Nourishing the gut: the impact of diet on host-gut microbiota interaction.

PURPOSE OF REVIEW: Understanding the spectrum of drivers that influence the gut microbiome (GM) remains a crucial field of investigation. Among these factors, diet has received particular attention, as it could explain up to 20% of the variability in GM composition between individuals. This review focuses on the complex relationships between different dietary patterns and GM in humans, based on recent findings. RECENT FINDINGS: Current evidence underscores the multifaceted impact of diet on GM richness, diversity, and overall composition. Key contributing factors encompass dietary habits, nutritional interventions, food quality and variety, macronutrient distribution, timing of feeding, and selective exclusion of certain foods. SUMMARY: The intricate interplay between diet and GM is of fundamental importance in shaping the interaction between the host and the environment. Further understanding the causal impact of diet on GM has promising potential for the advancement of strategies to promote health and mitigate cardio-metabolic disease risks through dietary interventions. GRAPHICAL ABSTRACT: http://links.lww.com/COCN/A21.

Upper small intestine microbiome in obesity and related metabolic disorders: A new field of investigation.

The study of the gut microbiome holds great promise for understanding and treating metabolic diseases, as its functions and derived metabolites can influence the metabolic status of the host. While research on the fecal microbiome has provided valuable insights, it tells us only part of the story. This limitation arises from the substantial variations in microorganism distribution throughout the gastrointestinal tract due to changes in physicochemical conditions. Thus, relying solely on the fecal microbiome may not be sufficient to draw comprehensive conclusions about metabolic diseases. The proximal part of the small intestine, particularly the jejunum, indeed, serves as the crucial site for digestion and absorption of nutrients, suggesting a potential role of its microbiome in metabolic regulation. Unfortunately, it remains relatively underexplored due to limited accessibility. This review presents current evidence regarding the relationships between the microbiome in the upper small intestine and various phenotypes, focusing on obesity and type 2 diabetes, in both humans and rodents. Research on humans is still limited with variability in the population and methods used. Accordingly, to better understand the role of the whole gut microbiome in metabolic diseases, studies exploring the human microbiome in different niches are needed.

Tissue pleiotropic effect of biotin and prebiotic supplementation in established obesity.

Combination therapies targeting multiple organs and metabolic pathways are promising therapeutic options to combat obesity progression and/or its comorbidities. The alterations in the composition of the gut microbiota initially observed in obesity have been extended recently to functional alterations. Bacterial functions involve metabolites synthesis that may contribute to both the gut microbiota and the host physiology. Among them are B vitamins, whose metabolism at the systemic, tissue or microbial level are dysfunctional in obesity. We previously reported that the combination of oral supplementation of a prebiotic (fructo-oligosaccharides, FOS) and vitamin B7/B8 (biotin) impedes fat mass accumulation and hyperglycemia in mice with established obesity. This was associated with an attenuation of dysbiosis with improved microbial vitamin metabolism. We now extend this study by characterizing whole-body energy metabolism along with adipose tissue transcriptome and histology in this mouse model. We observed that FOS resulted in increased caloric excretion in parallel with down-regulation of genes and proteins involved in jejunal lipid transport. The combined treatments also strongly inhibited the accumulation of subcutaneous fat mass, with a reduced adipocyte size and expression of lipid metabolism genes. Down-regulation of inflammatory and fibrotic genes and proteins was also observed in both visceral and brown adipose tissues and liver by combined FOS and biotin supplementation. In conclusion, oral administration of a prebiotic and biotin has a beneficial impact on the metabolism of key organs involved in the pathophysiology of obesity, which could have promising translational applications.

The human gut microbiota contributes to type-2 diabetes non-resolution 5-years after Roux-en-Y gastric bypass.

