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Diet is a major factor that shapes the gut microbiome 1 , but the consequences of diet-induced changes in the microbiome for host pathophysiology remain poorly understood. We conducted a randomized human intervention study using a very-low-calorie diet (NCT01105143). Although metabolic health was improved, severe calorie restriction led to a decrease in bacterial abundance and restructuring of the gut microbiome. Transplantation of post-diet microbiota to mice decreased their body weight and adiposity relative to mice that received pre-diet microbiota. Weight loss was associated with impaired nutrient absorption and enrichment in Clostridioides difficile , which was consistent with a decrease in bile acids and was sufficient to replicate metabolic phenotypes in mice in a toxin-dependent manner. These results emphasize the importance of diet–microbiome interactions in modulating host energy balance and the need to understand the role of diet in the interplay between pathogenic and beneficial symbionts. Severe caloric restriction in humans leads to reversible changes in the gut microbiota that promote weight loss and the expansion of an enteric pathogen in mice.

A randomized clinical trial reveals that the antidiabetic effects of metformin are at least partially due to beneficial changes in the microbiota. Metformin is widely used in the treatment of type 2 diabetes (T2D), but its mechanism of action is poorly defined. Recent evidence implicates the gut microbiota as a site of metformin action. In a double-blind study, we randomized individuals with treatment-naive T2D to placebo or metformin for 4 months and showed that metformin had strong effects on the gut microbiome. These results were verified in a subset of the placebo group that switched to metformin 6 months after the start of the trial. Transfer of fecal samples (obtained before and 4 months after treatment) from metformin-treated donors to germ-free mice showed that glucose tolerance was improved in mice that received metformin-altered microbiota. By directly investigating metformin–microbiota interactions in a gut simulator, we showed that metformin affected pathways with common biological functions in species from two different phyla, and many of the metformin-regulated genes in these species encoded metalloproteins or metal transporters. Our findings provide support for the notion that altered gut microbiota mediates some of metformin's antidiabetic effects.

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.

We aimed to assess the effects of 2 isoenergetic intervention diets (a freshwater fish-based diet [F group] or freshwater fish-based and red meat-based diets alternately [F/M group]) on liver steatosis and their relationship with intestinal flora in patients with nonalcoholic fatty liver disease (NAFLD). In this open-label, 84-day randomized controlled trial, 34 NAFLD patients with hepatic steatosis ≥10% were randomly assigned to the F group or F/M group in a 1:1 ratio using a computer-generated random number allocation by a researcher not involved in the study. Liver fat content and gut microbiota and its metabolites were measured. At the end of intervention, the absolute reduction of hepatic steatosis was significantly greater in the F group than in the F/M group (-4.89% vs -1.83%, P = 0.032). Of the 16 secondary clinical outcomes, the improvement in 7 in the F group was greater compared with the F/M group, including alanine aminotransferase and gamma-glutamyl transferase. Furthermore, dietary freshwater fish and red meat consumption alternately did not exacerbate NAFLD. Moreover, changes in the enrichment of Faecalibacterium, short-chain fatty acids, and unconjugated bile acids and the depletion of Prevotella 9 and conjugated bile acids in the F group were significantly greater compared with the F/M group. Higher intake of freshwater fish may be beneficial to NAFLD by regulating gut microbiota and its metabolites, whereas intake of a similar total of animal protein and fat from the alternating freshwater fish and red meat may not be harmful for NAFLD in the dietary management of patients with NAFLD.

