The gut microbiome-prostate cancer crosstalk is modulated by dietary polyunsaturated long-chain fatty acids.

The gut microbiota modulates response to hormonal treatments in prostate cancer (PCa) patients, but whether it influences PCa progression remains unknown. Here, we show a reduction in fecal microbiota alpha-diversity correlating with increase tumour burden in two distinct groups of hormonotherapy naïve PCa patients and three murine PCa models. Fecal microbiota transplantation (FMT) from patients with high PCa volume is sufficient to stimulate the growth of mouse PCa revealing the existence of a gut microbiome-cancer crosstalk. Analysis of gut microbial-related pathways in mice with aggressive PCa identifies three enzymes responsible for the metabolism of long-chain fatty acids (LCFA). Supplementation with LCFA omega-3 MAG-EPA is sufficient to reduce PCa growth in mice and cancer up-grading in pre-prostatectomy PCa patients correlating with a reduction of gut Ruminococcaceae in both and fecal butyrate levels in PCa patients. This suggests that the beneficial effect of omega-3 rich diet is mediated in part by modulating the crosstalk between gut microbes and their metabolites in men with PCa.

Rebaudioside D decreases adiposity and hepatic lipid accumulation in a mouse model of obesity.

Overconsumption of added sugars has been pointed out as a major culprit in the increasing rates of obesity worldwide, contributing to the rising popularity of non-caloric sweeteners. In order to satisfy the growing demand, industrial efforts have been made to purify the sweet-tasting molecules found in the natural sweetener stevia, which are characterized by a sweet taste free of unpleasant aftertaste. Although the use of artificial sweeteners has raised many concerns regarding metabolic health, the impact of purified stevia components on the latter remains poorly studied. The objective of this project was to evaluate the impact of two purified sweet-tasting components of stevia, rebaudioside A and D (RebA and RebD), on the development of obesity, insulin resistance, hepatic health, bile acid profile, and gut microbiota in a mouse model of diet-induced obesity. Male C57BL/6 J mice were fed an obesogenic high-fat/high-sucrose (HFHS) diet and orally treated with 50 mg/kg of RebA, RebD or vehicle (water) for 12 weeks. An additional group of chow-fed mice treated with the vehicle was included as a healthy reference. At weeks 10 and 12, insulin and oral glucose tolerance tests were performed. Liver lipids content was analyzed. Whole-genome shotgun sequencing was performed to profile the gut microbiota. Bile acids were measured in the feces, plasma, and liver. Liver lipid content and gene expression were analyzed. As compared to the HFHS-vehicle treatment group, mice administered RebD showed a reduced weight gain, as evidenced by decreased visceral adipose tissue weight. Liver triglycerides and cholesterol from RebD-treated mice were lower and lipid peroxidation was decreased. Interestingly, administration of RebD was associated with a significant enrichment of Faecalibaculum rodentium in the gut microbiota and an increased secondary bile acid metabolism. Moreover, RebD decreased the level of lipopolysaccharide-binding protein (LBP). Neither RebA nor RebD treatments were found to impact glucose homeostasis. The daily consumption of two stevia components has no detrimental effects on metabolic health. In contrast, RebD treatment was found to reduce adiposity, alleviate hepatic steatosis and lipid peroxidation, and decrease LBP, a marker of metabolic endotoxemia in a mouse model of diet-induced obesity.

Perturbations in lipid metabolism and gut microbiota composition precede cardiac dysfunction in a mouse model of thalassemia.

