Gut Microbiota-derived Short-chain Fatty Acids Research Articles

Microbiota-derived short-chain fatty acids promote Th1 cell IL-10 production to maintain intestinal homeostasis

T-cells are crucial in maintanence of intestinal homeostasis, however, it is still unclear how microbiota metabolites regulate T-effector cells. Here we show gut microbiota-derived short-chain fatty acids (SCFAs) promote microbiota antigen-specific Th1 cell IL-10 production, mediated by G-protein coupled receptors 43 (GPR43). Microbiota antigen-specific Gpr43−/− CBir1 transgenic (Tg) Th1 cells, specific for microbiota antigen CBir1 flagellin, induce more severe colitis compared with wide type (WT) CBir1 Tg Th1 cells in Rag−/− recipient mice. Treatment with SCFAs limits colitis induction by promoting IL-10 production, and administration of anti-IL-10R antibody promotes colitis development. Mechanistically, SCFAs activate Th1 cell STAT3 and mTOR, and consequently upregulate transcription factor B lymphocyte-induced maturation protein 1 (Blimp-1), which mediates SCFA-induction of IL-10. SCFA-treated Blimp1−/− Th1 cells produce less IL-10 and induce more severe colitis compared to SCFA-treated WT Th1 cells. Our studies, thus, provide insight into how microbiota metabolites regulate Th1 cell functions to maintain intestinal homeostasis.

Differential metabolic effects of oral butyrate treatment in lean versus metabolic syndrome subjects.

BackgroundGut microbiota-derived short-chain fatty acids (SCFAs) have been associated with beneficial metabolic effects. However, the direct effect of oral butyrate on metabolic parameters in humans has never been studied. In this first in men pilot study, we thus treated both lean and metabolic syndrome male subjects with oral sodium butyrate and investigated the effect on metabolism.MethodsHealthy lean males (n = 9) and metabolic syndrome males (n = 10) were treated with oral 4 g of sodium butyrate daily for 4 weeks. Before and after treatment, insulin sensitivity was determined by a two-step hyperinsulinemic euglycemic clamp using [6,6-2H2]-glucose. Brown adipose tissue (BAT) uptake of glucose was visualized using 18F-FDG PET-CT. Fecal SCFA and bile acid concentrations as well as microbiota composition were determined before and after treatment.ResultsOral butyrate had no effect on plasma and fecal butyrate levels after treatment, but did alter other SCFAs in both plasma and feces. Moreover, only in healthy lean subjects a significant improvement was observed in both peripheral (median Rd: from 71 to 82 µmol/kg min, p < 0.05) and hepatic insulin sensitivity (EGP suppression from 75 to 82% p < 0.05). Although BAT activity was significantly higher at baseline in lean (SUVmax: 12.4 ± 1.8) compared with metabolic syndrome subjects (SUVmax: 0.3 ± 0.8, p < 0.01), no significant effect following butyrate treatment on BAT was observed in either group (SUVmax lean to 13.3 ± 2.4 versus metabolic syndrome subjects to 1.2 ± 4.1).ConclusionsOral butyrate treatment beneficially affects glucose metabolism in lean but not metabolic syndrome subjects, presumably due to an altered SCFA handling in insulin-resistant subjects. Although preliminary, these first in men findings argue against oral butyrate supplementation as treatment for glucose regulation in human subjects with type 2 diabetes mellitus.

Abstract 148: Gut Microbial Metabolites Modulate Immune Response for Cardiac Repair

Antibiotic abuse has been a serious issue on human health and homeostasis. Appreciation of the role of gut microbiota in regulating vertebrate tissue repair has exploded recently. However, the effects of gut microbiota on cardiac repair after myocardial infarction (MI) remain to be elucidated. Here, we report that although administration of antibiotics doesn’t influence cardiac function before injury, antibiotic-mediated depletion of the gut microbiota caused high mortality in mice after MI. Since the effect happens only after the mice with MI have received antibiotics, it suggests that the gut microbiota is important for effective cardiac repair, especially in early stage after MI. Because the gut microbiota is an important immune modulator, we speculate that immune response, which plays an important role in cardiac repair, is significantly impaired in mice treated with antibiotics. We have determined that short-chain fatty acids (SCFAs), which are a gut microbiota-derived fermented product, contribute to efficacious cardiac repair after MI. Furthermore, the profile of gut microbiota dynamic changes clues a decisive role of Lactobacillus species in more powerful cardiac repair after MI. Mice with MI that were treated with Lactobacillus showed a significant improvement in left ventricular ejection fraction and smaller infarct size. Finally, the beneficial effects of Lactobacillus come from the alternation of SCFA metabolism which modulates the immune response in the heart. Our study demonstrates that the gut microbiota contributes to cardiac repair after MI via immune response modulation driven by gut microbiota-derived SCFAs. Manipulation of gut microbiota composition or its metabolites may provide opportunities to modulate pathological outcome in the heart after MI.

