IL-1β, TNF-γ, and malondialdehyde, and also elevated the level of superoxide dismutase. In addition, PLP treatment altered the gut microbiota, significantly increased the relative abundances of beneficial bacteria, including the phyla Bacteroidetes and Actinobacteria, the genus Collinsella, Megamonas, and Bifidobacterium; decreased the relative abundances of pathogenetic or diarrhea related bacteria, such as Proteobacteria, Fusobacteria, Clostridium_sensu_stricto_1, and Escherichia_Shigella. Moreover, PLP can increase the fecal concentrations of isobutyric acid, propionic acid, and pantothenate; lower the levels of PC [18:0/18:1(9Z)], arachidonic acid, and docosahexaenoic acid.DiscussionThus, the results suggested that the PLP may perform the therapeutic activity via alleviating intestinal inflammation and regulating gut microbiota, avoiding further dysbiosis to restore the metabolism of gut microbiota, and finally promoting the recovery of diarrhea. The change further mitigated intestinal inflammation and oxidative damage in diarrheal calves. This indicated that PLP might be a promising treatment to attenuate diarrhea in neonatal calves.
Rheumatoid arthritis (RA) is an autoimmune disease affected patients' quality of life severely. Our previous study found Lycium barbarum polysaccharide (LBP) alleviated RA, but it remains unknown whether gut microbiota is necessary for the alleviation. Here, RA models were established in rats with microbiota and rats treated by antibiotic cocktail, and LBP was applied for the intervention on rats. The biochemical test, 16S rDNA sequencing and metabolome analysis were applied to analyze the effects of LBP on gut microbiota, their metabolites and hosts. Results showed the LBP intervention improved RA by inhibiting pro-inflammatory cytokines IL-1α, IL-1β, TNF-α and IL-6 only in rats with microbiota, but not in pseudo-germ-free rats. The abundance of specific bacteria, including Romboutsia, Lactobacillus, Turicibacter, Clostridium_sensu_stricto_1, Faecalibacterium and Adlercreutzia, and several metabolites, including O-desmethylangolensin, 3-hydroxydodecanedioic acid, N-formyl-L-methionine, suberic acid, (S)-oleuropeic acid, prolyl-histidine, 13,14-dihydro PGF-1a, (R)-pelletierine and short-chain fatty acids increased only in RA rats with microbiota after the intervention. Our results suggest that intestinal bacteria are necessary for LBP alleviating RA alleviation. The fermentation metabolite acts on the host instead of LBP itself, which may be the reason for the improvement of RA.
Background
Dysregulation of gut microbiota-associated tryptophan metabolism has been observed in patients with multiple sclerosis. However, defining direct mechanistic links between this apparent metabolic rewiring and individual constituents of the gut microbiota remains challenging. We and others have previously shown that colonization with the gut commensal and putative probiotic species, Lactobacillus reuteri, unexpectedly enhances host susceptibility to experimental autoimmune encephalomyelitis (EAE), a murine model of multiple sclerosis. To identify underlying mechanisms, we characterized the genome of commensal L. reuteri isolates, coupled with in vitro and in vivo metabolomic profiling, modulation of dietary substrates, and gut microbiota manipulation.
Results
The enzymes necessary to metabolize dietary tryptophan into immunomodulatory indole derivatives were enriched in the L. reuteri genomes, including araT, fldH, and amiE. Moreover, metabolite profiling of L. reuteri monocultures and serum of L. reuteri-colonized mice revealed a depletion of kynurenines and production of a wide array of known and novel tryptophan-derived aryl hydrocarbon receptor (AhR) agonists and antagonists, including indole acetate, indole-3-glyoxylic acid, tryptamine, p-cresol, and diverse imidazole derivatives. Functionally, dietary tryptophan was required for L. reuteri-dependent EAE exacerbation, while depletion of dietary tryptophan suppressed disease activity and inflammatory T cell responses in the CNS. Mechanistically, L. reuteri tryptophan-derived metabolites activated the AhR and enhanced T cell production of IL-17.
Conclusions
Our data suggests that tryptophan metabolism by gut commensals, such as the putative probiotic species L. reuteri, can unexpectedly enhance autoimmunity, inducing broad shifts in the metabolome and immunological repertoire.
BfKwinXUUwxKhqz88rp9C3Video Abstract
Changes in microbiome composition are associated with a wide array of human diseases, turning the human microbiota into an attractive target for therapeutic intervention. Yet, clinical translation of these findings requires the establishment of causative connections between specific microbial taxa and their functional impact on host tissues. Here, we infuse gut organ cultures with longitudinal microbiota samples collected from therapy-naive patients with irritable bowel syndrome (IBS) under a low-fermentable oligo-, di-, mono-saccharides and polyols (FODMAP) diet. We show that post-diet microbiota regulates intestinal expression of inflammatory and neuro-muscular gene sets. Specifically, we identify Bifidobacterium adolescentis as a diet-sensitive pathobiont that alters tight junction integrity and disrupts gut barrier functions. Collectively, we present a pathway discovery platform for mechanistic dissection and identification of functional diet-host-microbiota modules. Our data support the hypothesis that the gut microbiota mediates the beneficial effects of a low-FODMAP diet and reinforce the potential feasibility of microbiome-based therapies in IBS.