Cardiomyopathy is a major complication of thalassemia, yet the precise underlying molecular mechanisms remain unclear. We examined whether altered lipid metabolism is an early driving factor in the development of cardiomyopathy using the Th3/+ mouse model of thalassemia. At age 20 weeks, male and female Th3/+ mice manifested anemia and iron overload; however, only males displayed metabolic defects and altered cardiac function. Untargeted lipidomics indicated that the circulating levels of 35 lipid species were significantly altered in Th3/+ mice compared to wild-type controls: triglycerides (TGs) with saturated fatty acids (FAs; TG42:0 and TG44:0) were elevated, while TGs with unsaturated FAs (TG(18:2_20:5_18:2 and TG54:8)) were reduced. Similarly, phosphatidylcholines (PCs) with long chain FAs (palmitic (16:0) or oleic (18:1)) were increased, while PCs with polyunsaturated FAs decreased. Circulating PC(16:0_14:0), GlcCer(d18:1/24:0) correlated significantly with iron overload and cardiac hypertrophy. 16S rRNA gene profiling revealed alterations in the intestinal microbiota of Th3/+ mice. Differentially abundant bacterial genera correlated with PC(39:6), PC(18:1_22:6), GlcCer(d18:1/24:1) and CE(14:0). These results provide new knowledge on perturbations in lipid metabolism and the gut microbiota of Th3/+ mice and identify specific factors which may represent early biomarkers or therapeutic targets to prevent development of cardiomyopathy in ß-thalassemia.

The metabolic benefits of substituting sucrose for maple syrup are associated with a shift in carbohydrate digestion and gut microbiota composition in high-fat high-sucrose diet-fed mice.

Overconsumption of added sugars is now largely recognized as a major culprit in the global situation of obesity and metabolic disorders. Previous animal studies reported that maple syrup (MS) is less deleterious than refined sugars on glucose metabolism and hepatic health, but the mechanisms remain poorly studied. Beyond its content in sucrose, MS is a natural sweetener containing several bioactive compounds, such as polyphenols and inulin, which are potential gut microbiota modifiers. We aimed to investigate the impact of MS on metabolic health and gut microbiota in male C57Bl/6J mice fed a high-fat high-sucrose (HFHS + S) diet or an isocaloric HFHS diet in which a fraction (10% of the total caloric intake) of the sucrose was substituted by MS (HFHS + MS). Insulin and glucose tolerance tests were performed at 5 and 7 wk into the diet, respectively. The fecal microbiota was analyzed by whole-genome shotgun sequencing. Liver lipids and inflammation were determined, and hepatic gene expression was assessed by transcriptomic analysis. Maple syrup was less deleterious on insulin resistance and decreased liver steatosis compared with mice consuming sucrose. This could be explained by the decreased intestinal α-glucosidase activity, which is involved in carbohydrate digestion and absorption. Metagenomic shotgun sequencing analysis revealed that MS intake increased the abundance of Faecalibaculum rodentium, Romboutsia ilealis, and Lactobacillus johnsonii, which all possess gene clusters involved in carbohydrate metabolism, such as sucrose utilization and butyric acid production. Liver transcriptomic analyses revealed that the cytochrome P450 (Cyp450) epoxygenase pathway was differently modulated between HFHS + S- and HFHS + MS-fed mice. These results show that substituting sucrose for MS alleviated dysmetabolism in diet-induced obese mice, which were associated with decreased carbohydrate digestion and shifting gut microbiota.NEW & NOTEWORTHY The natural sweetener maple syrup has sparked much interest as an alternative to refined sugars. This study aimed to investigate whether the metabolic benefits of substituting sucrose with an equivalent dose of maple syrup could be linked to changes in gut microbiota composition and digestion of carbohydrates in obese mice. We demonstrated that maple syrup is less detrimental than sucrose on metabolic health and possesses a prebiotic-like activity through novel gut microbiota and liver mechanisms.

Hypoabsorptive surgeries cause limb-dependent changes in the gut endocannabinoidome and microbiome in association with beneficial metabolic effects.