Purpose Chronic intakes of functional foods (probiotics, apples and oats) have been reported to have beneficial effects on hepatic lipid regulation and glycaemic control, but mechanistic human studies humans are limited. An ex-vivo study was performed to determine the chronic effects of probiotics, oats, and apples on the expression of genes related to markers of cardiometabolic health in peripheral blood monocular cells (PBMC). Methods In this CABALA sub-study ( n  = 59/61, age: 52 ± 12y), blood PBMC were also isolated before and 8 weeks after the daily consumption of either a probiotic with bile salt hydrolase activity (Lactobacillus reuteri ), porridge oats, Renetta Canada apples or a control. Relative PBMC mRNA gene expression was determined and correlations performed between the fold change in response to the functional interventions and change in cardiometabolic disease risk markers. Results Relative to baseline, there was an upregulation in the PBMC TLR4 mRNA expression in the control compared with the probiotics and apples groups (p 0.024). Moderate inverse correlations were found between the fold change in GPBAR1 mRNA expression and change in plasma total and secondary BAs, HMGCR and SREBF1 mRNA gene expressions and high-density lipoprotein-cholesterol, and SREBF1 and GIPR mRNA gene expressions and glucose. TLR4 and TNFSF14 mRNA gene expressions were associated with pro-inflammatory cytokines ( p =0.05). Conclusion Probiotic and apples interventions attenuated the upregulation in PBMC TLR4 mRNA expression observed with the control. Correlations between fold change in mRNA gene expression and changes in cardiometabolic disease risk markers in response to the functional interventions were in agreement with previous studies. Clinical trial registry The study was registered at clinical trials.gov (ref. NCT03369548).

Objective: To identify factors contributing to the variation in weight loss after Roux-en-Y gastric bypass (RYGB). Design: Cross-sectional study of patients with good (excess body mass index lost (EBL) >60%) and poor weight loss response (EBL <50%) >12 months after RYGB and a lean control group matched for age and gender. Materials and methods: Sixteen patients with good weight loss response, 17 patients with poor weight loss response, and eight control subjects were included in the study. Participants underwent dual energy X-ray absorptiometry scan, indirect calorimetry and a 9 h multiple-meal test with measurements of glucose, insulin, total bile acids (TBA), glucagon-like peptide (GLP)-1, peptide YY 3–36 (PYY), cholecystokinin (CCK), ghrelin, neurotensin and pancreatic polypeptide (PP) as well as assessment of early dumping and appetite. Results: Suppression of hunger was more pronounced in the good than the poor responders in response to the multiple-meal test ( P =0.006). In addition, the good responders had a larger release of GLP-1 ( P =0.009) and a greater suppression of ghrelin ( P =0.037) during the test, whereas the postprandial secretion of CCK was highest in the poor responders ( P =0.005). PYY, neurotensin, PP and TBA release did not differ between the RYGB-operated groups. Compared with control subjects, patients had exaggerated release of GLP-1 ( P <0.001), PYY ( P =0.008), CCK ( P =0.010) and neurotensin ( P <0.001). Early dumping was comparable in the good and poor responders, but more pronounced than in controlled subjects. Differences in resting energy expenditure between the three groups were entirely explained by differences in body composition. Conclusion: Favorable meal-induced changes in hunger and gut hormone release in patients with good compared with poor weight loss response support the role of gut hormones in the weight loss after RYGB.

Donor-derived fecal microbiota treatments are efficacious in preventing recurrent Clostridioides difficile infection (rCDI), but they have inherently variable quality attributes, are difficult to scale and harbor the risk of pathogen transfer. In contrast, VE303 is a defined consortium of eight purified, clonal bacterial strains developed for prevention of rCDI. In the phase 2 CONSORTIUM study, high-dose VE303 was well tolerated and reduced the odds of rCDI by more than 80% compared to placebo. VE303 organisms robustly colonized the gut in the high-dose group and were among the top taxa associated with non-recurrence. Multi-omic modeling identified antibiotic history, baseline stool metabolites and serum cytokines as predictors of both on-study CDI recurrence and VE303 colonization. VE303 potentiated early recovery of the host microbiome and metabolites with increases in short-chain fatty acids, secondary bile acids and bile salt hydrolase genes after antibiotic treatment for CDI, which is considered important to prevent CDI recurrences. These results support the idea that VE303 promotes efficacy in rCDI through multiple mechanisms. Results of multi-omic profiling of the microbiome and host immunity of individuals treated with VE303 to prevent recurrent Clostridioides difficile infection in the context of a phase 2 trial show robust colonization of VE303 and indicate potential biomarkers of response.

