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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.
... Patients with MS show significant alterations in metabolites that are closely associated with the gut microbiota [170]. Research has revealed that these changes in metabolites, particularly those involved in metabolic and immune pathways, may influence the pathophysiology of the disease ( [171][172][173][174][175][176][177][178]). ...
... This reduction correlates with a decreased abundance of SCFA-producing bacteria in their gut microbiota [171]. Notably, lower serum levels of propionate have been documented in MS patients [14], and treatments with propionate have shown promise in inhibiting the development of EAE, by promoting the expansion of Tregs [172]. SCFAs have been found to regulate ferroptosis; therefore, changes in these metabolites may indirectly regulate the development of MS by affecting the ferroptosis pathway. ...
... After two weeks of PA intake, there is a significant and sustained increase in functional Treg cells, and a significant decrease in Th1 and Th17 cells. After three years of PA treatment, the annual relapse rate decreases, disability stabilizes, and brain atrophy is reduced [172]. Oral butyrate significantly inhibits lysolecithin-induced demyelination and enhances myelin regeneration, promoting oligodendrocyte differentiation [197]. ...
Multiple sclerosis (MS) is a chronic autoimmune disorder marked by neuroinflammation, demyelination, and neuronal damage. Recent advancements highlight a novel interaction between iron-dependent cell death, known as ferroptosis, and gut microbiota, which may significantly influences the pathophysiology of MS. Ferroptosis, driven by lipid peroxidation and tightly linked to iron metabolism, is a pivotal contributor to the oxidative stress observed in MS. Concurrently, the gut microbiota, known to affect systemic immunity and neurological health, emerges as an important regulator of iron homeostasis and inflammatory responses, thereby influencing ferroptotic pathways. This review investigates how gut microbiota dysbiosis and ferroptosis impact MS, emphasizing their potential as therapeutic targets. Through an integrated examination of mechanistic pathways and clinical evidence, we discuss how targeting these interactions could lead to novel interventions that not only modulate disease progression but also offer personalized treatment strategies based on gut microbiota profiling. This synthesis aims at deepening insights into the microbial contributions to ferroptosis and their implications in MS, setting the stage for future research and therapeutic exploration.
... They regulate various physiological functions, including neuronal growth, energy homeostasis and immunity. Among these SCFAs, propionic acid has gained particular attention due to its anti-inflammatory properties [16][17][18]. It decreases the activity of pro-inflammatory T-helper cell responses (such as Th1 and Th17) while promoting regulatory T-cell activity, and thereby contributing to a balanced immune response [19]. ...
... Several reports have found low levels of propionate in the feces and plasma of pwMS patients independently of their disease course and ethnic origin [17,[32][33][34][35]. ...
... Propionate has multifocal effects on MS, including effects on the gut microbiome, immune system and central nervous system. The lower propionate levels in serum and feces of individuals with MS was more accentuated after a first relapse, suggesting that low propionate levels can be associated with worsening disease activity [17]. On the other hand, pwMS with higher propionate show fewer annual relapses, stabilization of disability, and reduced brain atrophy [17]. ...
Accumulating evidence suggests that multiple sclerosis (MS) is an environmentally influenced disorder with contributions from life-time exposure to factors including Epstein–Barr virus infection or shifts in microbiome, diet and lifestyle. One suggested factor is a deficiency in propionic acid, a short-chain fatty acid produced by gut bacteria that may contribute to the disease pathology both in animal models and in human cases of MS. Propionate appears to exert beneficial effects on the immune, peripheral and central nervous systems of people with MS (pwMS), showing immunoregulatory, neuroprotective and neurogenerative effects. These functions are crucial, given that MS is characterized by immune-mediated damage of myelin in the central nervous system. Accordingly, propionate supplementation or a modulated increase in its levels through the microbiome and diet may help counteract the pro-inflammatory state in MS by directly regulating immune system and/or by decreasing permeability of gut barrier and blood–brain barrier. This could potentially improve outcomes when used with immune-modulating therapy. However, while its broad effects are promising, further large clinical trials are necessary to evaluate its efficacy and safety in pwMS and clarify its role as a complementary therapeutic strategy. This review provides a comprehensive analysis of the evidence, challenges and limitations concerning propionic acid supplementation in MS.
... Functionally, the gut microbiota can impact both the innate and adaptive immune system in the CNS and/or periphery through direct interactions with host immune cell subsets to alter their development, maintenance, and function or through production of immunomodulatory metabolites including amino acid derivates, bile acids, and short-chain fatty acids (SCFAs). [13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32] SCFAs enter host systemic circulation by passively diffusing across cellular membranes and the BBB to exert far reaching effects on host physiology. 33 Functionally, SCFAs are considered broadly beneficial, aiding in maintenance of barrier integrity and exerting an anti-inflammatory effect by influencing regulatory T cell differentiation and inhibiting inflammatory function of immune cell subsets in the periphery and CNS and epithelial cells of the BBB. ...
... 53 Moreover, metabolomic evidence from pwMS suggests a reduction in SCFAs, including acetate, propionate, butyrate, isobutyrate, valerate, and isovalerate in serum, plasma, and/or fecal samples. [13][14][15][16][17]21,[54][55][56] Reduced SCFA levels were also found to correlate with increased intestinal permeability, inflammatory immunological responses, and/or disease worsening in MS. 15,17,54 Moreover, acetate, propionate, butyrate, mixtures of SCFAs, and high fiber diets, all have been shown to diminish pathogenesis of experimental autoimmune encephalomyelitis (EAE), the primary autoimmune model of MS, and exert an anti-inflammatory role. 13,16,[18][19][20]57 However, understanding the precise underlying drivers of reduced SCFA-producing gut microbiota in pwMS, including relevant interactions between constituents of the microbiota, their metabolites, and ultimately the consequences to the host, continues to be challenging. ...
... 119,120 Known SCFA-producing microbiota including Butyricimonas, Bacteroides, Lachnospiraceae, and Eubacterium, are all reduced in the MS gut microbiome. [14][15][16]52,121 Notably, our study is the first to provide a link between baseline composition of the gut microbiota and response to dietary fiber in CNS autoimmunity. In the context of excess fiber provision, while a near complete abrogation of disease pathogenesis was observed in both the B6 and B6 + L. reuteri microbiomes, moderate disease severity was still observed in the highly divergent PWD microbiome (Figure 7b-g), suggesting that: 1) suppression of EAE by high fiber is not absolute, and 2) that modulation of EAE by gut microbiota can occur independent of this major metabolic pathway. ...
Background
Short-chain fatty acids (SCFAs), produced by the gut microbiota, are thought to exert an anti-inflammatory effect on the host immune system. The levels of SCFAs and abundance of the microbiota that produce them are depleted in multiple sclerosis (MS), an autoimmune disease of the central nervous system (CNS). The mechanisms leading to this depletion are unknown. Using experimental autoimmune encephalomyelitis (EAE) as a model for MS, we have previously shown that gut microbiomes divergent in their abundance of specific commensal Lactobacillaceae, Limosilactobacillus reuteri (L. reuteri) and Ligilactobacillus murinus (L. murinus), differentially impact CNS autoimmunity. To determine the underlying mechanisms, we employed colonization by L. reuteri and L. murinus in disparate gut microbiome configurations in vivo and in vitro, profiling their impact on gut microbiome composition and metabolism, coupled with modulation of dietary fiber in the EAE model.
Results
We show that stable colonization by L. reuteri, but not L. murinus, exacerbates EAE, in conjunction with a significant remodeling of gut microbiome composition, depleting SCFA-producing microbiota, including Lachnospiraceae, Prevotellaceae, and Bifidobacterium, with a net decrease in bacterial metabolic pathways involved in butyrate production. In a minimal microbiome culture model in vitro, L. reuteri directly inhibited SCFA-producer growth and depleted butyrate. Genomic analysis of L. reuteri isolates revealed an enrichment in bacteriocins with known antimicrobial activity against SCFA-producing microbiota. Functionally, provision of excess dietary fiber, as the prebiotic substrate for SCFA production, elevated SCFA levels and abrogated the ability of L. reuteri to exacerbate EAE.
Conclustions
Our data highlight a potential mechanism for reduced SCFAs and their producers in MS through depletion by other members of the gut microbiome, demonstrating that interactions between microbiota can impact CNS autoimmunity in a diet-dependent manner. These data suggest that therapeutic restoration of SCFA levels in MS may require not only dietary intervention, but also modulation of the gut microbiome.
... 17 Only a few articles have been published measuring AA, BA, and/or PA in the serum or plasma of MS patients compared with those of HC. Our results are in accordance to some previous studies, [22][23][24] but not with others. 25,26 These discrepancies could be due to the low number of samples analyzed and the heterogeneous cohorts of MS patients recruited in these studies, with a 3 when they found that relative abundances of genera in the fecal microbiota were significantly altered between untreated and treated MS patients. ...
... Duscha et al. supplemented a small cohort of MS patients with PA during 14 days; authors detected an increase in both the number and functionality of T reg cells, a decrease in the relapse rate and a stabilization of disability. 23 Another study explored, in obese and non-obese MS patients, PA concentrations as well as peripheral Th17 and Treg frequencies before and after 90 days of daily PA intake; they concluded that the administration of PA helped to restore the imbalance of T reg/Th17 cells. 35 A 60-day PA supplementation study was performed in patients with end-stage renal disease, who suffer from a progressively increasing low-grade systemic inflammation; results show a significant reduction of inflammatory marker C-reactive protein under PA supplementation, and an expansion of circulating Tregs. ...
Objective
An alteration in the composition of the intestinal microbiota has been observed in patients with multiple sclerosis (pwMS) with respect to healthy controls (HC). Microorganism‐derived metabolites such as short‐chain fatty acids (SCFA) have been suggested to play a role in the disease. Thus, to analyze the association of SCFA with clinical and radiological parameters of the disease and with those related to the inflammatory response of the immune system.
Methods
Multicentric observational retrospective cross‐sectional study. In addition 161 pwMS and 130 HC were included. The following plasma SCFA were analyzed using liquid chromatography coupled to mass spectrometry: acetate (AA), propionate (PA) and butyrate (BA). Blood cell subpopulations and cytokine expression were analyzed by flow cytometry.
Results
Plasma PA and PA/AA ratio was lower in pwMS than in HC (P = 0.0001, and P = 0.00005, respectively). PA/AA and BA/AA ratios were lower in pwMS with higher disability (P = 0.001, and P = 0.001, respectively). T2 lesion load inversely correlated with PA/AA (r = −0.353; P = 0.002) and BA/AA (r = −0.322; P = 0.005) ratios. Plasma PA/AA and/or BA/AA ratios negatively correlated with the following pro‐inflammatory cytokines producing cells: GM‐CSF+CD4+T, GM‐CSF+CD8+T, TNF‐alpha+CD4+T, TNF‐alpha+CD8+T, IFN‐gamma+CD4+T, IFN‐gamma+CD8+T, and TNF‐alpha+B cells.