Rationale:
Inflammation drives pulmonary arterial hypertension (PAH). Gut dysbiosis causes immune dysregulation and systemic inflammation by altering circulating microbial metabolites; however, little is known about gut dysbiosis and microbial metabolites in PAH.
Objectives:
To characterize the gut microbiome and microbial metabolites in PAH patients.
Methods:
We performed 16S ribosomal ribonucleic acid gene and shotgun metagenomics sequencing on stool from PAH patients, family controls, and healthy controls. We measured markers of inflammation, gut permeability, and microbial metabolites in plasma from PAH patients, family controls, and healthy controls.
Main results:
The gut microbiome was less diverse in PAH patients. Shannon diversity index correlated with measures of pulmonary vascular disease but not with right ventricular function. PAH patients had a distinct gut microbial signature at the phylogenetic level with lower copies of gut microbial genes that produce anti-inflammatory short-chain fatty acids (SCFAs) and secondary bile acids and lower relative abundances of species encoding these genes. Consistent with the gut microbial changes, PAH patients had relatively lower plasma levels of SCFAs and secondary bile acids. PAH patients also had enrichment of species with the microbial genes that encoded the proinflammatory microbial metabolite trimethylamine. The changes in the gut microbiome and circulating microbial metabolites between PAH patients and family controls were not as substantial as the differences between PAH patients and healthy controls.
Conclusions:
PAH patients have proinflammatory gut dysbiosis in which lower circulating SCFAs and secondary bile acids may facilitate pulmonary vascular disease. These findings support investigating modulation of the gut microbiome as a potential treatment for PAH.
Multiple sclerosis is associated with Epstein-Barr virus (EBV) infection, B-cell dysfunction, gut dysbiosis, and environmental and genetic risk factors, including female sex. A disease model incorporating all these factors remains elusive. Here, we hypothesise that EBV-infected memory B cells (MBCs) migrate to gut-associated lymphoid tissue (GALT) through EBV-induced expression of LPAM-1, where they are subsequently activated by gut microbes and/or their products resulting in EBV reactivation and compartmentalised anti-EBV immune responses. These responses involve marginal zone (MZ) B cells that activate CD4 + T-cell responses, via HLA-DRB1, which promote downstream B-cell differentiation towards CD11c + /T-bet + MBCs, as well as conventional MBCs. Intrinsic expression of low-affinity B-cell receptors (BCRs) by MZ B cells and CD11c + /T-bet + MBCs promotes polyreactive BCR/antibody responses against EBV proteins (e.g. EBNA-1) that cross-react with central nervous system (CNS) autoantigens (e.g. GlialCAM). EBV protein/autoantigen-specific CD11c + /T-bet + MBCs migrate to the meningeal immune system and CNS, facilitated by their expression of CXCR3, and induce cytotoxic CD8 + T-cell responses against CNS autoantigens amplified by BAFF, released from EBV-infected MBCs. An increased abundance of circulating IgA + MBCs, observed in MS patients, might also reflect GALT-derived immune responses, including disease-enhancing IgA antibody responses against EBV and gut microbiota-specific regulatory IgA + plasma cells. Female sex increases MZ B-cell and CD11c + /T-bet + MBC activity while environmental risk factors affect gut dysbiosis. Thus, EBV infection, B-cell dysfunction and other risk factors converge in GALT to generate aberrant B-cell responses that drive pathogenic T-cell responses in the CNS.
The factor that is most relevant and strongly associated with the clinical course of multiple sclerosis is chronological age. Very young patients exclusively have relapsing remitting disease, whereas those with later onset disease face a more rapid development of permanent disability. For people with progressive multiple sclerosis, the poor response to current disease modifying therapies might be related to ageing in the immune system and CNS. Ageing is also associated with increased risks of side-effects caused by some multiple sclerosis therapies. Both somatic and reproductive ageing processes might contribute to development of progressive multiple sclerosis. Understanding the role of ageing in immune and neural cell function in patients with multiple sclerosis might be key to halting non-relapse-related progression. The growing literature on potential therapies that target senescent cells and ageing processes might provide effective strategies for remyelination and neuroprotection.