Roux-en-Y gastric bypass (RYGB) is efficient at inducing drastic albeit variable weight loss and type-2 diabetes (T2D) improvements in patients with severe obesity and T2D. We hypothesized a causal implication of the gut microbiota (GM) in these metabolic benefits, as RYGB is known to deeply impact its composition. In a cohort of 100 patients with baseline T2D who underwent RYGB and were followed for 5-years, we used a hierarchical clustering approach to stratify subjects based on the severity of their T2D (Severe vs Mild) throughout the follow-up. We identified via nanopore-based GM sequencing that the more severe cases of unresolved T2D were associated with a major increase of the class Bacteroidia, including 12 species comprising Phocaeicola dorei, Bacteroides fragilis, and Bacteroides caecimuris. A key observation is that patients who underwent major metabolic improvements do not harbor this enrichment in Bacteroidia, as those who presented mild cases of T2D at all times. In a separate group of 36 patients with similar baseline clinical characteristics and preoperative GM sequencing, we showed that this increase in Bacteroidia was already present at baseline in the most severe cases of T2D. To explore the causal relationship linking this enrichment in Bacteroidia and metabolic alterations, we selected 13 patients across T2D severity clusters at 5-years and performed fecal matter transplants in mice. Our results show that 14 weeks after the transplantations, mice colonized with the GM of Severe donors have impaired glucose tolerance and insulin sensitivity as compared to Mild-recipients, all in the absence of any difference in body weight and composition. GM sequencing of the recipient animals revealed that the hallmark T2D-severity associated bacterial features were transferred and were associated with the animals' metabolic alterations. Therefore, our results further establish the GM as a key contributor to long-term glucose metabolism improvements (or lack thereof) after RYGB.

Impairment of gut microbial biotin metabolism and host biotin status in severe obesity: effect of biotin and prebiotic supplementation on improved metabolism.

OBJECTIVES: Gut microbiota is a key component in obesity and type 2 diabetes, yet mechanisms and metabolites central to this interaction remain unclear. We examined the human gut microbiome's functional composition in healthy metabolic state and the most severe states of obesity and type 2 diabetes within the MetaCardis cohort. We focused on the role of B vitamins and B7/B8 biotin for regulation of host metabolic state, as these vitamins influence both microbial function and host metabolism and inflammation. DESIGN: We performed metagenomic analyses in 1545 subjects from the MetaCardis cohorts and different murine experiments, including germ-free and antibiotic treated animals, faecal microbiota transfer, bariatric surgery and supplementation with biotin and prebiotics in mice. RESULTS: Severe obesity is associated with an absolute deficiency in bacterial biotin producers and transporters, whose abundances correlate with host metabolic and inflammatory phenotypes. We found suboptimal circulating biotin levels in severe obesity and altered expression of biotin-associated genes in human adipose tissue. In mice, the absence or depletion of gut microbiota by antibiotics confirmed the microbial contribution to host biotin levels. Bariatric surgery, which improves metabolism and inflammation, associates with increased bacterial biotin producers and improved host systemic biotin in humans and mice. Finally, supplementing high-fat diet-fed mice with fructo-oligosaccharides and biotin improves not only the microbiome diversity, but also the potential of bacterial production of biotin and B vitamins, while limiting weight gain and glycaemic deterioration. CONCLUSION: Strategies combining biotin and prebiotic supplementation could help prevent the deterioration of metabolic states in severe obesity. TRIAL REGISTRATION NUMBER: NCT02059538.

Dysosmobacter welbionis is a newly isolated human commensal bacterium preventing diet-induced obesity and metabolic disorders in mice.

OBJECTIVE: To investigate the abundance and the prevalence of Dysosmobacter welbionis J115T, a novel butyrate-producing bacterium isolated from the human gut both in the general population and in subjects with metabolic syndrome. To study the impact of this bacterium on host metabolism using diet-induced obese and diabetic mice. DESIGN: We analysed the presence and abundance of the bacterium in 11 984 subjects using four human cohorts (ie, Human Microbiome Project, American Gut Project, Flemish Gut Flora Project and Microbes4U). Then, we tested the effects of daily oral gavages with live D. welbionis J115T on metabolism and several hallmarks of obesity, diabetes, inflammation and lipid metabolism in obese/diabetic mice. RESULTS: This newly identified bacterium was detected in 62.7%-69.8% of the healthy population. Strikingly, in obese humans with a metabolic syndrome, the abundance of Dysosmobacter genus correlates negatively with body mass index, fasting glucose and glycated haemoglobin. In mice, supplementation with live D. welbionis J115T, but not with the pasteurised bacteria, partially counteracted diet-induced obesity development, fat mass gain, insulin resistance and white adipose tissue hypertrophy and inflammation. In addition, live D. welbionis J115T administration protected the mice from brown adipose tissue inflammation in association with increased mitochondria number and non-shivering thermogenesis. These effects occurred with minor impact on the mouse intestinal microbiota composition. CONCLUSIONS: These results suggest that D. welbionis J115T directly and beneficially influences host metabolism and is a strong candidate for the development of next-generation beneficial bacteria targeting obesity and associated metabolic diseases.

