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The gut microbiota has been implicated in glucose intolerance and its progression towards type-2 diabetes mellitus (T2DM). Relevant randomized clinical trial with prebiotic intervention was inadequate. We sought to evaluate the impact of fructooligosaccharides (FOS) and galactooligosaccharides (GOS) on glycemia during oral glucose tolerance test (OGTT) and intestinal microbiota. A randomized double-blind cross-over study was performed with 35 adults treated with FOS and GOS for 14 days (16 g/day). Faeces sampling, OGTT and anthropometric parameters were performed. Short-term intake of high-dose prebiotics had adverse effect on glucose metabolism, as in FOS intervention demonstrated by OGTT (P < 0.001), and in GOS intervention demonstrated by fasting glucose (P < 0.05). A significant increase in the relative abundance of Bifidobacterium was observed both in FOS and GOS group, while the butyrate-producing bacteria like Phascolarctobacterium in FOS group and Ruminococcus in GOS group were decreased. A random forest model using the initial microbiota was developed to predict OGTT levels after prebiotic intervention with relative success (R = 0.726). Our study alerted even though FOS and GOS increased Bifidobacterium , they might have adverse effect on glucose metabolism by reducing butyrate-producing microbes. Individualized prebiotics intervention based on gut microbiome needs to be evaluated in future.

Background An increasing body of evidence implicates the resident gut microbiota as playing a critical role in type 2 diabetes (T2D) pathogenesis. We previously reported significant improvement in postprandial glucose control in human participants with T2D following 12-week administration of a 5-strain novel probiotic formulation (‘WBF-011’) in a double-blind, randomized, placebo controlled setting (NCT03893422). While the clinical endpoints were encouraging, additional exploratory measurements were needed in order to link the motivating mechanistic hypothesis - increased short-chain fatty acids - with markers of disease. Results Here we report targeted and untargeted metabolomic measurements on fasting plasma ( n  = 104) collected at baseline and end of intervention. Butyrate and ursodeoxycholate increased among participants randomized to WBF-011, along with compelling trends between butyrate and glycated haemoglobin (HbA1c). In vitro monoculture experiments demonstrated that the formulation’s C. butyricum strain efficiently synthesizes ursodeoxycholate from the primary bile acid chenodeoxycholate during butyrogenic growth. Untargeted metabolomics also revealed coordinated decreases in intermediates of fatty acid oxidation and bilirubin, potential secondary signatures for metabolic improvement. Finally, improvement in HbA1c was limited almost entirely to participants not using sulfonylurea drugs. We show that these drugs can inhibit growth of formulation strains in vitro. Conclusion To our knowledge, this is the first description of an increase in circulating butyrate or ursodeoxycholate following a probiotic intervention in humans with T2D, adding support for the possibility of a targeted microbiome-based approach to assist in the management of T2D. The efficient synthesis of UDCA by C. butyricum is also likely of interest to investigators of its use as a probiotic in other disease settings. The potential for inhibitory interaction between sulfonylurea drugs and gut microbiota should be considered carefully in the design of future studies.

Anti-microbial signaling pathways are normally triggered by innate immune receptors when detecting pathogenic microbes to provide protective immunity. Here we show that the inflammasome sensor Nlrp1 aggravates DSS-induced experimental mouse colitis by limiting beneficial, butyrate-producing Clostridiales in the gut. The colitis-protective effects of Nlrp1 deficiency are thus reversed by vancomycin treatment, but recapitulated with butyrate supplementation in wild-type mice. Moreover, an activating mutation in Nlrp1a increases IL-18 and IFNγ production, and decreases colonic butyrate to exacerbate colitis. We also show that, in patients with ulcerative colitis, increased NLRP1 in inflamed regions of the colon is associated with increased IFN-γ . In this context, NLRP1 , IL-18 or IFN-γ expression negatively correlates with the abundance of Clostridiales in human rectal mucosal biopsies. Our data identify the NLRP1 inflammasome to be a key negative regulator of protective, butyrate-producing commensals, which therefore promotes inflammatory bowel disease. The inflammasome is normally activated by pathogens to induce tissue inflammation. Here the authors show that, in mouse experimental colitis models, Nlrp1 inflammasome sensor activates IL-18 to reduce beneficial colonic Clostridiales species, thereby decreasing microbial butyrate and its protective effects on colitis.