Short-chain fatty acids (SCFAs), produced during bacterial fermentation, have been shown to be mediators in the microbiota-gut-brain axis. This axis has been proposed to influence psychiatric symptoms seen in attention deficit hyperactivity disorder (ADHD). However, there is no report of plasma SCFA concentrations in ADHD. The aim of this study was to explore the plasma concentrations of SCFAs in children and adults with ADHD and the possible factors that could influence those levels. We collected data on age group, sex, serum vitamin D levels, delivery mode, body mass index, diet, medication and blood samples from 233 ADHD patients and 36 family-related healthy controls. The concentrations of SCFAs and the intermediary metabolite succinic acid, were measured using liquid chromatography-mass spectrometry. Adults with ADHD had lower plasma concentrations of formic, acetic, propionic and succinic acid than their healthy family members. When adjusting for SCFA-influential factors among those with ADHD, children had lower concentrations of formic, propionic and isovaleric acid than adults, and those who had more antibiotic medications during the last 2 years had lower concentrations of formic, propionic and succinic acid. When adjusting for antibiotic medication, we found that among children, those currently on stimulant medication had lower acetic and propionic acid levels, and adults with ADHD had lower formic and propionic acid concentrations than adult healthy family members. In all, our findings show lower-than-normal plasma concentrations of SCFAs in ADHD explained in-part by antibiotic medication, age and stimulant medication. Whether or not this is of clinical significance is yet to be explored.
Carbohydrates serve as important energy sources and structural substances for human body as well as for gut microbes. As evidenced by the advances in immunometabolism, glucose metabolism and adenosine triphosphate (ATP) generation are deeply involved in immune cell activation, proliferation, and signaling transduction as well as trafficking and effector functions, thus contributing to immune response programming and assisting in host adaption to microenvironment changes. Increased glucose uptake, aberrant expression of glucose transporter 1 (e.g., GLU1), and abnormal glycosylation patterns have been identified in autoimmunity and are suggested as partially responsible for the dysregulated immune response and the modification of gut microbiome composition in the autoimmune pathogenesis. The interaction between gut microbiota and host carbohydrate metabolism is complex and bidirectional. Their impact on host immune homeostasis and the development of autoimmune diseases remains to be elucidated. This review summarized the current knowledge on the crosstalk of glucose metabolism and glycosylation in the host with intestinal microbiota and discussed their possible role in the development and progression of autoimmune diseases. Potential therapeutic strategies targeting glucose metabolism and glycosylation in modulating gut ecosystem and treating autoimmune diseases were discussed as well.
Clinical and animal studies have demonstrated beneficial effects of early consumption of dairy lipids and a probiotic, Lactobacillus fermentum (Lf), on infant gut physiology. The objective of this study was to investigate their long-term effects on gut microbiota and host entero-insular axis and metabolism. Piglets were suckled with a milk formula containing only plant lipids (PL), a half-half mixture of plant lipids and dairy lipids (DL), or this mixture supplemented with Lf (DL + Lf). They were weaned on a standard diet and challenged with a high-energy diet until postnatal day 140. DL and DL + Lf modulated gut microbiota composition and metabolism, increasing abundance of several Clostridia genera. Moreover, DL + Lf specifically decreased the faecal content of 2-oxoglutarate and lysine compared to PL and 5-aminovalerate compared to PL and DL. It also increased short-chain fatty acid concentrations like propionate compared to DL. Furthermore, DL + Lf had a beneficial effect on the endocrine function, enhancing caecal GLP-1 and GLP-1 meal-stimulated secretion. Correlations highlighted the consistent relationship between microbiota and gut physiology. Together, our results evidence a beneficial programming effect of DL + Lf in infant formula composition on faecal microbiota and entero-insular axis function.
Significance
Studies using experimental models have indicated that multiple sclerosis (MS)-like disease can be triggered in the gut following interactions of brain autoimmune T lymphocytes with local microbiota. Here we studied the gut microbiota from monozygotic human twin pairs discordant for multiple sclerosis. When we transferred human-derived microbiota into transgenic mice expressing a myelin autoantigen-specific T cell receptor, we found that gut microbiota from multiple sclerosis-affected twins induced CNS-specific autoimmunity at a higher incidence than microbiota from healthy co-twins. Our results offer functional evidence that human microbiome components contribute to CNS-specific autoimmunity.
Motivation: The rapidly expanding microbiomics field is generating increasingly larger datasets, characterizing the microbiota in diverse environments. Although classical numerical ecology methods provide a robust statistical framework for their analysis, software currently available is inadequate for large datasets and some computationally intensive tasks, like rarefaction and associated analysis.
Results: Here we present a software package for rarefaction analysis of large count matrices, as well as estimation and visualization of diversity, richness and evenness. Our software is designed for ease of use, operating at least 7x faster than existing solutions, despite requiring 10x less memory.
Availability and implementation: C ++ and R source code (GPL v.2) as well as binaries are available from https://github.com/hildebra/Rarefaction and from CRAN (https://cran.r-project.org/).