OBJECTIVE: To determine whether the metabolic benefits of hypoabsorptive surgeries are associated with changes in the gut endocannabinoidome (eCBome) and microbiome. METHODS: Biliopancreatic diversion with duodenal switch (BPD-DS) and single anastomosis duodeno-ileal bypass with sleeve gastrectomy (SADI-S) were performed in diet-induced obese (DIO) male Wistar rats. Control groups fed a high-fat diet (HF) included sham-operated (SHAM HF) and SHAM HF-pair-weighed to BPD-DS (SHAM HF-PW). Body weight, fat mass gain, fecal energy loss, HOMA-IR, and gut-secreted hormone levels were measured. The levels of eCBome lipid mediators and prostaglandins were quantified in different intestinal segments by LC-MS/MS, while expression levels of genes encoding eCBome metabolic enzymes and receptors were determined by RT-qPCR. Metataxonomic (16S rRNA) analysis was performed on residual distal jejunum, proximal jejunum, and ileum contents. RESULTS: BPD-DS and SADI-S reduced fat gain and HOMA-IR, while increasing glucagon-like peptide-1 (GLP-1) and peptide tyrosine tyrosine (PYY) levels in HF-fed rats. Both surgeries induced potent limb-dependent alterations in eCBome mediators and in gut microbial ecology. In response to BPD-DS and SADI-S, changes in gut microbiota were significantly correlated with those of eCBome mediators. Principal component analyses revealed connections between PYY, N-oleoylethanolamine (OEA), N-linoleoylethanolamine (LEA), Clostridium, and Enterobacteriaceae_g_2 in the proximal and distal jejunum and in the ileum. CONCLUSIONS: BPD-DS and SADI-S caused limb-dependent changes in the gut eCBome and microbiome. The present results indicate that these variables could significantly influence the beneficial metabolic outcome of hypoabsorptive bariatric surgeries.

Probiotic Supplementation, Hepatic Fibrosis, and the Microbiota Profile in Patients with Nonalcoholic Steatohepatitis: A Randomized Controlled Trial.

BACKGROUND: Promising results in improvement of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis (NASH) have been identified following probiotic (PRO) treatment. OBJECTIVES: To evaluate PRO supplementation on hepatic fibrosis, inflammatory and metabolic markers, and gut microbiota in NASH patients. METHODS: In a double-blind, placebo-controlled clinical trial, 48 patients with NASH with a median age of 58 y and median BMI of 32.7 kg/m2 were randomly assigned to receive PROs (Lactobacillus acidophilus 1 × 109 colony forming units and Bifidobacterium lactis 1 × 109 colony forming units) or a placebo daily for 6 mo. Serum aminotransferases, total cholesterol and fractions, C-reactive protein, ferritin, interleukin-6, tumor necrosis factor-α, monocyte chemoattractant protein-1, and leptin were assessed. To evaluate liver fibrosis, Fibromax was used. In addition, 16S rRNA gene-based analysis was performed to evaluate gut microbiota composition. All assessments were performed at baseline and after 6 mo. For the assessment of outcomes after treatment, mixed generalized linear models were used to evaluate the main effects of the group-moment interaction. For multiple comparisons, Bonferroni correction was applied (α = 0.05/4 = 0.0125). Results for the outcomes are presented as mean and SE. RESULTS: The AST to Platelet Ratio Index (APRI) score was the primary outcome that decreased over time in the PRO group. Aspartate aminotransferase presented a statistically significant result in the group-moment interaction analyses, but no statistical significance was found after the Bonferroni correction. Liver fibrosis, steatosis, and inflammatory activity presented no statistically significant differences between the groups. No major shifts in gut microbiota composition were identified between groups after PRO treatment. CONCLUSIONS: Patients with NASH who received PRO supplementation for 6 mo presented improvement in the APRI score after treatment. These results draw attention to clinical practice and suggest that supplementation with PROs alone is not sufficient to improve enzymatic liver markers, inflammatory parameters, and gut microbiota in patients with NASH. This trial was registered at clinicaltrials.gov as NCT02764047.

Gnotobiotic mice housing conditions critically influence the phenotype associated with transfer of faecal microbiota in a context of obesity.

