Moderate variations in the human diet impact the gut microbiota in humanized mice.

AIM: Drastic diet interventions have been shown to promote rapid and significant compositional changes of the gut microbiota, but the impact of moderate diet variations is less clear. Here, we aimed to clarify the impact of moderate diet variations that remain within the spectrum of the habitual human diet on gut microbiota composition. METHODS: We performed a pilot diet intervention where five healthy volunteers consumed a vegetarian ready-made meal for three days to standardize dietary intake before switching to a meat-based ready-made western-style meal and high sugar drink for two days. We performed 16S rRNA sequencing from daily fecal sampling to assess gut microbiota changes caused by the intervention diet. Furthermore, we used the volunteers' fecal samples to colonize germ-free mice that were fed the same sterilized diets to study the effect of a moderate diet intervention on the gut microbiota in a setting of reduced interindividual variation. RESULTS: In the human intervention, we found that fecal microbiota composition varied between and within individuals regardless of diet. However, when we fed the same diets to mice colonized with the study participants' feces, we observed significant, often donor-specific, changes in the mouse microbiota following this moderate diet intervention. CONCLUSION: Moderate variations in the habitual human diet have the potential to alter the gut microbiota. Feeding humanized mice human diets may facilitate our understanding of individual human gut microbiota responses to moderate dietary changes and help improve individualized interventions.

The interplay between dietary fatty acids and gut microbiota influences host metabolism and hepatic steatosis.

Dietary lipids can affect metabolic health through gut microbiota-mediated mechanisms, but the influence of lipid-microbiota interaction on liver steatosis is largely unknown. We investigate the impact of dietary lipids on human gut microbiota composition and the effects of microbiota-lipid interactions on steatosis in male mice. In humans, low intake of saturated fatty acids (SFA) is associated with increased microbial diversity independent of fiber intake. In mice, poorly absorbed dietary long-chain SFA, particularly stearic acid, induce a shift in bile acid profile and improved metabolism and steatosis. These benefits are dependent on the gut microbiota, as they are transmitted by microbial transfer. Diets enriched in polyunsaturated fatty acids are protective against steatosis but have minor influence on the microbiota. In summary, we find that diets enriched in poorly absorbed long-chain SFA modulate gut microbiota profiles independent of fiber intake, and this interaction is relevant to improve metabolism and decrease liver steatosis.

Synergy and oxygen adaptation for development of next-generation probiotics.

The human gut microbiota has gained interest as an environmental factor that may contribute to health or disease1. The development of next-generation probiotics is a promising strategy to modulate the gut microbiota and improve human health; however, several key candidate next-generation probiotics are strictly anaerobic2 and may require synergy with other bacteria for optimal growth. Faecalibacterium prausnitzii is a highly prevalent and abundant human gut bacterium associated with human health, but it has not yet been developed into probiotic formulations2. Here we describe the co-isolation of F. prausnitzii and Desulfovibrio piger, a sulfate-reducing bacterium, and their cross-feeding for growth and butyrate production. To produce a next-generation probiotic formulation, we adapted F. prausnitzii to tolerate oxygen exposure, and, in proof-of-concept studies, we demonstrate that the symbiotic product is tolerated by mice and humans (ClinicalTrials.gov identifier: NCT03728868 ) and is detected in the human gut in a subset of study participants. Our study describes a technology for the production of next-generation probiotics based on the adaptation of strictly anaerobic bacteria to tolerate oxygen exposures without a reduction in potential beneficial properties. Our technology may be used for the development of other strictly anaerobic strains as next-generation probiotics.

Absence of gut microbiota reduces neonatal survival and exacerbates liver disease in Cyp2c70-deficient mice with a human-like bile acid composition.

Mice with deletion of Cyp2c70 have a human-like bile acid composition, display age- and sex-dependent signs of hepatobiliary disease and can be used as a model to study interactions between bile acids and the gut microbiota in cholestatic liver disease. In the present study, we rederived Cyp2c70-/- mice as germ-free (GF) and colonized them with a human or a mouse microbiota to investigate whether the presence of a microbiota can be protective in cholangiopathic liver disease associated with Cyp2c70-deficiency. GF Cyp2c70-/- mice showed reduced neonatal survival, liver fibrosis, and distinct cholangiocyte proliferation. Colonization of germ-free breeding pairs with a human or a mouse microbiota normalized neonatal survival of the offspring, and particularly colonization with mouse microbiota from a conventionally raised mouse improved the liver phenotype at 6-10 weeks of age. The improved liver phenotype in conventionalized (CD) Cyp2c70-/- mice was associated with increased levels of tauro-ursodeoxycholic acid (TUDCA) and UDCA, resulting in a more hydrophilic bile acid profile compared with GF and humanized Cyp2c70-/- mice. The hydrophobicity index of biliary bile acids of CD Cyp2c70-/- mice was associated with changes in gut microbiota, liver weight, liver transaminases, and liver fibrosis. Hence, our results indicate that neonatal survival of Cyp2c70-/- mice seems to depend on the establishment of a gut microbiota at birth, and the improved liver phenotype in CD Cyp2c70-/- mice may be mediated by a larger proportion of TUDCA/UDCA in the circulating bile acid pool and/or by the presence of specific bacteria.