Fecal microbiota transplantation (FMT)—transferring fecal microbes from a healthy donor to a sick patient—has shown promise for gut diseases such as inflammatory bowel disease. However, unlike pharmaceuticals, fecal transplants are complex mixtures of living organisms, which must then interact with the microbes and immune system of the recipient. For fecal microbiota transplantation (FMT) to be successful in immune diseases like inflammatory bowel disease, it is assumed that therapeutic microbes and their beneficial functions and immune interactions must colonize a recipient patient and persist in sufficient quantity and for a sufficient period of time to produce a clinical benefit. Few studies, however, have comprehensively profiled the colonization and persistence of transferred microbes along with the transfer of their microbial functions and interactions with the host immune system. Using 16S, metagenomic, and immunoglobulin A (IgA) sequencing, we analyzed hundreds of longitudinal microbiome samples from a randomized controlled trial of 12 patients with ulcerative colitis who received fecal transplant or placebo for 12 weeks. We uncovered diverse competitive dynamics among donor and patient strains, showing that persistence of transferred microbes is far from static. Indeed, one patient experienced a dramatic loss of donor bacteria 10 weeks into the trial, coinciding with a bloom of pathogenic bacteria and worsening symptoms. We evaluated the transfer of microbial functions, including desired ones, such as butyrate production, and unintended ones, such as antibiotic resistance. By profiling bacteria coated with IgA, we identified bacteria associated with inflammation and found that microbial interactions with the host immune system can be transferred across people, which could play a role in gut microbiome therapeutics for immune-related diseases. Our findings shed light on the colonization dynamics of gut microbes and their functions in the context of FMT to treat a complex disease—information that may provide a foundation for developing more-targeted therapeutics. IMPORTANCE Fecal microbiota transplantation (FMT)—transferring fecal microbes from a healthy donor to a sick patient—has shown promise for gut diseases such as inflammatory bowel disease. Unlike pharmaceuticals, however, fecal transplants are complex mixtures of living organisms, which must then interact with the microbes and immune system of the recipient. We sought to understand these interactions by tracking the microbes of 12 inflammatory bowel disease patients who received fecal transplants for 12 weeks. We uncovered a range of dynamics. For example, one patient experienced successful transfer of donor bacteria, only to lose them after 10 weeks. We similarly evaluated transfer of microbial functions, including how they interacted with the recipient’s immune system. Our findings shed light on the colonization dynamics of gut microbes, as well as their functions in the context of FMT—information that may provide a critical foundation for the development of more-targeted therapeutics.

Abstract Background Mucosal healing is one of the principal therapeutic targets for ulcerative colitis (UC). Mitochondria are dynamic organelles that undergo constant fusion and fission; however, the process that is most conducive to mucosal healing remains unclear. This study investigated the role of mitochondrial fission in mucosal healing in UC patients. Methods Quantitative polymerase chain reaction, Western blotting, and immunostaining were used to detect mitochondrial fission in UC patients and a dextran sulfate sodium–induced colitis model. Colonic organoids were used to investigate the role of mitochondrial fission in butyrate metabolism. Enzyme activity assays were performed to identify the key proteins involved in this mechanism. Results It was found that inhibition of mitochondrial fission promoted mucosal healing in mice and that there was an increase in mitochondrial fission in colonic epithelial cells of UC patients. Excessive fission inhibits stem cell proliferation by impairing butyrate metabolism in colonic organoids. The mitochondrial fission antagonist P110 failed to promote mucosal healing in antibiotic-treated mice, and the addition of exogenous butyrate reversed this effect. Increased butyrate exposure in the colonic stem cell niche has also been observed in UC patients. Mechanistically, enzyme activity assays on colonic organoids revealed that excessive fission inhibits mitochondrial acetoacetyl-CoA thiolase activity via reactive oxygen species. Conclusions Collectively, these data indicate that excessive mitochondrial fission suppresses mucosal repair by inhibiting butyrate metabolism and provides a potential target for mucosal healing in patients with ulcerative colitis.