OBJECTIVE: Faecal microbiota transplantation (FMT) in germ-free (GF) mice is a common approach to study the causal role of the gut microbiota in metabolic diseases. Lack of consideration of housing conditions post-FMT may contribute to study heterogeneity. We compared the impact of two housing strategies on the metabolic outcomes of GF mice colonised by gut microbiota from mice treated with a known gut modulator (cranberry proanthocyanidins (PAC)) or vehicle. DESIGN: High-fat high-sucrose diet-fed GF mice underwent FMT-PAC colonisation in sterile individual positive flow ventilated cages under rigorous housing conditions and then maintained for 8 weeks either in the gnotobiotic-axenic sector or in the specific pathogen free (SPF) sector of the same animal facility. RESULTS: Unexpectedly, 8 weeks after colonisation, we observed opposing liver phenotypes dependent on the housing environment of mice. Mice housed in the GF sector receiving the PAC gut microbiota showed a significant decrease in liver weight and hepatic triglyceride accumulation compared with control group. Conversely, exacerbated liver steatosis was observed in the FMT-PAC mice housed in the SPF sector. These phenotypic differences were associated with housing-specific profiles of colonising bacterial in the gut and of faecal metabolites. CONCLUSION: These results suggest that the housing environment in which gnotobiotic mice are maintained post-FMT strongly influences gut microbiota composition and function and can lead to distinctive phenotypes in recipient mice. Better standardisation of FMT experiments is needed to ensure reproducible and translatable results.

Comparing Transgenic Production to Supplementation of ω-3 PUFA Reveals Distinct But Overlapping Mechanisms Underlying Protection Against Metabolic and Hepatic Disorders.

We compared endogenous ω-3 PUFA production to supplementation for improving obesity-related metabolic dysfunction. Fat-1 transgenic mice, who endogenously convert exogenous ω-6 to ω-3 PUFA, and wild-type littermates were fed a high-fat diet and a daily dose of either ω-3 or ω-6 PUFA-rich oil for 12 wk. The endogenous ω-3 PUFA production improved glucose intolerance and insulin resistance but not hepatic steatosis. Conversely, ω-3 PUFA supplementation fully prevented hepatic steatosis but failed to improve insulin resistance. Both models increased hepatic levels of ω-3 PUFA-containing 2-monoacylglycerol and N-acylethanolamine congeners, and reduced levels of ω-6 PUFA-derived endocannabinoids with ω-3 PUFA supplementation being more efficacious. Reduced hepatic lipid accumulation associated with the endocannabinoidome metabolites EPEA and DHEA, which was causally demonstrated by lower lipid accumulation in oleic acid-treated hepatic cells treated with these metabolites. While both models induced a significant fecal enrichment of the beneficial Allobaculum genus, mice supplemented with ω-3 PUFA displayed additional changes in the gut microbiota functions with a significant reduction of fecal levels of the proinflammatory molecules lipopolysaccharide and flagellin. Multiple-factor analysis identify that the metabolic improvements induced by ω-3 PUFAs were accompanied by a reduced production of the proinflammatory cytokine TNFα, and that ω-3 PUFA supplementation had a stronger effect on improving the hepatic fatty acid profile than endogenous ω-3 PUFA. While endogenous ω-3 PUFA production preferably improves glucose tolerance and insulin resistance, ω-3 PUFA intake appears to be required to elicit selective changes in hepatic endocannabinoidome signaling that are essential to alleviate high-fat diet-induced hepatic steatosis.

Copper fabric improves the metabolic profile of obese mice: Potential role of the gut microbiota.

Copper and copper alloys have antimicrobial activity through the rapid contact killing of viruses, bacteria and yeasts on their surface. Dysregulation of host microbiota can contribute to the pathogenesis of inflammatory diseases such as obesity, diabetes and cardiovascular disease. Anecdotal evidence noted improved overall well-being in individuals sleeping on copper-containing fabric bedding. We hypothesized that the beneficial effect of copper-infused fabric bedding on cardiometabolic health is linked to changes in gut microbiota composition. This study utilized a mouse model of diet-induced obesity to assess the beneficial effects of copper-infused fabric bedding on metabolic health. Body composition, inflammatory markers, metabolic and cardiovascular status and changes in the faecal microbiota composition were evaluated for up to 2 months in mice fed with a normal chow diet or high fat high cholesterol diet in the presence of bedding made with and without copper-infused fabric. Results showed that mice subjected to diet-induced obesity and housed in cages with copper-infused fabric liner displayed less body weight gain than mice in cages with control fabric. Mice housed with copper-infused fabric also displayed improved glucose tolerance and reduced inflammation biomarker lipocalin-2. We also observed a beneficial shift in gut bacterial composition of obese mice housed with copper fabric bedding. Taken in conjunction, our study provides direct animal-based evidence supporting the beneficial effects of copper fabric on metabolic health.