Interpretation
In MS, plasma PA/AA and BA/AA ratios are unbalanced, promoting an environment that could be boosting the mechanisms underlying the pathogenesis of the disease. Since we have found statistical significant associations with the EDSS and the number of T2 lesions, but not with the number of relapses or gadolinium enhancing lesions, PA/AA and BA/AA ratios could be more associated with those mechanisms of the disease related to the neurodegenerative processes than those related with the activity of the disease.
... We noted that in both PD and AD, acetate, butyrate, and propanoate levels decreased, alongside SCFA-producing bacteria such as Bacteroidetes, Lachnospiraceae, Faecalibacterium, and Veillonella. This reduction in SCFAs correlates with an increase in opportunistic pathogens like Escherichia in PD patients [114][115][116]. Acetate is known to increase the activity of T-reg cells while mitigating Th17 inflammation [115]. ...
... This reduction in SCFAs correlates with an increase in opportunistic pathogens like Escherichia in PD patients [114][115][116]. Acetate is known to increase the activity of T-reg cells while mitigating Th17 inflammation [115]. However, in SCFA-deficient patients, T-reg cell activity is reduced and Th17 inflammation is elevated. ...
Neurodegenerative diseases (NDs), including Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic
lateral sclerosis (ALS), and multiple sclerosis (MS), arise from complex interactions between genetic factors,
environmental exposures, and aging. Additionally, gut dysbiosis has been linked to systemic inflammation and
neurodegeneration. Advances in microbiome and metabolome profiling techniques have provided deeper insights
into how alterations in gut microbiota and dietary patterns affect metabolic pathways and contribute to
the progression of NDs. This review explores the profiles of gut microbiome and metabolome derived biomarkers
and their roles in NDs. Across phyla, families, and genera, we identified 55 microbial alterations in PD, 24 in AD,
4 in ALS, and 17 in MS. Some notable results include an increase in Akkermansia in PD, AD, and MS and a
decrease in short-chain fatty acids (SCFAs) in PD and AD. We examined the effects of probiotics, prebiotics, fecal
microbiota transplants (FMT), sleep, exercise, and diet on the microbiota, all of which contributed to delayed
onset and alleviation of symptoms. Further, artificial intelligence (AI) and machine learning (ML) algorithms
applied to omics data have been crucial in identifying novel therapeutic targets, diagnosing and predicting
prognosis, and enabling personalized medicine using microbiota-modulating therapies in NDs patients.
... We noted that in both PD and AD, acetate, butyrate, and propanoate levels decreased, alongside SCFA-producing bacteria such as Bacteroidetes, Lachnospiraceae, Faecalibacterium, and Veillonella. This reduction in SCFAs correlates with an increase in opportunistic pathogens like Escherichia in PD patients [114][115][116]. Acetate is known to increase the activity of T-reg cells while mitigating Th17 inflammation [115]. ...
... This reduction in SCFAs correlates with an increase in opportunistic pathogens like Escherichia in PD patients [114][115][116]. Acetate is known to increase the activity of T-reg cells while mitigating Th17 inflammation [115]. However, in SCFA-deficient patients, T-reg cell activity is reduced and Th17 inflammation is elevated. ...
Neurodegenerative diseases (NDs), including Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS), arise from complex interactions between genetic factors, environmental exposures, and aging. Additionally, gut dysbiosis has been linked to systemic inflammation and neurodegeneration. Advances in microbiome and metabolome profiling techniques have provided deeper in sights into how alterations in gut microbiota and dietary patterns affect metabolic pathways and contribute to the progression of NDs. This review explores the profiles of gut microbiome and metabolome derived biomarkers and their roles in NDs. Across phyla, families, and genera, we identified 55 microbial alterations in PD, 24 in AD, 4 in ALS, and 17 in MS. Some notable results include an increase in Akkermansia in PD, AD, and MS and a decrease in short-chain fatty acids (SCFAs) in PD and AD. We examined the effects of probiotics, prebiotics, fecal microbiota transplants (FMT), sleep, exercise, and diet on the microbiota, all of which contributed to delayed onset and alleviation of symptoms. Further, artificial intelligence (AI) and machine learning (ML) algorithms applied to omics data have been crucial in identifying novel therapeutic targets, diagnosing and predicting prognosis, and enabling personalized medicine using microbiota-modulating therapies in NDs patients.
... 5 Neuroprotective properties of PA on the peripheral nervous system have been observed. 6 Beneficial effects have also been observed in in vivo studies and case studies of acute motor and sensory axonal neuropathy (AMSAN), 7 multiple sclerosis, 4,8 and other autoimmune diseases 9 through immunomodulatory effects as well as in degenerative processes (such as Parkinson's disease) 10 and vascular calcification. 11 Although numerous studies have been and are being conducted on PA supplementation, there are no studies on PA absorption and the effect on PA-serum levels after oral administration. ...
... For the respective cohorts at the different time points, both analyses showed comparable PA serum concentrations in the range of 1.3 and 4.5 µmol/L, consistent with reported physiological values (Figure 1).8,14,15 Moreover, a significant increase in the PA serum level (Baseline to T1) was observed with both approaches 1 h after oral intake (A: p = 0.0208; B: p = 0.0001), returning to fasting baseline levels 2 h after supplementation. ...
Background
Short-chain fatty acids (SCFAs), including propionic acid (PA), are key in immunological research. Supplementing PA has shown benefits for autoimmune diseases. A comprehensive understanding of the PA pharmacokinetics is essential for the optimal design and execution of studies utilizing orally administered PA.
Objective
We propose two methods of measuring PA in serum, carried out by different laboratories.
Design
Blood samples from 20 volunteers were collected hourly following PA supplementation.
Methods
Serum propionate quantification was performed with two independent mass spectrometry-based (MS) analyses, including liquid-chromatography (LC)-MS and direct-infusion (DI)-MS.
Results
PA levels increased within 1 h of ingestion of 500 mg PA. Serum concentrations ranged from 1.3 to 4.5 µmol/L, rising significantly after 1 h (p < 0.05). Serum levels returned to baseline within 2 h. No significant differences were found regarding sex or diet.
Conclusion
The shown pharmacokinetics can be used in future PA research.
... We noted that in both PD and AD, acetate, butyrate, and propanoate levels decreased, alongside SCFA-producing bacteria such as Bacteroidetes, Lachnospiraceae, Faecalibacterium, and Veillonella. This reduction in SCFAs correlates with an increase in opportunistic pathogens like Escherichia in PD patients [114][115][116]. Acetate is known to increase the activity of T-reg cells while mitigating Th17 inflammation [115]. ...
... This reduction in SCFAs correlates with an increase in opportunistic pathogens like Escherichia in PD patients [114][115][116]. Acetate is known to increase the activity of T-reg cells while mitigating Th17 inflammation [115]. However, in SCFA-deficient patients, T-reg cell activity is reduced and Th17 inflammation is elevated. ...
... This represents an area of interest for future research, as demonstrated by preliminary evidence in other neuroimmunological disorders. Short-chain fatty acids supplementation in multiple sclerosis patients has been proven effective in reducing annual relapse rate, disability progression, and brain atrophy (101,102). In the mouse model, FMT from healthy donors was able to improve MG and experimental autoimmune encephalitis symptoms (103,104). ...
Cancer immunotherapy with immune checkpoint inhibitors (ICIs) has revolutionized oncology, significantly improving survival across multiple cancer types. ICIs, such as anti-PD-1 (e.g. nivolumab, pembrolizumab), anti-PD-L1 (e.g. atezolizumab, avelumab), and anti-CTLA-4 (e.g. ipilimumab), enhance T cell-mediated anti-tumor responses but can also trigger immune-related adverse events (irAEs). Neurological irAEs (n-irAEs), affecting 1-3% of patients, predominantly involve the peripheral nervous system; less commonly, n-irAEs can present as central nervous system disorders. Although irAEs suggest a possible correlation with treatment efficacy, their mechanisms remain unclear, with hypotheses ranging from antigen mimicry to cytokine dysregulation and microbiome alterations. Identifying patients at risk for n-irAEs and predicting their outcome through biomarkers would be highly desirable. For example, patients with high-risk onconeural antibodies (such as anti-Hu or Ma2), and elevated neurofilament light chain (NfL) levels often respond poorly to irAE treatment. However, interpreting neuronal antibody tests in the diagnosis of n-irAEs requires caution: positive results must align with the clinical context, as some cancer patients (e.g., SCLC) may have asymptomatic low antibody levels, and false positive results are common without tissue-based confirmation. Also, the use of biomarkers (e.g. IL-6) may lead to more targeted treatments of irAEs, minimizing adverse effects without compromising the anti-tumor efficacy of ICIs. This review provides a comprehensive overview of the latest findings on n-irAEs associated with ICIs, with a focus on their prediction, prevention, as well as precision treatment using autoantibodies, cytokines, and microbiota. The most interesting data concern neuronal antibodies, which we explore in their pathogenic roles and as biomarkers of neurotoxicity. Most of the available data on cytokines, both regarding their role as diagnostic and prognostic biomarkers and their role in supporting therapeutic decisions for toxicities, refer to non-neurological toxicities. However, in our review, we mention the potential role of CXCL10 and CXCL13 as biomarkers of n-irAEs and describe the current evidence, as well as the need for further studies, on the use of cytokines in guiding selection of second-line therapies for n-irAEs. Finally, no specific microbiome-related microbial signature has been proven to be linked to n-irAEs specifically, leading to the need of more future research on the topic.
... Propionic acid is involved in the immunomodulation of various diseases. Propionic acid regulates Treg/Th17 balance by mediating IL-10 to alleviate multiple sclerosis [65]. Propionate may alleviate vascular calcification by improving intestinal barrier function and weakening the inflammatory response through gut microbiota remodeling [66]. ...
Glycyrrhiza uralensis Fisch. is a medicinal herb that can be added to food to provide therapeutic effects and reduce the burden of medications. Herein, the immunomodulatory effects of Glycyrrhiza polysaccharides (GPs) were verified and illustrated by intervening immunocompromised rats treated with different doses of GPs, which were reflected for adjusting the composition and structure of the intestinal microbiota and altering the metabolic profile. The immunomodulatory effects of GPs were exerted by regulating the intestinal microenvironment. In particular, GPs could promote the growth of probiotic bacteria Allobaculum, norank__o_Clostridia_UCG-014, Dubosiella, and g__norank_o___RF39 and curb the growth of harmful bacteria Enterococcus. The results showed that GPs had a prebiotic effect, which contributed to improving the intestinal environment and maintaining intestinal health. In addition, the content of beneficial differential metabolites was up-regulated, especially short-chain fatty acids, with alanine, aspartate, and glutamate metabolism; arginine biosynthesis; glyoxylate and dicarboxylate metabolism being the most enriched pathways. These metabolic pathways imply the metabolic process of GPs, and the metabolic pathways and differential effector metabolites of it are focused. Overall, the purpose of this article lies in providing support for the application of GPs for regulating immune function.