Interactive effects of blueberry supplementation and GPR109A deletion on gut microbiome profiles in mice

Blueberry‐supplemented (BB) diets in rodent models have shown to improve skeletal mass, glucose tolerance and endothelial function. In addition to the bioactive and dietary fibre components of these diets, effects of blueberries may be in part via modulation and action of the gut microbiome. However, few studies have characterized gut microbiome composition following BB supplementation. Since phenolic acids and gut microbiota‐derived short‐chain fatty acids (SCFAs) such as butyrate can bind and activate GPR109A (nicotinic acid receptor) signaling, we examined the interactive roles of GPR109A and BB‐supplementation on microbiome profiles in mice. Male GPR109A global knockouts and WT littermates were fed control or BB‐supplemented diets (5% w/w) for 4 weeks (n=10). All diets were based on the AIN‐93G formulation and contained 19% calories from protein, 17% from fat and 64% from carbohydrates. Body weight, body composition (non‐invasively via Echo MRI) and food intake were measured weekly and did not differ between groups within the study period. At the end of 4 wk serum, liver, adipose tissue depots and cecal contents were collected for further analysis. Microbial community profiling was conducted by sequencing the 16S rRNA (V4 region) followed by analysis using QIIME. BB‐diet fed mice showed greater a‐diversity (OTU richness) in both WT and GPR109A‐KO. Interestingly, GPR109A loss per se was associated with significantly lower a‐diversity relative to WT mice (p&lt;0.05). Principal coordinate analysis of b‐diversity values showed highly significant effects of both genotype and diet (p&lt;0.00001). BB diets affected abundance of 15 genera in WT mice, of which only 5 genera were also affected in GRP109A KO with BB‐treatment (p&lt;0.05, two‐way ANOVA). However, BB diets in GPR109A KO altered 7 genera uniquely suggesting significant genotype‐diet interactions. Two‐way ANOVA analysis showed BB‐diets increased Bacteroidetes and decreased Firmicutes phyla (p&lt;0.001) in both WT and KO mice. OTU abundance of genera including Facklamia, Clostridium, Coprococcus, Dorea, and Ruminoccous was affected by both diet and genotype of mice (p&lt;0.01). LEfSE analysis confirmed enrichment of phyla Bacteroidetes with BB‐diets. Predictive functional metagenomics analysis using PiCRUST identified alterations of pathways involving immune and bacterial response, protein digestion, amino acid metabolism and xenobiotics biodegradation to be affected by genotype and BB‐diet. Associations between alterations in microbial abundance and diet‐associated changes in adipose tissue and liver gene expression will also be presented. Overall, these results suggest changes in microbial community structure with BB‐diets and also reveal novel host genotype dependent alterations in the microbiome. Support USDA CRIS 6206‐51000‐010‐05SSupport or Funding InformationSupport USDA CRIS 6206‐51000‐010‐05S

Commentary: Oxygen regulation of breathing through an olfactory receptor activated by lactate.

Commentary: Oxygen regulation of breathing through an olfactory receptor activated by lactate.

Gut microbiota, host defense and immunity: analysis with integrative omics approach

Complex host-gut microbiota interaction is involved in the formation of a unique ecosystem in our body, the "gut ecosystem". In order to understand the complex gut ecosystem, we propose integrated multi-omics approach, where multiple layers of unbiased cyclopedic analyses such as genomics, transcriptomics and metabolomics are combined. Applying this approach, we have revealed the mechanism that gut microbiota-derived acetate, a short-chain fatty acid, protects mice from enterohemorrhagic Escherichia coli O157-infectious death. We have also shown that butyrate produced by gut microbiota such as order Clostridiales promotes differentiation of regulatory T cells from naïve T cells in colonic lamina propria, through epigenetic modification. Epigenetic modification by butyrate also acts on colonic macrophages to confer anti-inflammatory phenotype by rendering them hyporesponsive to Toll-like receptor signaling. Short-chain fatty acids also signal via their G protein-coupled receptors. For example, it has been suggested that gut microbiota-derived short-chain fatty acids absorbed in the blood play a role in regulation of systemic inflammation by inducing apoptosis of neutrophils as well as chemotaxis of regulatory T cells.

Gut Microbiota-Derived Short-Chain Fatty Acids, T Cells, and Inflammation

T cells are central players in the regulation of adaptive immunity and immune tolerance. In the periphery, T cell differentiation for maturation and effector function is regulated by a number of factors. Various factors such as antigens, co-stimulation signals, and cytokines regulate T cell differentiation into functionally specialized effector and regulatory T cells. Other factors such as nutrients, micronutrients, nuclear hormones and microbial products provide important environmental cues for T cell differentiation. A mounting body of evidence indicates that the microbial metabolites short-chain fatty acids (SCFAs) have profound effects on T cells and directly and indirectly regulate their differentiation. We review the current status of our understanding of SCFA functions in regulation of peripheral T cell activity and discuss their impact on tissue inflammation.