Peanut Oral Immunotherapy (POIT) holds promise for remission of peanut allergy, though treatment is protracted and successful in only a subset of patients. Because the gut microbiome has been linked to food allergy, we sought to identify fecal predictors of POIT efficacy and mechanistic insights into treatment response. Here, we conducted a secondary analysis of the IMPACT randomized, double-blind, placebo-controlled POIT trial (NCT01867671), using longitudinal fecal samples from 90 children, and performed 16S rRNA sequencing, shotgun metagenomics, and untargeted metabolomics. Integrated multi-omics analyses revealed a relationship between gut microbiome metabolic capacity and treatment outcomes. Five fecal bile acids present prior to treatment initiation predicted POIT efficacy (AUC 0.71). Treatment failure was associated with a specific bile acid profile, enhanced amino acid utilization, and higher copy number of the ptpA gene encoding a bacterial hydrolase that cleaves tripeptides containing proline residues – a feature of immunogenic peanut Ara h 2 proteins. In vitro, peanut-supplemented fecal cultures of children for whom POIT failed to induce remission evidenced reduced Ara h 2 concentrations. Thus, distal gut microbiome metabolism appears to contribute to POIT failure. Peanut oral immunotherapy (POIT) can treat peanut allergy, but only a subset of patients achieve lasting remission. Here, the authors show that POIT efficacy is associated with the gut microbiome’s functional capacity, specifically bile and amino acid metabolism and protein degradation.

The timing of dietary total fat intake influences glucose homeostasis, however, the impact of unsaturated fat (USFA) intake has yet to be explored. This 12-week, double-blind, randomized, controlled, 2 × 2 factorial-designed feeding trial investigated the effects of timing (lunch or dinner) and types of dietary USFA (high monounsaturated fat or polyunsaturated fat diet) intake on glucose metabolism in seventy prediabetes participants (mean age, 57 years). Sixty participants with completed fecal samples were included in the final analysis ( n  = 15 for each group). Postprandial serum glucose was first primary outcome, postprandial insulin levels and insulin sensitivity indices were co-primary outcomes Secondary outcomes were continuous glucose levels, serum fatty acid profile, gut microbiome (metagenomic sequencing) and fecal metabolites. Results showed no significant differences in postprandial glucose between groups. However, USFA intake at lunch (vs. dinner) improved insulin sensitivity and reduced postprandial insulin and serum free saturated fatty acid ( P timing  < 0.05, P type  > 0.05, P interaction  > 0.05), which was associated with alterations in gut microbiome and bile acid metabolism, regardless of USFA type. In summary, these results suggest that advancing timing of USFA intake improves insulin sensitivity through the gut microbiome and bile acid metabolism. Trial registration: ChiCTR2100045645. Here, Ying Li et al. present the results of a randomized controlled feeding trial in prediabetes participants, finding that advancing timing of unsaturated fat (USFA) intake improves insulin sensitivity through the gut microbiome and bile acid metabolism, regardless of USFA type.

(1) Background: Dyslipidemia represents a major risk factor for atherosclerosis-driven cardiovascular disease. Emerging evidence suggests a close relationship between cholesterol metabolism and gut microbiota. Recently, we demonstrated that the short-chain fatty acid (SCFA) propionate (PA) reduces serum cholesterol levels through an immunomodulatory mechanism. Here, we investigated the effects of oral PA supplementation on the human serum metabolome and analyzed changes in the serum metabolome in relation to the cholesterol-lowering properties of PA. (2) Methods: The serum metabolome of patients supplemented with either placebo or propionate orally for 8 weeks was assessed using a combination of flow injection analysis-tandem (FIA-MS/MS) as well as liquid chromatography (LC-MS/MS) and mass spectrometry using a targeted metabolomics kit (MxP®Quant 500 kit: BIOCRATES Life Sciences AG, Innsbruck, Austria). A total of 431 metabolites were employed for further investigation in this study. (3) Results: We observed a significant increase in distinct bile acids (GCDCA: fold change = 1.41, DCA: fold change = 1.39, GUDCA: fold change = 1.51) following PA supplementation over the study period, with the secondary bile acid DCA displaying a significant negative correlation with the serum cholesterol levels. (4) Conclusions: Oral supplementation with PA modulates the serum metabolome with a particular impact on the circulatory bile acid profile. Since cholesterol and bile acid metabolism are interconnected, the elevation of the secondary bile acid DCA may contribute to the cholesterol-lowering effect of PA.