Contact:bork@embl.de, falk.hildebrand@embl.de
Supplementary information: Supplementary data are available at Bioinformatics online
Defects in mitochondrial respiratory chain complex IV (CIV) frequently cause encephalocardiomyopathies. Human CIV assembly involves 14 subunits of dual genetic origin and multiple nucleus‐encoded ancillary factors. Biogenesis of the mitochondrion‐encoded copper/heme‐containing COX1 subunit initiates the CIV assembly process. Here, we show that the intermembrane space twin CX9C protein CMC1 forms an early CIV assembly intermediate with COX1 and two assembly factors, the cardiomyopathy proteins COA3 and COX14. A TALEN‐mediated CMC1 knockout HEK293T cell line displayed normal COX1 synthesis but decreased CIV activity owing to the instability of newly synthetized COX1. We demonstrate that CMC1 stabilizes a COX1‐COA3‐COX14 complex before the incorporation of COX4 and COX5a subunits. Additionally, we show that CMC1 acts independently of CIV assembly factors relevant to COX1 metallation (COX10, COX11, and SURF1) or late stability (MITRAC7). Furthermore, whereas human COX14 and COA3 have been proposed to affect COX1 mRNA translation, our data indicate that CMC1 regulates turnover of newly synthesized COX1 prior to and during COX1 maturation, without affecting the rate of COX1 synthesis.
Genetic predisposition to multiple sclerosis (MS) only explains a fraction of the disease risk; lifestyle and environmental factors are key contributors to the risk of MS. Importantly, these nongenetic factors can influence pathogenetic pathways, and some of them can be modified. Besides established MS-associated risk factors — high latitude, female sex, smoking, low vitamin D levels caused by insufficient sun exposure and/or dietary intake, and Epstein–Barr virus (EBV) infection — strong evidence now supports obesity during adolescence as a factor increasing MS risk. Organic solvents and shift work have also been reported to confer increased risk of the disease, whereas factors such as use of nicotine or alcohol, cytomegalovirus infection and a high coffee consumption are associated with a reduced risk. Certain factors — smoking, EBV infection and obesity — interact with HLA risk genes, pointing at a pathogenetic pathway involving adaptive immunity. All of the described risk factors for MS can influence adaptive and/or innate immunity, which is thought to be the main pathway modulated by MS risk alleles. Unlike genetic risk factors, many environmental and lifestyle factors can be modified, with potential for prevention, particularly for people at the greatest risk, such as relatives of individuals with MS. Here, we review recent data on environmental and lifestyle factors, with a focus on gene–environment interactions.
In recent years, RNA sequencing (RNA-seq) has become a very widely used technology for profiling gene expression. One of the most common aims of RNA-seq profiling is to identify genes or molecular pathways that are differentially expressed (DE) between two or more biological conditions. This article demonstrates a computational workflow for the detection of DE genes and pathways from RNA-seq data by providing a complete analysis of an RNA-seq experiment profiling epithelial cell subsets in the mouse mammary gland. The workflow uses R software packages from the open-source Bioconductor project and covers all steps of the analysis pipeline, including alignment of read sequences, data exploration, differential expression analysis, visualization and pathway analysis. Read alignment and count quantification is conducted using the Rsubread package and the statistical analyses are performed using the edgeR package. The differential expression analysis uses the quasi-likelihood functionality of edgeR.
In recent years, RNA sequencing (RNA-seq) has become a very widely used technology for profiling gene expression. One of the most common aims of RNA-seq profiling is to identify genes or molecular pathways that are differentially expressed (DE) between two or more biological conditions. This article demonstrates a computational workflow for the detection of DE genes and pathways from RNA-seq data by providing a complete analysis of an RNA-seq experiment profiling epithelial cell subsets in the mouse mammary gland. The workflow uses R software packages from the open-source Bioconductor project and covers all steps of the analysis pipeline, including alignment of read sequences, data exploration, differential expression analysis, visualization and pathway analysis. Read alignment and count quantification is conducted using the Rsubread package and the statistical analyses are performed using the edgeR package. The differential expression analysis uses the quasi-likelihood functionality of edgeR.
In comparative high-throughput sequencing assays, a fundamental task is the analysis of count data, such as read counts per gene in RNA-seq, for evidence of systematic changes across experimental conditions. Small replicate numbers, discreteness, large dynamic range and the presence of outliers require a suitable statistical approach. We present DESeq2, a method for differential analysis of count data, using shrinkage estimation for dispersions and fold changes to improve stability and interpretability of estimates. This enables a more quantitative analysis focused on the strength rather than the mere presence of differential expression. The DESeq2 package is available at http://www.bioconductor.org/packages/release/bioc/html/DESeq2.html.