... The role of propionic acid in the metabolic phenotype has been debated. It is related to overweight, obesity and a higher risk of type 2 diabetes [72,[85][86][87][88]. Conversely, propionic acid can attenuate atherosclerosis [89], multiple sclerosis disease [90], autism [91], hemodialysis [92], nonalcoholic steatohepatitis and improves cerebrovascular functions [93]. These indicated that propionic acid exhibited complex and diverse functions depending on the disorder, and its negative relationship with urate warrants further research. ...
Background: High-altitude exposure has been associated with an increased risk of hyperuricemia (HU) and gout, though the underlying mechanisms remain poorly understood.
Methods: We conducted a comprehensive analysis of the serum metabolome and phenome in both discovery and validation cohorts of Han Chinese individuals who underwent long-term moderate-altitude exposure (~12 months), as well as in an independent cohort consisting of local Han Chinese and Tibetans residing in Nyingchi (> 5 years). Beta-Alanine intervention was applied in hypoxanthine and potassium oxonate-induced in vitro and in vivo experiments.
Results: Individuals exposed to moderate altitude exhibited elevated serum urate and an increase in overall medium-chain fatty acids (MCFAs), coupled with a decrease in overall amino acids (AAs) and short-chain fatty acids (SCFAs). Rmcorr correlation analysis revealed a significant negative association between Beta-Alanine and serum urate, whereas nonanoic acid was in versa, potentially driving lower serum urate in long-term exposed residents. Both in vitro and in vivo experiments demonstrated that Beta-Alanine inhibited xanthine oxidase (XOD) and reversed the HU phenotype in human hepatocytes and mice induced by hypoxanthine (HX) and potassium oxonate (PO), with a urate-lowering effect in mice. Hepatic pathology and transcriptome analysis of HU mice treated with Beta-Alanine indicated that the mechanisms involved the inhibition of XOD, amelioration of the inflammation phenotype in hepatocytes, and promotion of renal urate excretion. Furthermore, the 10-fold cross-validation random forest classification (RFC) predictive modeling based on selected metabolites and phenotypes achieved an area under receiver operating characteristic (ROC) curve (AUC) value of 0.93 (95% confidence interval (CI): 0.85-1.00) and 0.79 (95% CI: 0.59-0.98) for distinguishing individuals with high risk of asymptomatic HU (AHU) in the training dataset and validation dataset, respectively.
Conclusions: This study reveals serum urate and metabolome altered in moderate-altitude exposed individuals and Beta-Alanine intervention could ameliorate hyperuricemia. Our findings suggest that targeting the circulating metabolome may pave novel avenues to counter diseases associated with HU.
... Yet, we can find some overlap in the mechanisms by which these bacteria exert an immunomodulatory effect and accordingly why change of their abundance after treatment is possibly related to attenuated disease activity. The most consistently reported mechanism is the anti-inflammatory response of short-chain fatty acid producers, mostly of the phylum Firmicutes, but also some genera from the Bacteroidetes phylum (46)(47)(48)(49). Another potential anti-inflammatory mechanism is the expansion of regulatory T cells by binding of Lipid 654 to toll-like receptor 2. Lipid 654 is a bacterially derived product from species from the Bacteroidetes phylum (46,50). ...
Introduction
Cladribine tablets are an effective treatment for relapsing remitting multiple sclerosis (RRMS). However, almost half of the treated patients are not free of disease activity after two years. The aim of this study was to describe the changes that cladribine tablets effectuate in the gut and oral microbiota and the peripheral immunological profile between responders and non-responders.
Methods
In this pilot study of the multicenter, prospective, observational BIA (Brain-Immune-Intestine Axis) study, we included patients aged 18 to 55 years with RRMS who were scheduled to start treatment with cladribine tablets. We assessed the clinical status and the immunological and microbiological profile prior to the start of the treatment and after three and twelve months. At twelve months, we assessed the response status, based on clinical relapses, radiological activity and disability progression on the Expanded Disability Status Scale.
Results
The first twenty-five patients of the BIA study were included in this analysis. Ten patients (40%) were responders twelve months after treatment. Three months after treatment we found a significant decline of naïve and transitional B cells and memory B cells, and of CD57⁺ CD56dim NK cells. After twelve months the values recovered to baseline levels, except for the memory B cells. We did not find significant changes of the microbiological profile over time, except for a decline of the phylum Bacteroidetes in the oral samples twelve months after treatment. Baseline values and changes over time did not significantly differ between responders and non-responders. However, several phyla, genera or species (Bacteroidetes, Prevotella, Faecalibacterium prausnitzii) showed a higher relative abundance, and several phyla, genera or species (Proteobacteria, Escherichia coli) had a lower relative abundance in responders compared to non-responders.
Discussion
After treatment with cladribine tablets, we found significant changes in the immunological landscape. Also, the microbiological profile showed several differences in microbes with known anti- or pro-inflammatory properties between responders and non-responders. Overall, we showed that we can measure a treatment effect from cladribine tablets with our analyses. Future research on data from the BIA study, with a larger sample size and extended follow-up, can possibly confirm the reliability of our findings.
... Specifically, regulation of the JNK pathway decreased Aβ deposition and levels of Aβ 40 and Aβ 42 , which are known to mediate pathological cell death associated with AD [44]. Although mechanisms underlying the beneficial effects of PA on cognitive functions remain unclear, a recent clinical study has indicated that increased PA concentration in the cerebrospinal fluid of multiple sclerosis patients may enhance Treg cell mitochondrial function and morphology [45]. Moreover, lymphoblastoid cells from autism spectrum disorder patients have shown increased ability to use PA as fuel for energy production, although concentration-dependent effects on mitochondrial function may lead to excessive reactive oxygen species (ROS) production and impaired energy production [46]. ...
A 4‐month of time‐restricted feeding (TRF) intervention alleviated cognitive impairments in Alzheimer's disease (AD) patients, while a 3‐month TRF regimen improved spatial memory, reduced amyloid‐beta accumulation, and promoted microglial aggregation around plaques in AD mice. Antibiotic‐induced gut microbiota depletion partly abolished TRF's benefits. Through creatively integrating gut microbiota, metabolites, and hippocampal genes, Bifidobacterium pseudolongum (B. pseudolongum) and propionic acid (PA) were identified as key contributors to TRF's cognitive effects, with supplementation of either mimicking TRF's protective benefits. Positron emission tomography imaging revealed that PA directly crossed the blood‐brain barrier, and PA supplementation restored disrupted metabolism in AD mice. Knockdown of its receptor free fatty acid receptor 3 (FFAR3) diminished TRF's protective effects. A case‐control study showed a negative association between PA and cognitive status, while the TRF clinical intervention linked fecal PA to cognitive status. These findings suggest PA as a potential biomarker and underscore precise TRF‐based nutritional interventions as a promising strategy for managing neurodegenerative diseases. image
... Clinical studies with multiple sclerosis patients show propionic acid supplementation boosts Treg cells and interleukin-10 levels, potentially relevant findings for ME/CFS treatment strategies as well. [115][116][117][118][119][120][121][122][123] ...
The intricate relationship between gut microbiota and the brain has emerged as a pivotal area of research, particularly in understanding myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). This complex condition is characterized by debilitating fatigue, cognitive dysfunction, and a wide array of systemic manifestations, posing significant challenges for diagnosis and treatment. Recent studies highlight the microbiota-gut-brain axis as a crucial pathway in ME/CFS pathophysiology, suggesting that alterations in gut microbial composition may impact immune responses, neurochemical signaling, and neuronal health. This narrative review systematically explores English-language scholarly articles from January 1995 to January 2025, utilizing databases such as PubMed, Scopus, and Web of Science. The findings underscore the potential for targeted therapeutic interventions aimed at correcting gut dysbiosis. As research progresses, a deeper understanding of the microbiota-gut-brain connection could lead to innovative approaches for managing ME/CFS, ultimately enhancing the quality of life for affected individuals.
... In germ-free (GF) mice, the morphological and genetic phenotypes of immature microglia were recovered partially through supplementation of the three major SCFAs (butyric acid, acetic acid, and propionic acid) [117]. Supplementing propionate to therapy naïve MS patients significantly increases Tregs and a decrease in Th1 and Th17 cells; also, it can reduce the annual relapse rate in those patients [118]. In addition, SCFAs play a role in ameliorating sensorimotor and communicative defects, decreasing anxiety-like behavior, reducing oxidative stress, regulating BBB, and improving memory loss associated with neuroinflammatory disorders [119]. ...
Multiple sclerosis (MS) is defined as an inflammatory disorder that chronically affects the central nervous system of young people mostly and is distributed globally. It is associated with degeneration and demyelination of the myelin sheath around the nerves, resulting in multiple neurological disability symptoms ranging from mild to severe cases that end with paralysis sometimes. MS is one of the rising diseases globally that is unfortunately associated with reduced quality of life and adding national economic burdens. The definite MS mechanism is not clearly defined; however, all the previous researches confirm the role of the immune system as the master contributor in the pathogenesis. Innate and adaptive immune cells are activated peripherally then attracted toward the central nervous system (CNS) due to the breakdown of the blood–brain barrier. Recently, the gut-brain axis was shown to depend on gut metabolites that are produced by different microorganisms in the colon. The difference in microbiota composition between individuals is responsible for diversity in secreted metabolites that affect immune responses locally in the gut or systemically when reach blood circulation to the brain. It may enhance or suppress immune responses in the central nervous system (CNS) (repeated short forms); consequently, it may exacerbate or ameliorate MS symptoms. Recent data showed that some metabolites can be used as adjuvant therapy in MS and other inflammatory diseases. This review sheds light on the nature of MS and the possible interaction between gut microbiota and immune system regulation through the gut-brain axis, hence contributing to MS pathogenesis.
... Existen pocos estudios clínicos que hayan utilizado posbióticos (bacterias inactivadas por calor o AGCC) como inmunorreguladores o para mejorar los trastornos neurodegenerativos y/o el deterioro cognitivo. Duscha et al. 61 reportaron que la suplementación con ácido propiónico dio lugar a un aumento de las células T inmunorreguladoras (Treg), mientras que la prolongación del tratamiento a 3 años redujo la tasa de recaída asociada a la atrofia cerebral. Por el contrario, un nivel elevado de ácido propiónico en suero se asociaba a un aumento de las probabilidades de deterioro cognitivo 62 , sugiriéndose una desregulación metabólica como mecanismo en la relación entre el ácido propiónico y la salud cognitiva. ...