Changes in systolic blood pressure, postprandial glucose, and gut microbial composition following mango consumption in individuals with overweight and obesity.

This study aimed to explore the impact of daily mango consumption (Mangifera indica) on cardiometabolic health and gut microbiota in individuals with overweight and obesity. Changes in cardiometabolic variables, gut microbiota diversity and composition, physical activity habits, and dietary intakes were assessed in 8 males and 19 females with overweight and obesity who consumed 280 g/day of mango pulp for 8 weeks. There were no significant changes in body weight, waist circumference, or plasma lipid levels. However, after consuming mangos for 8 weeks, participants showed a 3.5% reduction in systolic blood pressure (-4 ± 6 mm Hg, p = 0.011) as well as a 10.5% reduction in 2-hour plasma glucose concentration after a 75-g oral glucose tolerance test (-0.58 ± 1.03 mmol/L, p = 0.008). These beneficial cardiometabolic outcomes were accompanied with enhanced gut microbiota diversity and with changes in the abundance of specific gut bacterial species. Mango consumption may have beneficial effects on both blood pressure and glucose homeostasis in individuals with overweight and obesity. Further studies are warranted to determine the impact of long-term and regular mango intake on cardiometabolic risk factors of individuals with overweight and obesity, and the potential mechanisms linking gut microbial changes to those health benefits. This study was registered with clinicaltrials.gov as NCT03825276. Novelty: A 3.5% reduction in systolic blood pressure is noted after consuming mangos for 8 weeks. A 10.5% reduction in 2-hour plasma glucose concentration of an oral glucose tolerance test is observed after consuming mangos for 8 weeks. Mango consumption for 8 weeks may enhance gut microbial diversity and abundance of specific bacterial species.

Raspberry consumption: identification of distinct immune-metabolic response profiles by whole blood transcriptome profiling.

Numerous studies have reported that diets rich in phenolic compounds are beneficial to immune-metabolic health, yet these effects are heterogeneous and the underlying mechanisms are poorly understood. To investigate the inter-individual variability of the immune-metabolic response to raspberry consumption, whole-blood RNAseq data from 24 participants receiving 280 g/d of raspberries for 8 weeks were used for the identification of responsiveness subgroups by using partial least squares-discriminant analysis (PLSDA) and hierarchical clustering. Transcriptomic-based clustering regrouped participants into two distinct subgroups of 13 and 11 participants, so-called responders and non-responders, respectively. Following raspberry consumption, a significant decrease in triglycerides, cholesterol and C-reactive protein levels were found in responders, as compared to non-responders. Two major gene expression components of 100 and 220 genes were identified by sparse PLSDA as those better discriminating responders from non-responders, and functional analysis identified pathways related to cytokine production, leukocyte activation and immune response as significantly enriched with most discriminant genes. As compared to non-responders, the plasma lipidomic profile of responders was characterized by a significant decrease in triglycerides and an increase in phosphatidylcholines following raspberry consumption. Prior to the intervention, a distinct metagenomic profile was identified by PLSDA between responsiveness subgroups, and the Firmicutes-to-Bacteroidota ratio was found significantly lower in responders, as compared to non-responders. Findings point to this transcriptomic-based clustering approach as a suitable tool to identify distinct responsiveness subgroups to raspberry consumption. This approach represents a promising framework to tackle the issue of inter-individual variability in the understanding of the impact of foods on immune-metabolic health.

Consistent gut bacterial and short-chain fatty acid signatures in hypoabsorptive bariatric surgeries correlate with metabolic benefits in rats.