Gut microbiota and vitamin status in persons with obesity: A key interplay.

There are numerous factors involved in obesity progression and maintenance including systemic low-grade inflammation, adipose tissue dysfunction, or gut microbiota dysbiosis. Recently, a growing interest has arisen for vitamins' role in obesity and related disorders, both at the host and gut bacterial level. Indeed, vitamins are provided mostly by food, but some, from the B and K groups in particular, can be synthesized by the gut bacterial ecosystem and absorbed in the colon. Knowing that vitamin deficiency can alter many important cellular functions and lead to serious health issues, it is important to carefully monitor the vitamin status of patients with obesity and potentially already existing comorbidities as well as to examine the dysbiotic gut microbiota and thus potentially altered bacterial metabolism of vitamins. In this review, we examined both murine and human studies, to assess the prevalence of sub-optimal levels of several vitamins in obesity and metabolic alterations. This review also examines the relationship between vitamins and the gut microbiota in terms of vitamin production and the modulation of the gut bacterial ecosystem in conditions of vitamin shortage or supplementation. Furthermore, some strategies to improve vitamin status of patients with severe obesity are proposed within this review.

Tolerogenic Dendritic Cells Shape a Transmissible Gut Microbiota That Protects From Metabolic Diseases.

Excess chronic contact between microbial motifs and intestinal immune cells is known to trigger a low-grade inflammation involved in many pathologies such as obesity and diabetes. The important skewing of intestinal adaptive immunity in the context of diet-induced obesity (DIO) is well described, but how dendritic cells (DCs) participate in these changes is still poorly documented. To address this question, we challenged transgenic mice with enhanced DC life span and immunogenicity (DChBcl-2 mice) with a high-fat diet. Those mice display resistance to DIO and metabolic alterations. The DIO-resistant phenotype is associated with healthier parameters of intestinal barrier function and lower intestinal inflammation. DChBcl-2 DIO-resistant mice demonstrate a particular increase in tolerogenic DC numbers and function, which is associated with strong intestinal IgA, T helper 17, and regulatory T-cell immune responses. Microbiota composition and function analyses reveal that the DChBcl-2 mice microbiota is characterized by lower immunogenicity and an enhanced butyrate production. Cohousing experiments and fecal microbial transplantations are sufficient to transfer the DIO resistance status to wild-type mice, demonstrating that maintenance of DCs' tolerogenic ability sustains a microbiota able to drive DIO resistance. The tolerogenic function of DCs is revealed as a new potent target in metabolic disease management.

From correlation to causality: the case of Subdoligranulum.

Gut microbes are considered as major factors contributing to human health. Nowadays, the vast majority of the data available in the literature are mostly exhibiting negative or positive correlations between specific bacteria and metabolic parameters. From these observations, putative detrimental or beneficial effects are then inferred. Akkermansia muciniphila is one of the unique examples for which the correlations with health benefits have been causally validated in vivo in rodents and humans. In this study, based on available metagenomic data in overweight/obese population and clinical variables that we obtained from two cohorts of individuals (n = 108) we identified several metagenomic species (MGS) strongly associated with A. muciniphila with one standing out: Subdoligranulum. By analyzing both qPCR and shotgun metagenomic data, we discovered that the abundance of Subdoligranulum was correlated positively with microbial richness and HDL-cholesterol levels and negatively correlated with fat mass, adipocyte diameter, insulin resistance, levels of leptin, insulin, CRP, and IL6 in humans. Therefore, to further explore whether these strong correlations could be translated into causation, we investigated the effects of the unique cultivated strain of Subdoligranulum (Subdoligranulum variabile DSM 15176 T) in obese and diabetic mice as a proof-of-concept. Strikingly, there were no significant difference in any of the hallmarks of obesity and diabetes measured (e.g., body weight gain, fat mass gain, glucose tolerance, liver weight, plasma lipids) at the end of the 8 weeks of treatment. Therefore, the absence of effect following the supplementation with S. variabile indicates that increasing the intestinal abundance of this bacterium is not translated into beneficial effects in mice. In conclusion, we demonstrated that despite the fact that numerous strong correlations exist between a given bacteria and health, proof-of-concept experiments are required to be further validated or not in vivo. Hence, an urgent need for causality studies is warranted to move from human observations to preclinical validations.