Objetivos: En la presente revisión, se sintetizan y evalúan los conocimientos actuales sobre los moduladores microbianos que poseen la capacidad de potenciar la función cognitiva en personas mayores. Asimismo, se exploran las nuevas estrategias existentes para su implementación en el tratamiento de condiciones clínicas difíciles de abordar, como el deterioro cognitivo leve y las enfermedades neurodegenerativas. Metodología: Revisión narrativa enfocada en analizar la literatura sobre intervenciones microbianas en el envejecimiento neurocognitivo. Entre abril y mayo de 2024, se consultaron diversas fuentes bibliográficas y se seleccionaron estudios relevantes para ofrecer una visión actualizada y completa del tema. Resultados: Se han revisado 34 intervenciones enfocadas en mejorar la salud cognitiva de los adultos mayores mediante la terapéutica microbiana. Existen pocos estudios clínicos basados en la utilización de psicobióticos para paliar el cuadro sindrómico asociado a las enfermedades neurodegenerativas. Los resultados más prometedores se han obtenido aplicando tratamientos probióticos, aunque las terapias prebióticas y sinbióticas también han demostrado alentadoras perspectivas. El trasplante de microbiota fecal parece ser una herramienta efectiva, pero todavía quedan muchas cuestiones por resolver antes de implementar un uso generalizado de este tipo de tratamiento. Conclusiones: Los estudios analizados reflejan resultados alentadores, pero su implementación clínica precisa de una comprensión más profunda respecto a los mecanismos subyacentes. Por este motivo, se requieren ensayos clínicos controlados y longitudinales que permitan identificar los beneficios de la terapéutica microbiana en la salud mental durante el envejecimiento. Esclarecer los factores que modulan las respuestas individuales resulta fundamental para desarrollar intervenciones personalizadas y enfocadas en el microbioma intestinal. A tal respecto, la terapia con psicobióticos puede constituir una prometedora estrategia de intervención para mejorar las funciones cognitivas en adultos mayores. Objectives: In the present review, current knowledge on microbial modulators that have the ability to enhance cognitive function in older adults is synthesized and evaluated. Likewise, new existing strategies are explored for their implementation in the treatment of clinical conditions that are difficult to address, such as mild cognitive impairment and neurodegenerative diseases. Methodology: Narrative review focused on analyzing the literature on microbial interventions in neurocognitive aging. Between April and May 2024, various bibliographic sources were consulted and relevant studies were selected to provide an updated and comprehensive overview of the topic. Results: A total of 34 interventions focused on improving the cognitive health of older adults through microbial therapy have been reviewed. There are few clinical studies based on the use of pychobiotics to alleviate the syndromic condition associated with neurodegenerative diseases. The most promising results have been obtained by applying probiotic treatments, although prebiotic and synbiotic therapies have also shown encouraging prospects. Fecal microbiota transplantation appears to be an effective tool, but there are still many issues to be resolved before widespread use of this type of treatment is implemented. Conclusions: The studies analyzed reflect encouraging results, but their clinical implementation requires a deeper understanding of the underlying mechanisms. For this reason, controlled and longitudinal clinical trials are required to identify the benefits of microbial therapeutics on mental health during aging. Clarifying the factors that modulate individual responses is essential to develop personalized interventions focused on the gut microbiome. In this regard, psychobiotic therapy may constitute a promising intervention strategy to improve cognitive functions in older adults.
... In addition, there was an increase in subcortical gray matter and a reduction in cerebral atrophy. Propionic acid appears to be an important component when treating patients with MS [95]. Another acid from the family of short-chain fatty acids is valeric acid (C5;0), which admittedly is not as abundant as, say, butyric acid or propionic acid, but is worth mentioning. ...
Lipids are essential components of human health, serving as critical structural elements of cell membranes, energy sources, and precursors for bioactive molecules. This narrative review aims to examine the multifaceted roles of lipids in clinical nutrition and health, focusing on their impact on chronic disease prevention, management, and the potential of lipid-based therapies. A narrative review was conducted utilizing Scopus, Google Scholar, and Web of Science databases. Key terms such as lipids, dietary fats, and cholesterol were used to identify and analyze relevant studies. A total of 145 articles meeting inclusion criteria were reviewed for their insights into lipid metabolism, dietary sources, and clinical implications. The analysis highlighted the metabolic significance of various lipid classes—saturated, monounsaturated, and polyunsaturated fatty acids—along with evidence-based recommendations for their dietary intake. Lipids were shown to play a pivotal role in managing chronic diseases such as cardiovascular disease, obesity, and metabolic syndrome. Emerging therapies, including omega-3 fatty acids and medium-chain triglycerides, demonstrated potential benefits in clinical practice. By synthesizing current knowledge, this narrative review provides healthcare professionals with an updated understanding of the roles of lipids in clinical nutrition. The findings emphasize the importance of tailored dietary interventions and lipid-based therapies in optimizing health and managing chronic diseases effectively. Additionally, this review successfully presents practical dietary recommendations to guide clinical practice.
... 45 In addition to serving as a primary source of energy for cells of the intestines, SCFAs can help maintain immune activity, host metabolism, and overall gut homeostasis. [45][46][47][48][49][50] Several factors shape the types and amounts of SCFAs products produced within the gastrointestinal tract. Bacterial species differ in their ability to utilize and degrade particular carbohydrates, giving rise to a diverse array of SCFAs. ...
The interplay between the gut microbiota and gastrointestinal hormones plays a pivotal role in the health of the host and the development of diseases. As a vital component of the intestinal microecosystem, the gut microbiota influences the synthesis and release of many gastrointestinal hormones through mechanisms such as modulating the intestinal environment, producing metabolites, impacting mucosal barriers, generating immune and inflammatory responses, and releasing neurotransmitters. Conversely, gastrointestinal hormones exert feedback regulation on the gut microbiota by modulating the intestinal environment, nutrient absorption and utilization, and the bacterial biological behavior and composition. The distributions of the gut microbiota and gastrointestinal hormones are anatomically intertwined, and close interactions between the gut microbiota and gastrointestinal hormones are crucial for maintaining gastrointestinal homeostasis. Interventions leveraging the interplay between the gut microbiota and gastrointestinal hormones have been employed in the clinical management of metabolic diseases and inflammatory bowel diseases, such as bariatric surgery and fecal microbiota transplantation, offering promising targets for the treatment of dysbiosis-related diseases.
... In addition, reduced SCFAs production in the gut, either due to dietary changes or reduced levels of gut microbiota, has been found to lead to impaired Treg cell function in animal models of autoimmune diseases, such as multiple sclerosis, inflammatory bowel disease, and type 1 diabetes [70][71][72]. In multiple sclerosis patients, propionic acid has been postulated to improve inhibitory Treg cell function [73]. In Parkinson's disease, SCFAs have been shown to act as neuroprotective and/or neuromodulators through epigenetic regulation [74]. ...
Background
Alzheimer’s disease (AD) is a prevalent neurodegenerative disease (ND). In recent years, multiple clinical and animal studies have shown that mitochondrial dysfunction may be involved in the pathogenesis of AD. In addition, short-chain fatty acids (SCFA) produced by intestinal microbiota metabolism have been considered to be important factors affecting central nervous system (CNS) homeostasis. Among the main mediators of host-microbe interactions, volatile fatty acids play a crucial role. Nevertheless, the influence and pathways of microorganisms and their metabolites on Alzheimer’s disease (AD) remain uncertain.
Results
In this study, we present distinctions in blood and fecal SCFA levels and microbiota composition between healthy individuals and those diagnosed with AD. We found that AD patients showed a decrease in the abundance of Akkermansia muciniphila and a decrease in propionic acid both in fecal and in blood. In order to further reveal the effects and the mechanisms of propionic acid on AD prevention, we systematically explored the effects of propionic acid administration on AD model mice and cultured hippocampal neuronal cells. Results showed that oral propionate supplementation ameliorated cognitive impairment in AD mice. Propionate downregulated mitochondrial fission protein (DRP1) via G-protein coupled receptor 41 (GPR41) and enhanced PINK1/PARKIN-mediated mitophagy via G-protein coupled receptor 43 (GPR43) in AD pathophysiology which contribute to maintaining mitochondrial homeostasis both in vivo and in vitro. Administered A. muciniphila to AD mice before disease onset showed improved cognition, mitochondrial division and mitophagy in AD mice.
Conclusions
Taken together, our results demonstrate that A. muciniphila and its metabolite propionate protect against AD-like pathological events in AD mouse models by targeting mitochondrial homeostasis, making them promising therapeutic candidates for the prevention and treatment of AD.
2Eefw-diaDYPDEcqvaR2iqVideo Abstract
... A reduction in SCFA-producing microbial species in the gut leads to compromised immune function (Angelini et al., 2014). For instance, propionic acid exerts immunomodulatory properties, inducing the expression of regulatory T cells (Duscha et al., 2020;. The decrease in certain SCFA-producing bacteria, such as Parabacteroides and Ruminococcus, has been closely linked to reduced levels of acetic acid, whereas a decrease in Parabacteroides, Ruminococcus, Fournierella, and Rikenellaceae_RC9_ gut_group has been shown to be closely related to a decrease in isocaproic acid content (Cui et al., 2023). ...
Introduction
Diarrhea is a prevalent disease among calves, which significantly hinders their growth and development, thereby impacting farm productivity and revenue. This study aimed to investigate the impact of diarrhea on calf growth.
Methods
Holstein male calves with similar birth weight (39.5 ± 4.2 kg) were included in this study, and key parameters such as fecal score, diarrhea incidence, and growth performance from birth to weaning were measured. Rectal fecal samples from both diarrheic (n = 24) and healthy calves (n = 24) aged 1–4 weeks were analyzed using 16S rRNA gene sequencing and untargeted metabolomics.
Results
Our findings indicated a high prevalence of diarrhea among calves between 1–4 weeks of age on pasture, which led to a marked decrease in growth performance, including average daily gain. At the genus level, the relative abundance of GCA-900066575 in one-week-old diarrheic calves was significantly higher; Escherichia-Shigella and Pseudoflavonifractor were more abundant in two-week-old calves; while Tyzzerella and Lachnospiraceae_UCG-004 increased significantly in four-week-old calves, and correlated negatively with average daily gain, suggesting that these bacteria may promote the occurrence of diarrhea. Correlation analysis revealed that fecal metabolites such as arachidonic acid, cis-vaccenic acid, oleic acid, choline, creatinine, and others were significantly negatively correlated with calf growth performance and were significantly increased in diarrheic calves. WGNCA identified that dark magenta module metabolites were significantly associated with diarrhea traits from 1–4 weeks. Thirteen metabolites, including glycerophospholipids (such as 1-stearoyl-2-hydroxy-sn-glycero-3-phosphoethanolamine), fatty acids (such as dodecanoic acid), and arachidonic acid, were positively correlated with GCA-900066575, Escherichia-shigella, Tyzzerella, and Clostridium_butyricum, but negatively correlated with UBA1819, Lachnoclostridium_sp_YL32, and Clostridium_scindens.