OBJECTIVE: The study aimed at comparing how changes in the gut microbiota are associated to the beneficial effects of the most clinically efficient hypoabsorptive bariatric procedures, namely Roux-en-Y gastric bypass (RYGB), biliopancreatic diversion with duodenal switch (BPD-DS) and single anastomosis duodeno-ileal bypass with sleeve gastrectomy (SADI-S). METHODS: Diet-induced obese (DIO) male Wistar rats were divided into seven groups. In addition to the groups subjected to RYGB, BPD-DS and SADI-S, the following four control groups were included: SHAM-operated rats fed a high-fat diet (SHAM HF), SHAM fed a low-fat diet (SHAM LF), SHAM HF-pair-weighed to BPD-DS (SHAM HF-PW) and sleeve-gastrectomy (SG) rats. Body weight, food intake, glucose tolerance, insulin sensitivity/resistance, and L-cell secretion were assessed. The gut microbiota (16 S ribosomal RNA gene sequencing) as well as the fecal and cæcal contents of short-chain fatty acids (SCFAs) were also analyzed prior to, and after the surgeries. RESULTS: The present study demonstrates the beneficial effect of RYGB, BPD-DS and SADI-S on fat mass gain and glucose metabolism in DIO rats. These benefits were proportional to the effect of the surgeries on food digestibility (BPD-DS > SADI-S > RYGB). Notably, hypoabsorptive surgeries led to consonant microbial signatures characterized by decreased abundance of the Ruminococcaceae (Oscillospira and Ruminococcus), Oscillospiraceae (Oscillibacter) and Christensenellaceae, and increased abundance of the Clostridiaceae (Clostridium), Sutterellaceae (Sutterella) and Enterobacteriaceae. The gut bacteria following hypoabsorptive surgeries were associated with higher fecal levels of propionate, butyrate, isobutyrate and isovalerate. Increases in the fecal SCFAs were in turn positively and strongly correlated with the levels of peptide tyrosine-tyrosine (PYY) and with the beneficial effects of the surgery. CONCLUSION: The present study emphasizes the consistency with which the three major hypoabsorptive bariatric procedures RYGB, BPD-DS and SADI-S create a gut microbial environment capable of producing a SCFA profile favorable to the secretion of PYY and to beneficial metabolic effects.

The Concentration of Organic Acids in Cranberry Juice Modulates the Gut Microbiota in Mice.

A daily consumption of cranberry juice (CJ) is linked to many beneficial health effects due to its richness in polyphenols but could also awake some intestinal discomforts due to its organic acid content and possibly lead to intestinal inflammation. Additionally, the impact of such a juice on the gut microbiota is still unknown. Thus, this study aimed to determine the impacts of a daily consumption of CJ and its successive deacidification on the intestinal inflammation and on the gut microbiota in mice. Four deacidified CJs (DCJs) (deacidification rates of 0, 40, 60, and 80%) were produced by electrodialysis with bipolar membrane (EDBM) and administered to C57BL/6J mice for four weeks, while the diet (CHOW) and the water were ad libitum. Different parameters were measured to determine intestinal inflammation when the gut microbiota was profiled. Treatment with a 0% DCJ did not induce intestinal inflammation but increased the gut microbiota diversity and induced a modulation of its functions in comparison with control (water). The effect of the removal of the organic acid content of CJ on the decrease of intestinal inflammation could not be observed. However, deacidification by EDBM of CJ induced an additional increase, in comparison with a 0% DCJ, in the Lachnospiraceae family which have beneficial effects and functions associated with protection of the intestine: the lower the organic acid content, the more bacteria of the Lachnospiraceae family and functions having a positive impact on the gut microbiota.

Effects of Herring Milt Hydrolysates and Fractions in a Diet-Induced Obesity Model.