Electronic supplementary material
The online version of this article (doi:10.1186/s13059-014-0550-8) contains supplementary material, which is available to authorized users.
Chronic inflammation due to obesity contributes to the development of metabolic diseases, autoimmune diseases, and cancer. Reciprocal interactions between metabolic systems and immune cells have pivotal roles in the pathogenesis of obesity-associated diseases, although the mechanisms regulating obesity-associated inflammatory diseases are still unclear. In the present study, we performed transcriptional profiling of memory phenotype CD4 T cells in high-fat-fed mice and identified acetyl-CoA carboxylase 1 (ACC1, the gene product of Acaca) as an essential regulator of Th17 cell differentiation in vitro and of the pathogenicity of Th17 cells in vivo. ACC1 modulates the DNA binding of RORγt to target genes in differentiating Th17 cells. In addition, we found a strong correlation between IL-17A-producing CD45RO(+)CD4 T cells and the expression of ACACA in obese subjects. Thus, ACC1 confers the appropriate function of RORγt through fatty acid synthesis and regulates the obesity-related pathology of Th17 cells.
Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
We present primary results from the Sequencing Quality Control (SEQC) project, coordinated by the US Food and Drug Administration. Examining Illumina HiSeq, Life Technologies SOLiD and Roche 454 platforms at multiple laboratory sites using reference RNA samples with built-in controls, we assess RNA sequencing (RNA-seq) performance for junction discovery and differential expression profiling and compare it to microarray and quantitative PCR (qPCR) data using complementary metrics.
At all sequencing depths, we discover unannotated exon-exon junctions, with >80% validated by qPCR. We find that measurements of relative expression are accurate and reproducible across sites and platforms if specific filters are used.
In contrast, RNA-seq and microarrays do not provide accurate absolute measurements, and gene-specific biases are observed
for all examined platforms, including qPCR. Measurement performance depends on the platform and data analysis pipeline,
and variation is large for transcript-level profiling. The complete SEQC data sets, comprising >100 billion reads (10Tb),
provide unique resources for evaluating RNA-seq analyses for clinical and regulatory settings.
Lysine acetylation is a conserved protein post-translational modification that links acetyl-coenzyme A metabolism and cellular signalling. Recent advances in the identification and quantification of lysine acetylation by mass spectrometry have increased our understanding of lysine acetylation, implicating it in many biological processes through the regulation of protein interactions, activity and localization. In addition, proteins are frequently modified by other types of acylations, such as formylation, butyrylation, propionylation, succinylation, malonylation, myristoylation, glutarylation and crotonylation. The intricate link between lysine acylation and cellular metabolism has been clarified by the occurrence of several such metabolite-sensitive acylations and their selective removal by sirtuin deacylases. These emerging findings point to new functions for different lysine acylations and deacylating enzymes and also highlight the mechanisms by which acetylation regulates various cellular processes.
Ribosomal Database Project (RDP; http://rdp.cme.msu.edu/) provides the research community with aligned and annotated rRNA gene sequence data, along with tools to allow researchers
to analyze their own rRNA gene sequences in the RDP framework. RDP data and tools are utilized in fields as diverse as human
health, microbial ecology, environmental microbiology, nucleic acid chemistry, taxonomy and phylogenetics. In addition to
aligned and annotated collections of bacterial and archaeal small subunit rRNA genes, RDP now includes a collection of fungal
large subunit rRNA genes. RDP tools, including Classifier and Aligner, have been updated to work with this new fungal collection.
The use of high-throughput sequencing to characterize environmental microbial populations has exploded in the past several
years, and as sequence technologies have improved, the sizes of environmental datasets have increased. With release 11, RDP
is providing an expanded set of tools to facilitate analysis of high-throughput data, including both single-stranded and paired-end
reads. In addition, most tools are now available as open source packages for download and local use by researchers with high-volume
needs or who would like to develop custom analysis pipelines.
Intestinal microbes provide multicellular hosts with nutrients and confer resistance to infection. The delicate balance between pro- and anti-inflammatory mechanisms, essential for gut immune homeostasis, is affected by the composition of the commensal microbial community. Regulatory T cells (Treg cells) expressing transcription factor Foxp3 have a key role in limiting inflammatory responses in the intestine. Although specific members of the commensal microbial community have been found to potentiate the generation of anti-inflammatory Treg or pro-inflammatory T helper 17 (TH17) cells, the molecular cues driving this process remain elusive. Considering the vital metabolic function afforded by commensal microorganisms, we reasoned that their metabolic by-products are sensed by cells of the immune system and affect the balance between pro- and anti-inflammatory cells. We tested this hypothesis by exploring the effect of microbial metabolites on the generation of anti-inflammatory Treg cells. We found that in mice a short-chain fatty acid (SCFA), butyrate, produced by commensal microorganisms during starch fermentation, facilitated extrathymic generation of Treg cells. A boost in Treg-cell numbers after provision of butyrate was due to potentiation of extrathymic differentiation of Treg cells, as the observed phenomenon was dependent on intronic enhancer CNS1 (conserved non-coding sequence 1), essential for extrathymic but dispensable for thymic Treg-cell differentiation. In addition to butyrate, de novo Treg-cell generation in the periphery was potentiated by propionate, another SCFA of microbial origin capable of histone deacetylase (HDAC) inhibition, but not acetate, which lacks this HDAC-inhibitory activity. Our results suggest that bacterial metabolites mediate communication between the commensal microbiota and the immune system, affecting the balance between pro- and anti-inflammatory mechanisms.