Discussion
Therefore, GCA-900066575, Escherichia-shigella, Lachnospiraceae_UCG-004, and Tyzzerella are likely key bacterial genera causing diarrhea in calves, while arachidonic acid, glycerol phospholipids, and fatty acids are critical metabolites associated with this condition. These alterations in the fecal microbiota and metabolite composition were found to be the principal contributors to growth retardation in diarrheic calves.
... [3][4][5][6][7][8][9][10][11][12][13] Low-grade inflammation can be triggered through dysbiosis and its derived metabolites. 14 Combining clinical and experimental studies, we identified microbial short-chain fatty acids (SCFA) and tryptophan metabolites [15][16][17][18][19][20] to be important for CVD and multiple sclerosis (MS). SCFA (acetate, propionate, and butyrate) exert beneficial effects on the host. ...
Aims
The gastrointestinal (GI) tract is composed of distinct sub-regions, which exhibit segment-specific differences in microbial colonization and (patho)physiological characteristics. Gut microbes can be collectively considered as an active endocrine organ. Microbes produce metabolites, which can be taken up by the host and can actively communicate with the immune cells in the gut lamina propria with consequences for cardiovascular health. Variation in bacterial load and composition along the GI tract may influence the mucosal microenvironment and thus be reflected its interstitial fluid (IF). Characterization of the segment-specific microenvironment is challenging and largely unexplored because of lack of available tools.
Methods and results
Here, we developed methods, namely tissue centrifugation and elution, to collect IF from the mucosa of different intestinal segments. These methods were first validated in rats and mice, and the tissue elution method was subsequently translated for use in humans. These new methods allowed us to quantify microbiota-derived metabolites, mucosa-derived cytokines, and proteins at their site-of-action. Quantification of short-chain fatty acids showed enrichment in the colonic IF. Metabolite and cytokine analyses revealed differential abundances within segments, often significantly increased compared to plasma, and proteomics revealed that proteins annotated to the extracellular phase were site-specifically identifiable in IF. Lipopolysaccharide injections in rats showed significantly higher ileal IL-1β levels in IF compared to the systemic circulation, suggesting the potential of local as well as systemic effect.
Conclusion
Collection of IF from defined segments and the direct measurement of mediators at the site-of-action in rodents and humans bypasses the limitations of indirect analysis of faecal samples or serum, providing direct insight into this understudied compartment.
... 14 In autoimmunity, the microbiome and metabolites produced by commensal microbes also impact treatment response. 15,16 In vaccination, the microbiota can act as an adjuvant, boosting immunogenicity of interventions. [17][18][19][20] These studies suggest that the microbiome and molecules they produce could shape patients' baseline immune states and influence immune responses to treatment. ...
Human immune systems are highly variable, with most variation attributable to non-genetic sources. The gut microbiome crucially shapes the immune system; however, its relationship with the baseline immune states of healthy humans remains incompletely understood. Therefore, we performed multi-omic profiling of 110 healthy participants through the ImmunoMicrobiome study. A factor-based integrative approach identified coordinated variation, revealing that the tonic interferon response was amongst the most variable immune features in healthy participants. Microbiome composition, pathways, and stool metabolites varied concomitantly with interferon response pathways. Distinct transcriptional programs involving inflammation and TGF-β in SIGLEC-1 high monocytes and CD69 high activated MAIT and NK cells were representative of these programs. Our study provides extensive data to examine the relationship between the immune states and microbiomes of healthy individuals at steady state, which paves the way for delineating inter-individual differences relevant for disease susceptibility and responses to therapy.
... Research has shown that propionate mediated immune and metabolic signal transduction is associated with various chronic inflammatory diseases and metabolic disorders. It is worth noting that increasing the production of propionate in the colon through dietary intervention is a potential strategy for maintaining host immunity and metabolic homeostasis [20][21][22]. Diversified dietary interventions that alter dietary fibre have been shown effects on gut microbiota and improve the health status of participants. However, the exact mechanisms behind these observations remain elusive, especially at the molecular pathway level of bacteria. ...
Propionate is one of the main short chain fatty acids in the gut. Previously, we found that propionate significantly down‐regulated the expression of NleH. NleH is a virulence effector secreted by Citrobacter rodentium (C. rodentium, C.r.) and is essential for its intestinal colonisation and infection. Therefore, this study intends to explore the effect and mechanism of propionate on C.r. infection by regulating the expression of NleH. Wild‐type C.r. and its NleH mutant (C.r.△NleH), E.coli and its NleH1 mutant (E.coli△NleH1) were co‐cultured with propionate separately, changes in strain growth and invasion adhesion were detected. Meanwhile, C57BL/6J mice were infected with C.r. and C.r.△NleH to establish animal model, and propionate intervention was given. Through detecting the invasive and infectious ability of strains in mice and the changes related to colon inflammation, to analyse the effect of propionate on C.r. infection by regulating NleH expression. The results showed that propionate can reduce the adhesion of C.r. and intestinal damage by down‐regulating NleH expression, meanwhile changes of microbial functional metabolism enhance the resistance to C.r. infection in mice.
... A growing body of research has indicated that SCFAs play critical roles in IBD [42][43][44][45]. Our results provide evidence indicating that T. spiralis-enriched Muribaculum and unclassified_Muribulaceae are correlated with enhanced production of SCFAs [37], especially propionic acid, which has been demonstrated to possess functions in reducing the relapse rate and disability progression of multiple sclerosis by increasing expression of Treg-cell-inducing genes, such as IL-10 [46], as well as alleviating intestinal inflammation by enhancing goblet cell differentiation and mucus function [47]. ...
Background
Inflammatory bowel disease (IBD) increases the risk of colorectal cancer, and it has the potential to diminish the quality of life. Clinical and experimental evidence demonstrate protective aspects of parasitic helminth infection against IBD. However, studies on the inhibition of inflammation by helminth infection have overlooked a key determinant of health: the gut microbiota. Although infection with helminths induces alterations in the host microbiota composition, the potential influence and mechanism of helminth infections induced changes in the gut microbiota on the development of IBD has not yet been elucidated. In this study, we analyzed the intersection of helminth Trichinella spiralis and gut bacteria in the regulation of colitis and related mechanisms.
Methodology/Principal findings
T. spiralis infected mice were treated with antibiotics or cohoused with wild type mice, then challenged with dextran sodium sulfate (DSS)-colitis and disease severity, immune responses and goblet cells assessed. Gut bacteria composition was assessed by 16S rRNA sequencing and short-chain fatty acids (SCFAs) were measured. We found that protection against disease by infection with T. spiralis was abrogated by antibiotic treatment, and cohousing with T. spiralis- infected mice suppressed DSS-colitis in wild type mice. Bacterial community profiling revealed an increase in the abundance of the bacterial genus Muribaculum and unclassified_Muribaculaceae in mice with T. spiralis infection or mice cohoused with T. spiralis- infected mice. Metabolomic analysis demonstrated significantly increased propionic acid in feces from T. spiralis- infected mice. Data also showed that the gut microbiome modulated by T. spiralis exhibited enhanced goblet cell differentiation and elevated IL-10 levels in mice.
Conclusions
These findings identify the gut microbiome as a critical component of the anti- colitic effect of T. spiralis and gives beneficial insights into the processes by which helminth alleviates colitis.
... It is essential to underline that GPR41 and GPR43 are expressed by entero-endocrine cells where they can be directly associated with the activation of the production of glucagon-like peptide-1 (GLP-1) and the appetite-regulating hormone peptide YY (PYY) [70]. Moreover, the expression of these receptors is directly associated with the production and activations of specific immune cells, providing clear evidence for the beneficial roles of the SCFAs, especially those involving immune response and inflammation [71]. ...
The intestinal microbiota is a complex ecosystem where the microbial community (including bacteria) can metabolize available substrates via metabolic pathways specific to each species, often related in symbiotic relations. As a consequence of using available substrates and microbial growth, specific beneficial metabolites can be produced. When this reflects the health benefits for the host, these substrates can be categorized as prebiotics. Given that most prebiotic candidates must have a low molecular weight to be further metabolized by the microbiota, the role in the preliminary biological pretreatment is crucial. To provide proper substrates to the intestinal microbiota, a strategy could be to decrease the complexity of polysaccharides and reduce the levels of polymerization to low molecular weight for the target molecules, driving better solubilization and the consequent metabolic use by intestinal bacteria. When high molecular weight pectin is degraded (partially depolymerized), its solubility increases, thereby improving its utilization by gut microbiota. With regards to application, prebiotics have well-documented advantages when applied as food additives, as they improve gut health and can enhance drug effects, all shown by in vitro, in vivo, and clinical trials. In this review, we aim to provide systematic evidence for the mechanisms of action and the modulation of gut microbiota by the pectin-derived oligosaccharides produced by decreasing overall molecular weight after physical and/or chemical treatments and to compare with other types of prebiotics.
... 9,10 In addition to a later diagnosis and the use of fewer (highly effective) treatment options, LOMS patients display a faster disability progression. Nutritional and lifestyle factors such as smoking, [11][12][13] saturated, long chain fatty acids, 14 and a sugar-rich diet 15 may increase the risk of MS or MS severity, while physical activity, 16,17 low carbohydrate, and "Mediterranean" diets, 15,18 as well as the intake of short chain fatty acids 19 are considered as protective. Detrimental effects of high salt intake, 20,21 or the protective effects of alcohol consumption 22,23 are in part critically discussed. ...
Background
Multiple sclerosis (MS) is a chronic immune-mediated disease of the central nervous system affecting approximately 2.8 million people worldwide. In addition to genetic and environmental factors, various lifestyle factors contribute to disease development and progression.
Objectives
We performed a monocentric retrospective study and investigated the effect of lifestyle factors such as obesity, smoking, alcohol consumption, physical activity, and dietary habits on the degree of disability in a cohort of people with MS (pwMS) with an average onset of disease after the age of 55.
Design
This late-onset MS (LOMS) study group (n = 47) was characterized by a mean age of 60.9 years and a mean duration of disease of 5.0 years. The LOMS study group was compared with two control groups. The study participants in the “old control group” (Cold) were on average as old and in the “young control group” (Cyoung) as long suffering from MS as the pwMS in the LOMS group.
Methods
Data from medical documentation and a questionnaire were analyzed using descriptive frequency analyses and testing for correlation between different variables also by generalized estimating equations. The Expanded Disabilty Status Scale (EDSS) score and the progression index were used as a measure of disability.
Results
We found a significant association between smoking history and the current EDSS score in the Cyoung group, but not in the two older study groups. For physical activity, there was a significant negative correlation with EDSS score in the study group and the Cold group, alcoholic beverage consumption correlated with decreased EDSS in the Cold group. The intake of meat negatively correlated with the progression index in the LOMS group.