Gut Microbiota-Induced Changes in ß-Hydroxybutyrate Metabolism Are Linked to Altered Sociability and Depression in Alcohol Use Disorder.

Patients with alcohol use disorder (AUD) present with important emotional, cognitive, and social impairments. The gut microbiota has been recently shown to regulate brain functions and behavior but convincing evidence of its role in AUD is lacking. Here, we show that gut dysbiosis is associated with metabolic alterations that affect behavioral (depression, sociability) and neurobiological (myelination, neurotransmission, inflammation) processes involved in alcohol addiction. By transplanting the gut microbiota from AUD patients to mice, we point out that the production of ethanol by specific bacterial genera and the reduction of lipolysis are associated with a lower hepatic synthesis of ß-hydroxybutyrate (BHB), which thereby prevents the neuroprotective effect of BHB. We confirm these results in detoxified AUD patients, in which we observe a persisting ethanol production in the feces as well as correlations among low plasma BHB levels and social impairments, depression, or brain white matter alterations.

Rhubarb Supplementation Prevents Diet-Induced Obesity and Diabetes in Association with Increased Akkermansia muciniphila in Mice.

Obesity and obesity-related disorders, such as type 2 diabetes have been progressively increasing worldwide and treatments have failed to counteract their progression. Growing evidence have demonstrated that gut microbiota is associated with the incidence of these pathologies. Hence, the identification of new nutritional compounds, able to improve health through a modulation of gut microbiota, is gaining interest. In this context, the aim of this study was to investigate the gut-driving effects of rhubarb extract in a context of diet-induced obesity and diabetes. Eight weeks old C57BL6/J male mice were fed a control diet (CTRL), a high fat and high sucrose diet (HFHS) or a HFHS diet supplemented with 0.3% (g/g) of rhubarb extract for eight weeks. Rhubarb supplementation fully prevented HFHS-induced obesity, diabetes, visceral adiposity, adipose tissue inflammation and liver triglyceride accumulation, without any modification in food intake. By combining sequencing and qPCR methods, we found that all these effects were associated with a blooming of Akkermansia muciniphila, which is strongly correlated with increased expression of Reg3γ in the colon. Our data showed that rhubarb supplementation is sufficient to protect against metabolic disorders induced by a diet rich in lipid and carbohydrates in association with a reciprocal interaction between Akkermansia muciniphila and Reg3γ.

Discovery of the gut microbial signature driving the efficacy of prebiotic intervention in obese patients.

OBJECTIVE: The gut microbiota has been proposed as an interesting therapeutic target for metabolic disorders. Inulin as a prebiotic has been shown to lessen obesity and related diseases. The aim of the current study was to investigate whether preintervention gut microbiota characteristics determine the physiological response to inulin. DESIGN: The stools from four obese donors differing by microbial diversity and composition were sampled before the dietary intervention and inoculated to antibiotic-pretreated mice (hum-ob mice; humanised obese mice). Hum-ob mice were fed with a high-fat diet and treated with inulin. Metabolic and microbiota changes on inulin treatment in hum-ob mice were compared with those obtained in a cohort of obese individuals supplemented with inulin for 3 months. RESULTS: We show that hum-ob mice colonised with the faecal microbiota from different obese individuals differentially respond to inulin supplementation on a high-fat diet. Among several bacterial genera, Barnesiella, Bilophila, Butyricimonas, Victivallis, Clostridium XIVa, Akkermansia, Raoultella and Blautia correlated with the observed metabolic outcomes (decrease in adiposity and hepatic steatosis) in hum-ob mice. In addition, in obese individuals, the preintervention levels of Anaerostipes, Akkermansia and Butyricicoccus drive the decrease of body mass index in response to inulin. CONCLUSION: These findings support that characterising the gut microbiota prior to nutritional intervention with prebiotics is important to increase the positive outcome in the context of obesity and metabolic disorders.