Gut commensal microbes shape the mucosal immune system by regulating the differentiation and expansion of several types of T cell. Clostridia, a dominant class of commensal microbe, can induce colonic regulatory T (Treg) cells, which have a central role in the suppression of inflammatory and allergic responses. However, the molecular mechanisms by which commensal microbes induce colonic Treg cells have been unclear. Here we show that a large bowel microbial fermentation product, butyrate, induces the differentiation of colonic Treg cells in mice. A comparative NMR-based metabolome analysis suggests that the luminal concentrations of short-chain fatty acids positively correlates with the number of Treg cells in the colon. Among short-chain fatty acids, butyrate induced the differentiation of Treg cells in vitro and in vivo, and ameliorated the development of colitis induced by adoptive transfer of CD4(+) CD45RB(hi) T cells in Rag1(-/-) mice. Treatment of naive T cells under the Treg-cell-polarizing conditions with butyrate enhanced histone H3 acetylation in the promoter and conserved non-coding sequence regions of the Foxp3 locus, suggesting a possible mechanism for how microbial-derived butyrate regulates the differentiation of Treg cells. Our findings provide new insight into the mechanisms by which host-microbe interactions establish immunological homeostasis in the gut.
We introduce a methodology to assess differential abundance in sparse high-throughput microbial marker-gene survey data. Our approach, implemented in the metagenomeSeq Bioconductor package, relies on a novel normalization technique and a statistical model that accounts for undersampling-a common feature of large-scale marker-gene studies. Using simulated data and several published microbiota data sets, we show that metagenomeSeq outperforms the tools currently used in this field.
Regulatory T cells (Tregs) that express the transcription factor Foxp3 are critical for regulating intestinal inflammation. Candidate microbe approaches
have identified bacterial species and strain-specific molecules that can affect intestinal immune responses, including species
that modulate Treg responses. Because neither all humans nor mice harbor the same bacterial strains, we posited that more prevalent factors
exist that regulate the number and function of colonic Tregs. We determined that short-chain fatty acids, gut microbiota–derived bacterial fermentation products, regulate the size and
function of the colonic Treg pool and protect against colitis in a Ffar2-dependent manner in mice. Our study reveals that a class of abundant microbial metabolites underlies adaptive immune microbiota
coadaptation and promotes colonic homeostasis and health.
In recent years, multiple sclerosis (MS) research has progressed on several fronts, prompting numerous clinical trials, primarily for immunotherapeutics. Although several new therapies have been disappointing and some were revealed to have devastating side effects, others have shown benefits and all have generated valuable knowledge about the progression of MS, the key contributors to pathogenesis, and on natural surveillance mechanisms for brain infections. This makes now a useful time to take stock of recent advances in developing MS treatments and consider new approaches for adding information where the gaps are greatest - mainly in understanding the degenerative processes responsible for most of the long-term disability. Here, we summarize currently accepted therapeutic principles and the drugs in late stages of development, as well as spotlighting potential novel openings for future research.
SILVA (from Latin silva, forest, http://www.arb-silva.de) is a comprehensive web resource for up to date, quality-controlled databases of aligned ribosomal RNA (rRNA) gene sequences
from the Bacteria, Archaea and Eukaryota domains and supplementary online services. The referred database release 111 (July 2012) contains 3 194 778 small subunit
and 288 717 large subunit rRNA gene sequences. Since the initial description of the project, substantial new features have
been introduced, including advanced quality control procedures, an improved rRNA gene aligner, online tools for probe and
primer evaluation and optimized browsing, searching and downloading on the website. Furthermore, the extensively curated SILVA
taxonomy and the new non-redundant SILVA datasets provide an ideal reference for high-throughput classification of data from
next-generation sequencing approaches.
Motivation:
Accurate alignment of high-throughput RNA-seq data is a challenging and yet unsolved problem because of the non-contiguous transcript structure, relatively short read lengths and constantly increasing throughput of the sequencing technologies. Currently available RNA-seq aligners suffer from high mapping error rates, low mapping speed, read length limitation and mapping biases.