Conclusion
In summary, different life-style factors correlated with disability depending on patient age and disease duration. These life-style factors may be considered in the future counseling of pwMS at older ages.
... First, it is a natural substance-a microorganism metabolite produced by gut microbial fermentation. Secondly, several studies emphasize the success of oral administration of propionate as a dietary supplement for the correction of neuroinflammation, especially of autoimmune origin [15][16][17]. ...
Many complications associated with type 2 diabetes mellitus (T2DM) are closely linked with the generation of reactive species or free radicals leading to oxidative/nitrosative stress. The aim of this study was to investigate the effect of combined administration of metformin with propionate on the degree of oxidative/nitrosative damage in the brain of rats with an experimental model of T2DM. Male Wistar rats were divided into control (healthy rats); rats with T2DM and no further therapy; rats with T2DM that received: metformin, propionate, propionate + metformin. Ventromedial hypothalamus samples were analyzed by transmission electron microscopy, gas–liquid chromatography, Western blotting, RT-PCR and electron paramagnetic resonance. Combined treatment resulted in normalization of the neuronal NOS levels and reduction of mRNA level of induced nitric oxide synthase (NOS) and superoxide radicals compared to untreated T2DM rats. A decrease was also observed in the level of 8-oxyguanine with normalization of fatty acids distribution. The combined treatment partially mitigated ultrastructural alterations resulting from oxidative/nitrosative damage in neurons' mitochondria in T2DM. Thus, we demonstrated a positive effect of the combined use of metformin and propionate on all indicators of oxidative/nitrosative stress in T2DM.
... levels in multiple sclerosis (MS) patients, Duscha et al. administered 1000 mg/day sodium propionate to MS patients and controls in a small clinical trial (91 MS patients, 24 healthy controls).58 Propionate reduced Th17 cells and increased Tregs in MS patients, which was associated with reduced annual relapse rate, increased disability stabilization, and reduced brain atrophy after 3 years. ...
Alzheimer's disease (AD) is the most common neurodegenerative disorder and cause of dementia. Despite the prevalence of AD, there is a lack of effective disease modifying therapies. Recent evidence indicates that the gut microbiome (GMB) may play a role in AD through its regulation of innate and adaptive immunity. Gut microbes regulate physiology through their production of metabolites and byproducts. Microbial metabolites may be beneficial or detrimental to the pathogenesis and progression of inflammatory diseases. A better understanding of the role GMB‐derived metabolites play in AD may lead to the development of therapeutic strategies for AD. In this review, we summarize the function of bioactive GMB‐derived metabolites and byproducts and their roles in AD models. We also call for more focus on this area in the gut–brain axis field in order to create effective therapies for AD.
... Different infections, including Epstein Barr virus (EBV), may also play a role. There are likely complex interactions between various environmental factors with patient genetics, and understanding these pathways is an area of ongoing research (15,16). Smoking increases the risk of MS, but some other uses of tobacco may actually reduce the risk of MS. ...
Multiple sclerosis (MS) is a disease of the central nervous system characterized by
inflammation, demyelination, and neuronal damage. Epstein–Barr virus (EBV) is a
human DNA herpes virus infecting more than 90% of the world’s population. EBV
is the etiological agent of infectious mononucleosis (Pfeiffer’s disease). Major predisposing
factors for MS are certain tissue types (e.g., HLA DRB1*15:01), vitamin
D deficiency, smoking, obesity, and infection with Epstein-Barr virus (EBV). This
review summarizes current knowledge on the association between EBV and MS.
... Indeed, in multiple sclerosis (MS), a decrease in SCFA and the bacteria responsible for their production has been associated with autoimmune inflammation. Substituting with the SCFA propionate has been shown to improve in clinical outcomes [43]. An increased presence of var-ious Firmicutes species responsible for SCFA production may promote Th17 activation and contribute to autoimmunity in CIDP [11,44]. ...
The aim of the present study is to explore the bacterial diversity within the gut microbiome of chronic inflammatory demyelinating polyneuropathy patient. A stool sample was collected and analyzed to study the gut microbiota through bacterial 16S rRNA gene sequencing. The gut microbiota of chronic inflammatory demyelinating polyneuropathy patient exhibited a dominance of Firmicutes and Bacteroides phyla, with 58.19% and 33.31%, respectively. The data showed a notable abundance of Lachnospiraceae bacterium and Bacteroides sp species, 17.79% and 16.56%, respectively within the gut microbiota chronic inflammatory demyelinating polyneuropathy patient. Lachnospiraceae, a member of the Firmicutes phylum, plays a pivotal role in the production of short-chain fatty acids. At high concentration, short-chain fatty acids can trigger autoimmune leading to the chronic inflammatory demyelinating polyneuropathy. These findings strengthen the possible involvement of short-chain fatty acids in the chronic inflammatory demyelinating polyneuropathy pathogenesis process and could pave new paths in its diagnosis and therapies based on regulation of microbiota dysbiosis.
Aim
Over the past several decades, optical sectioning technologies have emerged as valuable tools for evaluating tissue histology. Unlike conventional tissue sectioning, these technologies allow for real-time intraoperative assessments and more efficient tissue triage. In the era of digital pathology, the demand for high-quality, high-throughput optical sectioning platforms is increasing, as they eliminate the need for traditional slide preparation and scanning, potentially transforming anatomical pathology workflows. While non-linear microscopy (NLM) has demonstrated promise in histological evaluation across various tissue types, its application in gastrointestinal tissue assessment remains unexplored.
Methods
This study extends the use of NLM to gastrointestinal histology and develops an image atlas to highlight its potential as an automated digital pathology platform.
Results
Our results indicate that NLM generates diagnostic-quality images comparable to traditional H&E slides. Moreover, NLM provides valuable three-dimensional (3D) spatial information, improving clinical evaluations of key histological features such as depth of invasion, lymphovascular and perineural invasion, tumour budding and margin assessment. Time-lapse videos further demonstrate NLM’s capability to capture 3D histological structures up to a depth of approximately 100 µm.
Conclusion
Our findings demonstrate that NLM can serve as an optical sectioning platform for gastrointestinal histology, providing both diagnostic-quality imaging and advanced 3D visualisation. The introduction of an NLM-based atlas has the potential to redefine anatomical pathology workflows and advance digital pathology image analysis.
Alzheimer’s disease (AD) is the most common neurodegenerative disease worldwide. Amyloid-β (Aβ) accumulation and neurofibrillary tangles are two key histological features resulting in progressive and irreversible neuronal loss and cognitive decline. The macrophages of the central nervous system (CNS) belong to the innate immune system and comprise parenchymal microglia and CNS-associated macrophages (CAMs) at the CNS interfaces (leptomeninges, perivascular space and choroid plexus). Microglia and CAMs have received attention as they may play a key role in disease onset and progression e. g., by clearing amyloid beta (Aβ) through phagocytosis. Genome-wide association studies (GWAS) have revealed that human microglia and CAMs express numerous risk genes for AD, further highlighting their potentially critical role in AD pathogenesis. Microglia and CAMs are tightly controlled by environmental factors, such as the host microbiota. Notably, it was further reported that the composition of the gut microbiota differed between AD patients and healthy individuals. Hence, emerging studies have analyzed the impact of gut bacteria in different preclinical mouse models for AD as well as in clinical studies, potentially enabling promising new therapeutic options.
Background
The optimal treatment methods for delayed encephalopathy after acute carbon monoxide (CO) poisoning (DEACMP) were not identified. Thus, this study was conducted to compare the efficacies of intermittent theta burst stimulation (iTBS) and short-chain fatty acids (SCFAs) in treating cognitive dysfunction and anxiety symptoms of DEACMP rat.
Methods
In phase I, a DEACMP rat model was built to assess the inflammation levels in the hippocampus and levels of SCFAs in the serum of DEACMP rats. In phase II, DEACMP rats were randomly assigned into four groups: DEACMP + placebo, DEACMP + SCFAs, DEACMP + sham iTBS, and DEACMP + iTBS. The intervention was continued for 2 weeks. A Morris water maze and open field tests were used to assess cognitive function and anxiety symptoms, respectively.
Results
The levels of three inflammatory factors (IL-1β, IL-6, and TNF-α) and two SCFAs (acetate and propionate) were significantly increased and decreased, respectively, in DEACMP rats. After treatment, cognitive dysfunction and anxiety symptoms were significantly improved in the DEACMP + iTBS group and the DEACMP + SCFAs (consisting of acetate and propionate) group. Both SCFAs and iTBS could significantly improve the increased levels of IL-1β, IL-6, and TNF-α in the hippocampus, and SCFAs could also improve the decreased levels of GPR41, GPR43, dopamine, and norepinephrine in the hippocampus of DEACMP rats.
Conclusion
These results indicate that both iTBS and SCFA solutions consisting of acetate and propionate produced good effects on DEACMP rats by regulating inflammation levels in the hippocampus, and acetate/propionate–GPR41/GPR43–IL-1β/IL-6/TNF-α–dopamine/norepinephrine may be a potential pathway in SCFAs for the treatment of DEACMP.
Kidney transplantation (KT) is the best treatment for end-stage kidney disease, with graft survival critically affected by the recipient's immune response. The role of the gut microbiome in modulating this immune response remains underexplored. Our study investigates how microbiome alterations might associate with allograft rejection by analyzing the gut microbiome using 16S rRNA gene amplicon sequencing of a multicenter prospective study involving 562 samples from 245 individuals of which 217 received KT. Overall, gut microbiome composition showed gradual recovery post-KT, mirroring CKD-to-health transition as indicated by an increase of Shannon diversity. Prior to graft rejection, we observed a decrease in microbial diversity and SCFA-producing taxa. Functional analysis highlighted a decreased potential for SCFA production in patients preceding the rejection event, validated by quantitative PCR for the production potential of propionate and butyrate. Post-rejection analysis revealed normalization of these microbiome features. Comparison to published microbiome signatures from CKD patients demonstrated a partial overlap of the microbiome alterations preceding graft rejection with the alterations typically found in CKD. Our findings suggest that alterations in gut microbiome composition and function may precede and influence KT rejection, suggesting potential implications as biomarkers or for early therapeutic microbiome-targeting interventions.
Recently, researchers have been interested in the potential connection between gut microbiota composition and various neuropsychological disorders. Dementia significantly affects the socioeconomics of families. Gut microbiota is considered as a probable factor in its pathogenesis. Multiple bacterial metabolites such as short-chain fatty acids, lipopolysaccharides, and various neurotransmitters that are responsible for the incidence and progression of dementia can be produced by gut microbiota. Various bacterial species such as Bifidobacterium breve , Akkermansia muciniphila , Streptococcus thermophilus , Escherichia coli , Blautia hydrogenotrophica , etc. are implicated in the pathogenesis of dementia. Gut microbiota can be a great target for imitating or inhibiting their metabolites as an adjunctive therapy based on their role in its pathogenesis. Therefore, some diets can prevent or decelerate dementia by altering the gut microbiota composition. Moreover, probiotics can modulate gut microbiota composition by increasing beneficial bacteria and reducing detrimental species. These therapeutic modalities are considered novel methods that are probably safe and effective. They can enhance the efficacy of traditional medications and improve cognitive function.