Dysosmobacter welbionis gen. nov., sp. nov., isolated from human faeces and emended description of the genus Oscillibacter.

A strictly anaerobic, Gram-stain-negative, non-spore-forming, non-motile, non-pigmented bacterium, strain J115T, was isolated from human faeces. Cells of strain J115T were straight rods, generally 1.8-3.0 µm, but could be up to 18 µm long. Growth occurred below 2 % (w/v) NaCl and 2 % (v/v) bile. Strain J115T produced acid from myo-inositol but not from d-glucose, d-ribose or d-xylose. Butyric acid was the major end-product from myo-inositol. The genomic DNA G+C content was 58.92 mol%. Phylogenetic analysis based on 16S rRNA gene sequencing indicated that the closest cultivated neighbours of strain J115T were Oscillibacter ruminantium GH1T (95.4 % similarity) and Oscillibacter valericigenes Sjm18-20T (94.1 %). Strain J115T was also related to the not-yet-cultured bacterium Oscillospira guilliermondii(92-93 % similarity). Coherently with the 16S rRNA gene sequence results, the ANI scores don't have units of strain J115T to O. ruminantium GH1T and O. valericigenes Sjm18-20T were 73.37 and 73.24, respectively, while in silico estimations of DNA-DNA hybridization were both 20.4 %, with confidence intervals of 18.2-22.9 % and 18.2-22.8 %, respectively. The major fatty acids were iso-C15 : 0 (24.2 %), C18 : 0 DMA (18.4 %), anteiso-C15 : 0 (15.2 %) and C16 : 0 DMA (7.6 %). No respiratory quinone was detected. Based on phenotypic features and phylogenetic position, it is proposed that this isolate represents a novel species in a new genus, Dysosmobacter welbionis gen. nov., sp. nov. The type strain of Dysosmobacter welbionis is J115T (DSM 106889T=LMG 30601T).

The intestinal microbiota regulates host cholesterol homeostasis.

BACKGROUND: Management of blood cholesterol is a major focus of efforts to prevent cardiovascular diseases. The objective of this study was to investigate how the gut microbiota affects host cholesterol homeostasis at the organism scale. RESULTS: We depleted the intestinal microbiota of hypercholesterolemic female Apoe-/- mice using broad-spectrum antibiotics. Measurement of plasma cholesterol levels as well as cholesterol synthesis and fluxes by complementary approaches showed that the intestinal microbiota strongly regulates plasma cholesterol level, hepatic cholesterol synthesis, and enterohepatic circulation. Moreover, transplant of the microbiota from humans harboring elevated plasma cholesterol levels to recipient mice induced a phenotype of high plasma cholesterol levels in association with a low hepatic cholesterol synthesis and high intestinal absorption pattern. Recipient mice phenotypes correlated with several specific bacterial phylotypes affiliated to Betaproteobacteria, Alistipes, Bacteroides, and Barnesiella taxa. CONCLUSIONS: These results indicate that the intestinal microbiota determines the circulating cholesterol level and may thus represent a novel therapeutic target in the management of dyslipidemia and cardiovascular diseases.

Butyricimonas faecalis sp. nov., isolated from human faeces and emended description of the genus Butyricimonas.