Background: African Americans (AA) are disproportionally affected by hypertension (HTN). Gut microbiome metabolites (e.g., butyrate) may mediate the relationship between the microbiome and blood pressure (BP). Previous research reports a consistent indirect relationship between gut butyrate, a product of gut microbial nutrient fermentation, and BP. Thus, this study assessed the relationship between individual diet intake on BP changes after a butyrate treatment. Methods: AA aged 30–50 with HTN underwent treatment with a blinded placebo (5 mmol) and butyrate enema (80 mmol) with a one-week washout period. Ambulatory BP monitors collected measures up to 24 h post-enema. The Nutrition Data System for Research was used to assess diet and Healthy Eating Index (HEI-2015) scores from diet records. Paired t-tests and Kendall’s correlation tests determined group differences and relationships between variables (p < 0.05). Results: Positive correlations were found between other vegetables and 24 h diastolic BP (r = 0.64), daytime diastolic BP (r = 0.68), and MAP (r = 0.72). Positive correlations were also found between 24 h systolic BP and HEI-2015 greens and beans sub-scores (r = 0.64) and 24 h DBP and total vegetables (r = 0.64). Negative correlations were found between nighttime arterial stiffness and total grain intake (r = −0.71). Conclusion: These data suggest diet impacts BP measures in response to acutely increasing gut butyrate. These results provide preliminary evidence linking food groups, not individual nutrients, with BP outcomes and gut butyrate availability.

Altered interactions between the gut mucosa and bacteria during HIV infection seem to contribute to chronic immune dysfunction. A deeper understanding of how nutritional interventions could ameliorate gut dysbiosis is needed. Forty-four subjects, including 12 HIV+ viremic untreated (VU) patients, 23 antiretroviral therapy-treated (ART+) virally suppressed patients (15 immunological responders and 8 non-responders) and 9 HIV− controls (HIV−), were blindly randomized to receive either prebiotics (scGOS/lcFOS/glutamine) or placebo (34/10) over 6 weeks in this pilot study. We assessed fecal microbiota composition using deep 16S rRNA gene sequencing and several immunological and genetic markers involved in HIV immunopathogenesis. The short dietary supplementation attenuated HIV-associated dysbiosis, which was most apparent in VU individuals but less so in ART+ subjects, whose gut microbiota was found more resilient. This compositional shift was not observed in the placebo arm. Significantly, declines in indirect markers of bacterial translocation and T-cell activation, improvement of thymic output, and changes in butyrate production were observed. Increases in the abundance of Faecalibacterium and Lachnospira strongly correlated with moderate but significant increases of butyrate production and amelioration of the inflammatory biomarkers soluble CD14 and high-sensitivity C-reactive protein, especially among VU. Hence, the bacterial butyrate synthesis pathway holds promise as a viable target for interventions.