Abstract
Aims
Gut dysbiosis modulates CNS complications and cognitive decline through the gut-brain axis. The study aims to investigate the molecular mechanisms involved in gut dysbiosis-associated cognitive changes and the potential effects of probiotics in high fat-high carbohydrate diet-induced gut dysbiosis-associated neurodegeneration.
Materials and methods
We used high fat, high-carbohydrate diet (HFHCD) and high-fat diet (HFD) to induce gut dysbiosis-associated neurodegeneration in C57BL/6 mice. IVIS imaging system and biochemical changes using ELISA measured intestinal inflammation. We used fecal samples for qPCR profiling of intestinal bacteria, and serum was used for inflammatory marker analysis using ELISA. Behavioral studies measured cognitive changes, while histopathology, immunohistochemistry, and western blot analysis of hippocampal samples measured protein changes.
Key findings
The behavioral studies showed a significant decrease in cognitive function associated with gut dysbiosis in HFHCD and HFD animals. Gut dysbiosis was associated with intestinal inflammation and increased intestinal permeability, followed by systemic and neuroinflammatory changes. Molecular signaling studies showed the involvement of AIM2 inflammasome and cGAS–STING signaling pathways in neurodegeneration for HFHCD animals. Administration of probiotics restored the above processes and prevented gut dysbiosis-associated memory decline in mice.
Significance
The study shows that alteration in microbial composition due to prolonged HFHCD could contribute to intestinal inflammation and increased intestinal permeability, facilitating the translocation of microbial toxins like LPS, leading to systemic inflammation, which eventually leads to neuroinflammation and neurodegeneration.
The previous part of the review examined the role of the intestinal microbiota as a susceptibility factor to multiple sclerosis. This part of the review provides facts that confirm the trigger role of intestinal microbiota. The main attention is paid to the initial stages of pathogenesis, which, according to the modern concept of multiple sclerosis, occur in the gastrointestinal tract.
This review elucidates the pivotal role of pyroptosis, triggered by gut microbiota, in the development of multiple sclerosis (MS), emphasizing its significance within the gut-brain axis. Our comprehensive analysis of recent literature reveals how dysbiosis in the gut microbiota of MS patients—characterized by reduced microbial diversity and shifts in bacterial populations—profoundly impacts immune regulation and the integrity of the central nervous system (CNS). Pyroptosis, an inflammatory form of programmed cell death, significantly exacerbates MS by promoting the release of inflammatory cytokines and causing substantial damage to CNS tissues. The gut microbiota facilitates this detrimental process through metabolites such as short-chain fatty acids and neuroactive compounds, or self-structural products like lipopolysaccharides (LPS), which modulate immune responses and influence neuronal survival. This review highlights the potential of modulating gut microbiota to regulate pyroptosis, thereby suggesting that targeting this pathway could be a promising therapeutic strategy to mitigate inflammatory responses and preserve neuronal integrity in patients with MS.
There is no question that the quantity of food and milk consumed, in addition to the relative abundance of nutrients in the diet, has an effect on brain function. There is currently a considerable body of research suggesting that proper nutrition in one's diet can help in neurologic symptoms treatment and prevention of pathological disorders variety. Important processes responsible for nutrients' impact on brain health include dietary factors on mitochondrial dysfunction, modification of epigenetics, and neuroinflammation. In this chapter, we discuss dietary intervention evidence, such as dietary supplementation that can potent neurological disorders treatment, for example, therapeutic response. In conclusion, also, an innovative hypothesis is that dietary nutritional supplementation can repair brain dysfunction by reshaping the metabolism-epigenetics-immunity loop. Targeting metabolism, a new strategy for overcoming neurological deficiencies will be outlined by the epigenetics-immunity network.
The formation of glutenin protein corona alleviated gut microbiota dysbiosis, increased the short chain fatty acid production, improved the gut barrier function, mitigated mitochondrial dysfunction, and reduced reactive oxygen species.
The gut microbiota has emerged as a pivotal regulator of host inflammatory processes after traumatic brain injury (TBI). However, the mechanisms by which the gut microbiota communicates to the brain in TBI are still under investigation. We previously reported that gut microbiota depletion (GMD) using antibiotics after TBI resulted in increased microglial activation, reduced neurogenesis, and reduced T cell infiltration. In the present study, we have demonstrated that intestinal T cells contribute to the pool of cells infiltrating the brain after TBI. Depletion or genetic deletion of T cells before injury reversed GMD induced reductions in post-TBI neurogenesis. Short-chain fatty acid supplementation increased T regulatory and T helper1 cell infiltration to the brain along with restoring neurogenesis and microglia activation after TBI with GMD. These data suggest that T cell subsets are essential cellular mediators by which the gut microbiota modulates TBI pathogenesis, a finding with important therapeutic implications.
Inflammatory environments induce the generation of dysfunctional IFNγ ⁺ T‐bet ⁺ FOXP3 ⁺ Th1‐like Tregs, which show defective function and are found in autoimmune conditions including multiple sclerosis (MS). The pathways that control the generation of Th1‐like Tregs are not well understood. Sphingosine‐1‐phosphate (S1P) signalling molecules are upregulated in Th1‐like Tregs, and in vivo S1P inhibition with Fingolimod (FTY720) inhibits the expression of genes responsible for Treg plasticity in MS patients. However, the underlying mechanisms are unknown. Here we show that S1P signalling inhibition by FTY720 inhibits the generation of Th1‐like Tregs and rescues their suppressive function. These effects are mediated by a decrease in mTORC1 signalling and reversal of the mitochondrial uncoupling that Tregs undergo during their reprogramming into Th1‐like Tregs in vitro. Finally, these results are validated in in vivo‐generated Th1‐like Tregs, as Tregs from MS patients treated with FTY720 display decreased Th1‐like Treg frequency, increased suppressive function and mitochondrial metabolism rebalance. These results highlight the involvement of mitochondrial uncoupling in Treg reprogramming and identify S1P signalling inhibition as a target to suppress the generation of dysfunctional Th1‐like Tregs.
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
Recent evidence indicates that mitochondria lie at the heart of immunity. Mitochondrial DNA acts as a danger-associated molecular pattern (DAMP), and the mitochondrial outer membrane is a platform for signaling molecules such as MAVS in RIG-I signaling, and for the NLRP3 inflammasome. Mitochondrial biogenesis, fusion and fission have roles in aspects of immune-cell activation. Most important, Krebs cycle intermediates such as succinate, fumarate and citrate engage in processes related to immunity and inflammation, in both innate and adaptive immune cells. These discoveries are revealing mitochondrial targets that could potentially be exploited for therapeutic gain in inflammation and cancer.
Investigation of host-environment interactions in the gut would benefit from a culture system that maintained tissue architecture yet allowed tight experimental control. We devised a microfabricated organ culture system that viably preserves the normal multicellular composition of the mouse intestine, with luminal flow to control perturbations (e.g., microbes, drugs). It enables studying short-term responses of diverse gut components (immune, neuronal, etc.). We focused on the early response to bacteria that induce either Th17 or RORg⁺ T-regulatory (Treg) cells in vivo. Transcriptional responses partially reproduced in vivo signatures, but these microbes elicited diametrically opposite changes in expression of a neuronal-specific gene set, notably nociceptive neuropeptides. We demonstrated activation of sensory neurons by microbes, correlating with RORg⁺ Treg induction. Colonic RORg⁺ Treg frequencies increased in mice lacking TAC1 neuropeptide precursor and decreased in capsaicin-diet fed mice. Thus, differential engagement of the enteric nervous system may partake in bifurcating pro- or anti-inflammatory responses to microbes.
A novel liquid chromatography tandem mass spectrometry (LCMSMS) method for the quantitative measurement of gut microbial-derived short-chain fatty acids (SCFAs) in human infant stool has been developed and validated. Baseline chromatographic resolution was achieved for 12 SCFAs (acetic, butyric, caproic, 2,2-dimethylbutyric, 2-ethylbutyric, isobutyric, isovaleric, 2-methylbutyric, 4-methylvaleric, propionic, pivalic and valeric acids) within an analysis time of 15 min. A novel sequential derivatization of endogenous and spiked SCFAs in stool via ¹²C- and ¹³C-aniline respectively, facilitated the accurate quantitation of ¹²C-aniline derivatized endogenous SCFAs based on calibration of exogenously ¹³C-derivatized SCFAs. Optimized quenching of derivatization agents prior to LCMSMS analysis further reduced to negligible levels the confounding chromatographic peak due to in-line derivatization of unquenched aniline with residual acetic acid present within the LCMS system. The effect of residual acetic acid, a common LCMS modifier, in analysis of SCFAs has not been addressed in previous SCFA assays. For the first time, a total of 9 SCFAs (acetic, butyric, caproic, isobutyric, isovaleric, 2-methylbutyric, 4-methylvaleric, propionic and valeric acids) were detected and quantitated in 107 healthy infant stool samples. The abundance and diversity of SCFAs in infant stool vary temporally from 3 weeks onwards and stabilize towards the end of 12 months. This in turn reflects the maturation of infant SCFA-producing gut microbiota community. In summary, this novel method is applicable to future studies that investigate the biological roles of SCFAs in paediatric health and diseases.
The intestinal microbiota influence neurodevelopment, modulate behavior, and contribute to neurological disorders. However, a functional link between gut bacteria and neurodegenerative diseases remains unexplored. Synucleinopathies are characterized by aggregation of the protein α-synuclein (αSyn), often resulting in motor dysfunction as exemplified by Parkinson’s disease (PD). Using mice that overexpress αSyn, we report herein that gut microbiota are required for motor deficits, microglia activation, and αSyn pathology. Antibiotic treatment ameliorates, while microbial re-colonization promotes, pathophysiology in adult animals, suggesting that postnatal signaling between the gut and the brain modulates disease. Indeed, oral administration of specific microbial metabolites to germ-free mice promotes neuroinflammation and motor symptoms. Remarkably, colonization of αSyn-overexpressing mice with microbiota from PD-affected patients enhances physical impairments compared to microbiota transplants from healthy human donors. These findings reveal that gut bacteria regulate movement disorders in mice and suggest that alterations in the human microbiome represent a risk factor for PD.