A Gram-negative, strictly anaerobic, non-spore forming, non-motile, non-pigmented bacterial strain, designated H184T, was isolated from human faeces. 16S rRNA gene sequence analysis showed that strain H184T represents a member of the genus Butyricimonas. Strain H184T is related to but distinct from Butyricimonasvirosa JCM 15149T and Butyricimonasparavirosa JCM 18677T, with 16S rRNA gene sequence similarities of 96.32 and 96.24 %, respectively. Strain H184T shared 90.50 % hsp60 gene sequence similarity to B. virosa JCM 15149T and B. paravirosa JCM 18677T. Growth occurs between 25 and 42 °C with an optimum at 37 °C. Bile and NaCl concentration range allowing growth are 0-3.75 % and 0-1.8 %, respectively. pH range for growth is 5.5-8. The strain produced propionate as the major end product from glucose. The major cellular fatty acids of strain H184T were iso-C15 : 0 (63.5 %) and iso-C17 : 0 3-OH (12.8%). The major menaquinone of the strain was MK-10 (86 %). DNA G+C content of the isolate H184T was 44.2 mol%. The genome-based comparison between strain H184T and B. virosa JCM 15149T by pairwise average nucleotide identity indicated a clear distinction with a score of 87.22. On the basis of these data, strain H184T represents a novel species of the genus Butyricimonas, for which the name Butyricimonas faecalis sp. nov. is proposed. The type strain of B. faecalis is H184T (DSM 106867T, LMG 30602T).

Comparative Evaluation of Microbiota Engraftment Following Fecal Microbiota Transfer in Mice Models: Age, Kinetic and Microbial Status Matter.

The intestinal microbiota and its functions are intricately interwoven with host physiology. Colonizing rodents with donor microbiota provides insights into host-microbiota interactions characterization and the understanding of disease physiopathology. However, a better assessment of inoculation methods and recipient mouse models is needed. Here, we compare the engraftment at short and long term of genetically obese mice microbiota in germ-free (GF) mice and juvenile and adult specific pathogen free (SPF) mice. We also tested the effects of initial microbiota depletion before microbiota transfer. In the present work, donor microbiota engraftment was better in juvenile SPF mice than in adult SPF mice. In juvenile mice, initial microbiota depletion using laxatives or antibiotics improved donor microbiota engraftment 9 weeks but not 3 weeks after microbiota transfer. Microbiota-depleted juvenile mice performed better than GF mice 3 weeks after the microbiota transfer. However, 9 weeks after transfer, colonized GF mice microbiota had the lowest Unifrac distance to the donor microbiota. Colonized GF mice were also characterized by a chronic alteration in intestinal absorptive function. With these collective results, we show that the use of juvenile mice subjected to initial microbiota depletion constitutes a valid alternative to GF mice in microbiota transfer studies.

Immune cell-derived cytokines contribute to obesity-related inflammation, fibrogenesis and metabolic deregulation in human adipose tissue.

Adipose tissue contains a variety of immune cells, which vary in abundance and phenotype with obesity. The contribution of immune cell-derived factors to inflammatory, fibrotic and metabolic alterations in adipose tissue is not well established in human obesity. Human primary adipose tissue cells, including pre-adipocytes, endothelial cells and mature adipocytes, were used to investigate deregulation of cell- and pathway-specific gene profiles. Among factors known to alter adipose tissue biology, we focus on inflammatory (IL-1ß and IL-17) and pro-fibrotic (TGF-ß1) factors. rIL-1ß and rIL-17 induced concordant pro-inflammatory transcriptional programs in pre-adipocytes and endothelial cells, with a markedly more potent effect of IL-1ß than IL-17. None of these cytokines had significant effect on fibrogenesis-related gene expression, contrasting with rTGF-ß1-induced up-regulation of extracellular matrix components and pro-fibrotic factors. In mature adipocytes, all three factors promoted down-regulation of genes functionally involved in lipid storage and release. IL-1ß and IL-17 impacted adipocyte metabolic genes in relation with their respective pro-inflammatory capacity, while the effect of TGF-ß1 occurred in face of an anti-inflammatory signature. These data revealed that IL-1ß and IL-17 had virtually no effect on pro-fibrotic alterations but promote inflammation and metabolic dysfunction in human adipose tissue, with a prominent role for IL-1ß.

Recent Patents on Hypocholesterolemic Therapeutic Strategies: An Update.

Worldwide, the cardiovascular diseases constitute a major cause of death with an ever growing incidence. Many medical approaches were developed against this physiopathology and patented; however up to now, no efficient treatment exists. Future developments are not only focusing on the identification of new therapeutic strategies against the cardiovascular diseases but also on a better understanding of the determinants of these multifactorial diseases. In this report, we reviewed the most recent patents that have been reported in this field of research.