Results:
To align our large (>80 billon reads) ENCODE Transcriptome RNA-seq dataset, we developed the Spliced Transcripts Alignment to a Reference (STAR) software based on a previously undescribed RNA-seq alignment algorithm that uses sequential maximum mappable seed search in uncompressed suffix arrays followed by seed clustering and stitching procedure. STAR outperforms other aligners by a factor of >50 in mapping speed, aligning to the human genome 550 million 2 × 76 bp paired-end reads per hour on a modest 12-core server, while at the same time improving alignment sensitivity and precision. In addition to unbiased de novo detection of canonical junctions, STAR can discover non-canonical splices and chimeric (fusion) transcripts, and is also capable of mapping full-length RNA sequences. Using Roche 454 sequencing of reverse transcription polymerase chain reaction amplicons, we experimentally validated 1960 novel intergenic splice junctions with an 80-90% success rate, corroborating the high precision of the STAR mapping strategy.
Availability and implementation:
STAR is implemented as a standalone C++ code. STAR is free open source software distributed under GPLv3 license and can be downloaded from http://code.google.com/p/rna-star/.
16S ribosomal RNA gene (rDNA) amplicon analysis remains the standard approach for the cultivation-independent investigation
of microbial diversity. The accuracy of these analyses depends strongly on the choice of primers. The overall coverage and
phylum spectrum of 175 primers and 512 primer pairs were evaluated in silico with respect to the SILVA 16S/18S rDNA non-redundant reference dataset (SSURef 108 NR). Based on this evaluation a selection
of ‘best available’ primer pairs for Bacteria and Archaea for three amplicon size classes (100–400, 400–1000, ≥1000 bp) is provided. The most promising bacterial primer pair (S-D-Bact-0341-b-S-17/S-D-Bact-0785-a-A-21),
with an amplicon size of 464 bp, was experimentally evaluated by comparing the taxonomic distribution of the 16S rDNA amplicons
with 16S rDNA fragments from directly sequenced metagenomes. The results of this study may be used as a guideline for selecting
primer pairs with the best overall coverage and phylum spectrum for specific applications, therefore reducing the bias in
PCR-based microbial diversity studies.
The heterogeneity in the healthy human immune system, and the immunological changes that portend various diseases, have been only partially described. Their comprehensive elucidation has been termed the 'Human Immunology Project'. The accurate measurement of variations in the human immune system requires precise and standardized assays to distinguish true biological changes from technical artefacts. Thus, to be successful, the Human Immunology Project will require standardized assays for immunophenotyping humans in health and disease. A major tool in this effort is flow cytometry, which remains highly variable with regard to sample handling, reagents, instrument setup and data analysis. In this Review, we outline the current state of standardization of flow cytometry assays and summarize the steps that are required to enable the Human Immunology Project.
A flexible statistical framework is developed for the analysis of read counts from RNA-Seq gene expression studies. It provides the ability to analyse complex experiments involving multiple treatment conditions and blocking variables while still taking full account of biological variation. Biological variation between RNA samples is estimated separately from the technical variation associated with sequencing technologies. Novel empirical Bayes methods allow each gene to have its own specific variability, even when there are relatively few biological replicates from which to estimate such variability. The pipeline is implemented in the edgeR package of the Bioconductor project. A case study analysis of carcinoma data demonstrates the ability of generalized linear model methods (GLMs) to detect differential expression in a paired design, and even to detect tumour-specific expression changes. The case study demonstrates the need to allow for gene-specific variability, rather than assuming a common dispersion across genes or a fixed relationship between abundance and variability. Genewise dispersions de-prioritize genes with inconsistent results and allow the main analysis to focus on changes that are consistent between biological replicates. Parallel computational approaches are developed to make non-linear model fitting faster and more reliable, making the application of GLMs to genomic data more convenient and practical. Simulations demonstrate the ability of adjusted profile likelihood estimators to return accurate estimators of biological variability in complex situations. When variation is gene-specific, empirical Bayes estimators provide an advantageous compromise between the extremes of assuming common dispersion or separate genewise dispersion. The methods developed here can also be applied to count data arising from DNA-Seq applications, including ChIP-Seq for epigenetic marks and DNA methylation analyses.
Chimeric DNA sequences often form during polymerase chain reaction amplification, especially when sequencing single regions (e.g. 16S rRNA or fungal Internal Transcribed Spacer) to assess diversity or compare populations. Undetected chimeras may be misinterpreted as novel species, causing inflated estimates of diversity and spurious inferences of differences between populations. Detection and removal of chimeras is therefore of critical importance in such experiments.