It is widely accepted that obesity and associated metabolic diseases, including type 2 diabetes, are intimately linked to diet. However, the gut microbiota has also become a focus for research at the intersection of diet and metabolic health. Mechanisms that link the gut microbiota with obesity are coming to light through a powerful combination of translation-focused animal models and studies in humans. A body of knowledge is accumulating that points to the gut microbiota as a mediator of dietary impact on the host metabolic status. Efforts are focusing on the establishment of causal relationships in people and the prospect of therapeutic interventions such as personalized nutrition.
We present the open-source software package DADA2 for modeling and correcting Illumina-sequenced amplicon errors (https://github.com/benjjneb/dada2). DADA2 infers sample sequences exactly and resolves differences of as little as 1 nucleotide. In several mock communities, DADA2 identified more real variants and output fewer spurious sequences than other methods. We applied DADA2 to vaginal samples from a cohort of pregnant women, revealing a diversity of previously undetected Lactobacillus crispatus variants.
Growing empirical evidence suggests that nutrition and bacterial metabolites might impact the systemic immune response in the context of disease and autoimmunity. We report that long-chain fatty acids (LCFAs) enhanced differentiation and proliferation of T helper 1 (Th1) and/or Th17 cells and impaired their intestinal sequestration via p38-MAPK pathway. Alternatively, dietary short-chain FAs (SCFAs) expanded gut T regulatory (Treg) cells by suppression of the JNK1 and p38 pathway. We used experimental autoimmune encephalomyelitis (EAE) as a model of T cell-mediated autoimmunity to show that LCFAs consistently decreased SCFAs in the gut and exacerbated disease by expanding pathogenic Th1 and/or Th17 cell populations in the small intestine. Treatment with SCFAs ameliorated EAE and reduced axonal damage via long-lasting imprinting on lamina-propria-derived Treg cells. These data demonstrate a direct dietary impact on intestinal-specific, and subsequently central nervous system-specific, Th cell responses in autoimmunity, and thus might have therapeutic implications for autoimmune diseases such as multiple sclerosis.
Summary: 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
Mitochondrial dysfunction is a common feature in neurodegeneration and aging. We identify mitochondrial dysfunction in xeroderma pigmentosum group A (XPA), a nucleotide excision DNA repair disorder with severe neurodegeneration, in silico and in vivo. XPA-deficient cells show defective mitophagy with excessive cleavage of PINK1 and increased mitochondrial membrane potential. The mitochondrial abnormalities appear to be caused by decreased activation of the NAD(+)-SIRT1-PGC-1α axis triggered by hyperactivation of the DNA damage sensor PARP-1. This phenotype is rescued by PARP-1 inhibition or by supplementation with NAD(+) precursors that also rescue the lifespan defect in xpa-1 nematodes. Importantly, this pathogenesis appears common to ataxia-telangiectasia and Cockayne syndrome, two other DNA repair disorders with neurodegeneration, but absent in XPC, a DNA repair disorder without neurodegeneration. Our findings reveal a nuclear-mitochondrial crosstalk that is critical for the maintenance of mitochondrial health.
Regulatory T cells are the central element for the maintenance of peripheral tolerance. Several subtypes of regulatory T (Treg) cells have been described, and most of them belong to the CD4+ T-helper (Th) cell lineage. These specific subtypes can be discriminated according to phenotype and function. Forkhead box protein 3 (FoxP3)-expressing natural Treg cells (Tregs) and IL-10-producing, T-regulatory type 1 cells (Tr1) are the best-studied types of CD4+ regulatory T cells in humans and experimental animal models. It was shown that they play a crucial role during autoimmune neuroinflammation. Both cells types seem to be particularly important for multiple sclerosis (MS). Here, we discuss the role of CD4+ regulatory T cells in autoimmune neuroinflammation with an emphasis on Tregs and Tr1 cells in MS.
Next-generation sequencing technologies generate millions of short sequence reads, which are usually aligned to a reference genome. In many applications, the key information required for downstream analysis is the number of reads mapping to each genomic feature, for example to each exon or each gene. The process of counting reads is called read summarization. Read summarization is required for a great variety of genomic analyses but has so far received relatively little attention in the literature.
We present featureCounts, a read summarization program suitable for counting reads generated from either RNA or genomic DNA sequencing experiments. featureCounts implements highly efficient chromosome hashing and feature blocking techniques. It is considerably faster than existing methods (by an order of magnitude for gene-level summarization) and requires far less computer memory. It works with either single or paired-end reads and provides a wide range of options appropriate for different sequencing applications.
featureCounts is available under GNU General Public License as part of the Subread (http://subread.sourceforge.net) or Rsubread (http://www.bioconductor.org) software packages.
shi@wehi.edu.au.
Amplified marker-gene sequences can be used to understand microbial community structure, but they suffer from a high level of sequencing and amplification artifacts. The UPARSE pipeline reports operational taxonomic unit (OTU) sequences with ≤1% incorrect bases in artificial microbial community tests, compared with >3% incorrect bases commonly reported by other methods. The improved accuracy results in far fewer OTUs, consistently closer to the expected number of species in a community.
When small RNA is sequenced on current sequencing machines, the resulting reads are usually longer than the RNA and therefore contain parts of the 3' adapter. That adapter must be found and removed error-tolerantly from each read before read mapping. Previous solutions are either hard to use or do not offer required features, in particular support for color space data. As an easy to use alternative, we developed the command-line tool cutadapt, which supports 454, Illumina and SOLiD (color space) data, offers two adapter trimming algorithms, and has other useful features.
Cutadapt, including its MIT-licensed source code, is available for download at http://code.google.com/p/cutadapt/
The immunomodulatory effect of probiotics has been shown mainly in gastro-intestinal immune disorders and little information is available on the inflammation of central nervous system. Recently we reported that IRT5 probiotics, a mixture of 5 probiotics, could suppress diverse experimental inflammatory disorders. In this study, we evaluated the prophylactic and therapeutic effects of IRT5 probiotics in experimental autoimmune encephalomyelitis (EAE), a T cell mediated inflammatory autoimmune disease of the central nervous system. Pretreatment of IRT5 probiotics before disease induction significantly suppressed EAE development. In addition, treatment with IRT5 probiotics to the ongoing EAE delayed the disease onset. Administration of IRT5 probiotics inhibited the pro-inflammatory Th1/Th17 polarization, while inducing IL10 producing or/and Foxp3 regulatory T cells, both in the peripheral immune system and at the site of inflammation. Collectively, our data suggest that IRT5 probiotics could be applicable to modulate T cell mediated neuronal autoimmune diseases, including multiple sclerosis.
To cause disease, Salmonella must invade the intestinal epithelium employing genes encoded within Salmonella Pathogenicity Island 1 (SPI1). We show here that propionate, a fatty acid abundant in the intestine of animals, repressed SPI1 at physiologically relevant concentration and pH, reducing expression of SPI1 transcriptional regulators and consequently decreasing expression and secretion of effector proteins, leading to reduced bacterial penetration of cultured epithelial cells. Essential to repression was hilD, which occupies the apex of the regulatory cascade within SPI1, as loss of only this gene among those of the regulon prevented repression of SPI1 transcription by propionate. Regulation through hilD, however, was achieved through the control of neither transcription nor translation. Instead, growth of Salmonella in propionate significantly reduced the stability of HilD. Extending protein half-life using a Lon protease mutant demonstrated that protein stability itself did not dictate the effects of propionate and suggested modification of HilD with subsequent degradation as the means of action. Furthermore, repression was significantly lessened in a mutant unable to produce propionyl-CoA, while further metabolism of propionyl-CoA appeared not to be required. These results suggest a mechanism of control of Salmonella virulence in which HilD is post-translationally modified using the high energy intermediate propionyl-CoA.
Certain autoimmune diseases as well as asthma have increased in recent decades, particularly in developed countries. The hygiene hypothesis has been the prevailing model to account for this increase; however, epidemiology studies also support the contribution of diet and obesity to inflammatory diseases. Diet affects the composition of the gut microbiota, and recent studies have identified various molecules and mechanisms that connect diet, the gut microbiota, and immune responses. Herein, we discuss the effects of microbial metabolites, such as short chain fatty acids, on epithelial integrity as well as immune cell function. We propose that dysbiosis contributes to compromised epithelial integrity and disrupted immune tolerance. In addition, dietary molecules affect the function of immune cells directly, particularly through lipid G-protein coupled receptors such as GPR43.
In Multiple Sclerosis (MS), detection of T2-hyperintense white matter (WM) lesions on magnetic resonance imaging (MRI) has become a crucial criterion for diagnosis and predicting prognosis in early disease. Automated lesion detection is not only desirable with regard to time and cost effectiveness but also constitutes a prerequisite to minimize user bias. Here, we developed and evaluated an algorithm for automated lesion detection requiring a three-dimensional (3D) gradient echo (GRE) T1-weighted and a FLAIR image at 3 Tesla (T). Our tool determines the three tissue classes of gray matter (GM) and WM as well as cerebrospinal fluid (CSF) from the T1-weighted image, and, then, the FLAIR intensity distribution of each tissue class in order to detect outliers, which are interpreted as lesion beliefs. Next, a conservative lesion belief is expanded toward a liberal lesion belief. To this end, neighboring voxels are analyzed and assigned to lesions under certain conditions. This is done iteratively until no further voxels are assigned to lesions. Herein, the likelihood of belonging to WM or GM is weighed against the likelihood of belonging to lesions. We evaluated our algorithm in 53 MS patients with different lesion volumes, in 10 patients with posterior fossa lesions, and 18 control subjects that were all scanned at the same 3T scanner (Achieva, Philips, Netherlands). We found good agreement with lesions determined by manual tracing (R2 values of over 0.93 independent of FLAIR slice thickness up to 6mm). These results require validation with data from other protocols based on a conventional FLAIR sequence and a 3D GRE T1-weighted sequence. Yet, we believe that our tool allows fast and reliable segmentation of FLAIR-hyperintense lesions, which might simplify the quantification of lesions in basic research and even clinical trials.
Active multiple sclerosis lesions show inflammatory changes suggestive of a combined attack by autoreactive T and B lymphocytes against brain white matter. These pathogenic immune cells derive from progenitors that are normal, innocuous components of the healthy immune repertoire but become autoaggressive upon pathological activation. The stimuli triggering this autoimmune conversion have been commonly attributed to environmental factors, in particular microbial infection. However, using the relapsing-remitting mouse model of spontaneously developing experimental autoimmune encephalomyelitis, here we show that the commensal gut flora-in the absence of pathogenic agents-is essential in triggering immune processes, leading to a relapsing-remitting autoimmune disease driven by myelin-specific CD4(+) T cells. We show further that recruitment and activation of autoantibody-producing B cells from the endogenous immune repertoire depends on availability of the target autoantigen, myelin oligodendrocyte glycoprotein (MOG), and commensal microbiota. Our observations identify a sequence of events triggering organ-specific autoimmune disease and these processes may offer novel therapeutic targets.