Over the past years, promising results from studies have shown that herring milt hydrolysates (HMH) can counter immune-metabolic disorders associated with obesity. However, more studies must corroborate these results. Thus, three commercial hydrolysates (HMH1, HMH2, and HMH3) as well as the fractions of two of them (HMH4 and HMH5) obtained by electrodialysis with ultrafiltration membranes (EDUF) were evaluated in vivo at higher doses compared to a previous study. To achieve this, seven groups of mice were fed for 8 weeks with either a control Chow diet or an obesogenic diet rich in fat and sucrose (HFHS) and supplemented by daily gavage with water or 312.5 mg/kg of one of the five HMH products. In summary, HMH supplements had no impact on weight gain. In the insulin tolerance test (ITT), HMH2 and its HMH5 fraction significantly reduced the blood sugar variation (p < 0.05). However, during the glucose tolerance (OGTT), HMH2 supplement increased the hyperinsulinemia variation (p < 0.05) induced by the HFHS diet. HMH1, HMH2, and HMH5 supplements generated potentially beneficial changes for health in the gut microbiota. These results reveal that HMH do not counteract obesity effects but may decrease certain physiological effects induced by obesity.

Feeding diversified protein sources exacerbates hepatic insulin resistance via increased gut microbial branched-chain fatty acids and mTORC1 signaling in obese mice.

Animal models of human diseases are classically fed purified diets that contain casein as the unique protein source. We show that provision of a mixed protein source mirroring that found in the western diet exacerbates diet-induced obesity and insulin resistance by potentiating hepatic mTORC1/S6K1 signaling as compared to casein alone. These effects involve alterations in gut microbiota as shown by fecal microbiota transplantation studies. The detrimental impact of the mixed protein source is also linked with early changes in microbial production of branched-chain fatty acids (BCFA) and elevated plasma and hepatic acylcarnitines, indicative of aberrant mitochondrial fatty acid oxidation. We further show that the BCFA, isobutyric and isovaleric acid, increase glucose production and activate mTORC1/S6K1 in hepatocytes. Our findings demonstrate that alteration of dietary protein source exerts a rapid and robust impact on gut microbiota and BCFA with significant consequences for the development of obesity and insulin resistance.

Dietary fat and low fiber in purified diets differently impact the gut-liver axis to promote obesity-linked metabolic impairments.

Selecting the most relevant control diet is of critical importance for metabolic and intestinal studies in animal models. Chow and LF-purified diet differentially impact metabolic and gut microbiome outcomes resulting in major changes in intestinal integrity in LF-fed animals which contributes to altering metabolic homeostasis. Dietary fat and low fiber both contribute to the deleterious metabolic effect of purified HF diets through both selective and overlapping mechanisms.

Deletion of intestinal epithelial AMP-activated protein kinase alters distal colon permeability but not glucose homeostasis.

OBJECTIVE: The intestinal epithelial barrier (IEB) restricts the passage of microbes and potentially harmful substances from the lumen through the paracellular space, and rupture of its integrity is associated with a variety of gastrointestinal disorders and extra-digestive diseases. Increased IEB permeability has been linked to disruption of metabolic homeostasis leading to obesity and type 2 diabetes. Interestingly, recent studies have uncovered compelling evidence that the AMP-activated protein kinase (AMPK) signaling pathway plays an important role in maintaining epithelial cell barrier function. However, our understanding of the function of intestinal AMPK in regulating IEB and glucose homeostasis remains sparse. METHODS: We generated mice lacking the two α1 and α2 AMPK catalytic subunits specifically in intestinal epithelial cells (IEC AMPK KO) and determined the physiological consequences of intestinal-specific deletion of AMPK in response to high-fat diet (HFD)-induced obesity. We combined histological, functional, and integrative analyses to ascertain the effects of gut AMPK loss on intestinal permeability in vivo and ex vivo and on the development of obesity and metabolic dysfunction. We also determined the impact of intestinal AMPK deletion in an inducible mouse model (i-IEC AMPK KO) by measuring IEB function, glucose homeostasis, and the composition of gut microbiota via fecal 16S rRNA sequencing. RESULTS: While there were no differences in in vivo intestinal permeability in WT and IEC AMPK KO mice, ex vivo transcellular and paracellular permeability measured in Ussing chambers was significantly increased in the distal colon of IEC AMPK KO mice. This was associated with a reduction in pSer425 GIV phosphorylation, a marker of leaky gut barrier. However, the expression of tight junction proteins in intestinal epithelial cells and pro-inflammatory cytokines in the lamina propria were not different between genotypes. Although the HFD-fed AMPK KO mice displayed suppression of the stress polarity signaling pathway and a concomitant increase in colon permeability, loss of intestinal AMPK did not exacerbate body weight gain or adiposity. Deletion of AMPK was also not sufficient to alter glucose homeostasis or the acute glucose-lowering action of metformin in control diet (CD)- or HFD-fed mice. CD-fed i-IEC AMPK KO mice also presented higher permeability in the distal colon under homeostatic conditions but, surprisingly, this was not detected upon HFD feeding. Alteration in epithelial barrier function in the i-IEC AMPK KO mice was associated with a shift in the gut microbiota composition with higher levels of Clostridiales and Desulfovibrionales. CONCLUSIONS: Altogether, our results revealed a significant role of intestinal AMPK in maintaining IEB integrity in the distal colon but not in regulating glucose homeostasis. Our data also highlight the complex interaction between gut microbiota and host AMPK.