We describe UCHIME, a new program that detects chimeric sequences with two or more segments. UCHIME either uses a database of chimera-free sequences or detects chimeras de novo by exploiting abundance data. UCHIME has better sensitivity than ChimeraSlayer (previously the most sensitive database method), especially with short, noisy sequences. In testing on artificial bacterial communities with known composition, UCHIME de novo sensitivity is shown to be comparable to Perseus. UCHIME is >100× faster than Perseus and >1000× faster than ChimeraSlayer.
robert@drive5.com
Source, binaries and data: http://drive5.com/uchime.
Supplementary data are available at Bioinformatics online.
Odoribacter splanchnicus (Werner et al. 1975) Hardham et al. 2008 is the type species of the genus Odoribacter, which belongs to the family Porphyromonadaceae in the order 'Bacteroidales'. The species is of interest because members of the Odoribacter form an isolated cluster within the Porphyromonadaceae. This is the first completed genome sequence of a member of the genus Odoribacter and the fourth sequence from the family Porphyromonadaceae. The 4,392,288 bp long genome with its 3,672 protein-coding and 74 RNA genes and is a part of the Genomic Encyclopedia of Bacteria and Archaea project.
It is expected that emerging digital gene expression (DGE) technologies will overtake microarray technologies in the near future for many functional genomics applications. One of the fundamental data analysis tasks, especially for gene expression studies, involves determining whether there is evidence that counts for a transcript or exon are significantly different across experimental conditions. edgeR is a Bioconductor software package for examining differential expression of replicated count data. An overdispersed Poisson model is used to account for both biological and technical variability. Empirical Bayes methods are used to moderate the degree of overdispersion across transcripts, improving the reliability of inference. The methodology can be used even with the most minimal levels of replication, provided at least one phenotype or experimental condition is replicated. The software may have other applications beyond sequencing data, such as proteome peptide count data.
Availability: The package is freely available under the LGPL licence from the Bioconductor web site (http://bioconductor.org).
Contact: mrobinson@wehi.edu.au
mothur aims to be a comprehensive software package that allows users to use a single piece of software to analyze community
sequence data. It builds upon previous tools to provide a flexible and powerful software package for analyzing sequencing
data. As a case study, we used mothur to trim, screen, and align sequences; calculate distances; assign sequences to operational
taxonomic units; and describe the α and β diversity of eight marine samples previously characterized by pyrosequencing of
16S rRNA gene fragments. This analysis of more than 222,000 sequences was completed in less than 2 h with a laptop computer.
Immunometabolism is important to T cell dysfunction in chronic infections. A recent publication in The Journal of Clinical Investigation (2018;128:5083–5094) [1] shows reduced mitochondrial fitness in regulatory CD4⁺ T cells (Tregs) of patients with HIV and failed immune restoration on antiretroviral therapy (ART). This defect can be reversed by IL-15, revealing a new immunotherapy target for regulatory T cell restoration.
Bacterial involvement in autoimmunity
The composition of the commensal microbiota is known to influence autoimmune disease development and persistence. Manfredo Vieira et al. identified a gut microbe, Enterococcus gallinarum , that translocates from the gut into the organs of mice with a genetic predisposition to lupus-like autoimmunity (see the Perspective by Citi). Molecular signatures of gut barrier disintegration and pathogenic T helper cells were evident in the gut, liver, and lymphoid organs during colonization with the pathobiont. The ensuing pathology could be reversed by vancomycin treatment and by vaccination against E. gallinarum . The same bug was also found in liver biopsies of autoimmune patients, but not in healthy controls.
Science , this issue p. 1156 ; see also p. 1097
The gut microbiota contributes to the regulation of glucose metabolism in pregnancy. Abundance of the genus Collinsella is positively correlated with circulating insulin; however, it is unclear what determines Collinsella abundance. This study aims to validate the correlation between Collinsella and insulin and to elucidate if macronutrient intake alters Collinsella abundance and gut microbiota composition.
Gut microbiota profiles were assessed by 16S rRNA sequencing in 57 overweight and 73 obese pregnant women from the SPRING (Study of PRobiotics IN Gestational diabetes) trial at 16 weeks gestation and correlated with metabolic hormone levels and macronutrient intake. Gut microbiota composition in the top and bottom 10% of dietary fiber intake was evaluated through network analysis.
Collinsella abundance correlated positively with circulating insulin (rho = 0.30, p = 0.0006), independent of maternal BMI, but negatively with dietary fiber intake (rho = -0.20, p = 0.025) in this cohort. Low dietary fiber intake was associated with a gut microbiota favoring lactate fermentation while high fiber intake promotes short-chain fatty acid-producing bacteria.
Low dietary fiber may enable overgrowth of Collinsella and alter the overall fermentation pattern in gut microbiota. This suggests that dietary choices during pregnancy can modify the nutritional ecology of the gut microbiota, with potential deleterious effects on the metabolic and inflammatory health of the host.
Trial registration: ANZCTR 12611001208998, registered 23/11/2011