Butyrate plays a crucial role in osteoarthritis (OA) development. However, the relationship between butyrate metabolism-related genes (BMRGs) and OA remains unclear. This study investigates the potential correlation between BMRGs and OA using OA-related datasets (GSE55235, GSE12021 and GSE143514). Differential expression analysis identified 38 differentially expressed butyrate metabolism-related genes (DE-BMRGs) from the overlap of 782 OA-related differentially expressed genes (DEGs) and 385 BMRGs in GSE55235. Enrichment analysis indicated that these DE-BMRGs were tightly associated with cell proliferation, differentiation, and apoptosis, which are key processes in OA pathogenesis. Six candidate biomarkers (IL1B, IGF1, CXCL8, PTGS2, SERPINE1, MMP9) were identified through two machine-learning algorithms. IL1B, CXCL8, and PTGS2 were upregulated in controls, exhibiting consistent patterns across validation datasets. Gene set enrichment analysis (GSEA) revealed that dysregulated expression of these biomarkers lead to abnormal cell proliferation and differentiation, contributing to OA progression. Furthermore, significant differences in immune cell infiltration—particularly activated and resting mast cells—along with correlations to immune regulatory factors (CD86, CXCL12, TNFSF9, IL6), highlighted potential therapeutic targets. Quantitative RT-PCR further confirmed elevated expression of IL1B, CXCL8 and PTGS2 in control group. This study identifies IL1B, CXCL8 and PTGS2 as OA-related biomarkers linked to butyrate metabolism, offering a theoretical foundation and potential therapeutic strategies.

Background/Objectives: Severe infection (sInfection; either late-onset culture-proven sepsis or necrotizing enterocolitis) in very low birth weight (VLBW) infants increases mortality rates and may show long-term progression. The fecal microbiome composition in VLBW infants with and without sInfection was classified in the sInfection and non-sInfection groups. Methods: Gut microbiomes, secondary information from a previous randomized trial, were analyzed using QIIME 2 software. The biodiversity and abundance of the gut microbiota between the sInfection and non-sInfection groups were compared. Results: Fifty-one neonates were included in the sInfection (n = 9) and non-sInfection (n = 42) groups; no significant differences in the fecal microbiome were observed in both alpha and beta diversities. Analysis of relative abundance revealed that in both groups, the predominant gut microbiota phylum, class, and genus were Proteobacteria, Gammaproteobacteria, and Klebsiella, respectively. The main fecal microbiome in the non-sInfection group included Faecalibacterium, Clostridium butyricum, and Bacteroides fragilis. Clostridium_sensu_stricto _1 was significantly more abundant in the non-sInfection group than in the sInfection group. Conclusions: Clostridium_sensu_stricto_1 was the main gut microbiota in the non-sInfection group. Considering the potential taxa as synbiotics (correlations among prebiotics, probiotics, and postbiotics), therapeutics may be useful for preventing and managing necrotizing enterocolitis or late-onset culture-proven sepsis in VLBW infants.

(1) Background: Alterations in the structural composition of the human gut microbiota have been identified in various disease entities along with exciting mechanistic clues by reductionist gnotobiotic modeling. Improving health by beneficially modulating an altered microbiota is a promising treatment approach. Prebiotics, substrates selectively used by host microorganisms conferring a health benefit, are broadly used for dietary and clinical interventions. Herein, we sought to investigate the microbiota-modelling effects of the soluble fiber, partially hydrolyzed guar gum (PHGG). (2) Methods: We performed a 9 week clinical trial in 20 healthy volunteers that included three weeks of a lead-in period, followed by three weeks of an intervention phase, wherein study subjects received 5 g PHGG up to three times per day, and concluding with a three-week washout period. A stool diary was kept on a daily basis, and clinical data along with serum/plasma and stool samples were collected on a weekly basis. PHGG-induced alterations of the gut microbiota were studied by 16S metagenomics of the V1–V3 and V3–V4 regions. To gain functional insight, we further studied stool metabolites using nuclear magnetic resonance (NMR) spectroscopy. (3) Results: In healthy subjects, PHGG had significant effects on stool frequency and consistency. These effects were paralleled by changes in α- (species evenness) and β-diversity (Bray–Curtis distances), along with increasing abundances of metabolites including butyrate, acetate and various amino acids. On a taxonomic level, PHGG intake was associated with a bloom in Ruminococcus, Fusicatenibacter, Faecalibacterium and Bacteroides and a reduction in Roseburia, Lachnospiracea and Blautia. The majority of effects disappeared after stopping the prebiotic and most effects tended to be more pronounced in male participants. (4) Conclusions: Herein, we describe novel aspects of the prebiotic PHGG on compositional and functional properties of the healthy human microbiota.