Repurposing Metformin in Nondiabetic People With HIV: Influence on Weight and Gut Microbiota.

BACKGROUND: People with HIV (PWH) taking antiretroviral therapy (ART) may experience weight gain, dyslipidemia, increased risk of non-AIDS comorbidities, and long-term alteration of the gut microbiota. Both low CD4/CD8 ratio and chronic inflammation have been associated with changes in the gut microbiota of PWH. The antidiabetic drug metformin has been shown to improve gut microbiota composition while decreasing weight and inflammation in diabetes and polycystic ovary syndrome. Nevertheless, it remains unknown whether metformin may benefit PWH receiving ART, especially those with a low CD4/CD8 ratio. METHODS: In the Lilac pilot trial, we recruited 23 nondiabetic PWH receiving ART for more than 2 years with a low CD4/CD8 ratio (<0.7). Blood and stool samples were collected during study visits at baseline, after a 12-week metformin treatment, and 12 weeks after discontinuation. Microbiota composition was analyzed by 16S rDNA gene sequencing, and markers of inflammation were assessed in plasma. RESULTS: Metformin decreased weight in PWH, and weight loss was inversely correlated with plasma levels of the satiety factor GDF-15. Furthermore, metformin changed the gut microbiota composition by increasing the abundance of anti-inflammatory bacteria such as butyrate-producing species and the protective Akkermansia muciniphila. CONCLUSIONS: Our study provides the first evidence that a 12-week metformin treatment decreased weight and favored anti-inflammatory bacteria abundance in the microbiota of nondiabetic ART-treated PWH. Larger randomized placebo-controlled clinical trials with longer metformin treatment will be needed to further investigate the role of metformin in reducing inflammation and the risk of non-AIDS comorbidities in ART-treated PWH.

Type 2 diabetes influences bacterial tissue compartmentalisation in human obesity.

Visceral obesity is a key risk factor for type 2 diabetes (T2D). Whereas gut dysbiosis appears to be instrumental for this relationship, whether gut-associated signatures translocate to extra-intestinal tissues and how this affects host metabolism remain elusive. Here we provide a comparative analysis of the microbial profile found in plasma, liver and in three distinct adipose tissues of individuals with morbid obesity. We explored how these tissue microbial signatures vary between individuals with normoglycaemia and those with T2D that were matched for body mass index. We identified tissue-specific signatures with higher bacterial load in the liver and omental adipose tissue. Gut commensals, but also environmental bacteria, showed tissue- and T2D-specific compartmentalisation. T2D signatures were most evident in mesenteric adipose tissue, in which individuals with diabetes displayed reduced bacterial diversity concomitant with fewer Gram-positive bacteria, such as Faecalibacterium, as opposed to enhanced levels of typically opportunistic Gram-negative Enterobacteriaceae. Plasma samples of individuals with diabetes were similarly enriched in Enterobacteriaceae, including the pathobiont Escherichia-Shigella. Our work provides evidence for the presence of selective plasma and tissue microbial signatures in individuals with severe obesity and identifies new potential microbial targets and biomarkers of T2D.