Approaches to discern if microbiome associations reflect causation in metabolic and immune disorders.

Our understanding of microorganisms residing within our gut and their roles in the host metabolism and immunity advanced greatly over the past 20 years. Currently, microbiome studies are shifting from association and correlation studies to studies demonstrating causality of identified microbiome signatures and identification of molecular mechanisms underlying these interactions. This transformation is crucial for the efficient translation into clinical application and development of targeted strategies to beneficially modulate the intestinal microbiota. As mechanistic studies are still quite challenging to perform in humans, the causal role of microbiota is frequently evaluated in animal models that need to be appropriately selected. Here, we provide a comprehensive overview on approaches that can be applied in addressing causality of host-microbe interactions in five major animal model organisms (Caenorhabditis elegans, Drosophila melanogaster, zebrafish, rodents, and pigs). We particularly focused on discussing methods available for studying the causality ranging from the usage of gut microbiota transfer, diverse models of metabolic and immune perturbations involving nutritional and chemical factors, gene modifications and surgically induced models, metabolite profiling up to culture-based approached. Furthermore, we addressed the impact of the gut morphology, physiology as well as diet on the microbiota composition in various models and resulting species specificities. Finally, we conclude this review with the discussion on models that can be applied to study the causal role of the gut microbiota in the context of metabolic syndrome and host immunity. We hope this review will facilitate important considerations for appropriate animal model selection.

Microbiome and metabolome features of the cardiometabolic disease spectrum.

Previous microbiome and metabolome analyses exploring non-communicable diseases have paid scant attention to major confounders of study outcomes, such as common, pre-morbid and co-morbid conditions, or polypharmacy. Here, in the context of ischemic heart disease (IHD), we used a study design that recapitulates disease initiation, escalation and response to treatment over time, mirroring a longitudinal study that would otherwise be difficult to perform given the protracted nature of IHD pathogenesis. We recruited 1,241 middle-aged Europeans, including healthy individuals, individuals with dysmetabolic morbidities (obesity and type 2 diabetes) but lacking overt IHD diagnosis and individuals with IHD at three distinct clinical stages-acute coronary syndrome, chronic IHD and IHD with heart failure-and characterized their phenome, gut metagenome and serum and urine metabolome. We found that about 75% of microbiome and metabolome features that distinguish individuals with IHD from healthy individuals after adjustment for effects of medication and lifestyle are present in individuals exhibiting dysmetabolism, suggesting that major alterations of the gut microbiome and metabolome might begin long before clinical onset of IHD. We further categorized microbiome and metabolome signatures related to prodromal dysmetabolism, specific to IHD in general or to each of its three subtypes or related to escalation or de-escalation of IHD. Discriminant analysis based on specific IHD microbiome and metabolome features could better differentiate individuals with IHD from healthy individuals or metabolically matched individuals as compared to the conventional risk markers, pointing to a pathophysiological relevance of these features.

Combinatorial, additive and dose-dependent drug-microbiome associations.

During the transition from a healthy state to cardiometabolic disease, patients become heavily medicated, which leads to an increasingly aberrant gut microbiome and serum metabolome, and complicates biomarker discovery1-5. Here, through integrated multi-omics analyses of 2,173 European residents from the MetaCardis cohort, we show that the explanatory power of drugs for the variability in both host and gut microbiome features exceeds that of disease. We quantify inferred effects of single medications, their combinations as well as additive effects, and show that the latter shift the metabolome and microbiome towards a healthier state, exemplified in synergistic reduction in serum atherogenic lipoproteins by statins combined with aspirin, or enrichment of intestinal Roseburia by diuretic agents combined with beta-blockers. Several antibiotics exhibit a quantitative relationship between the number of courses prescribed and progression towards a microbiome state that is associated with the severity of cardiometabolic disease. We also report a relationship between cardiometabolic drug dosage, improvement in clinical markers and microbiome composition, supporting direct drug effects. Taken together, our computational framework and resulting resources enable the disentanglement of the effects of drugs and disease on host and microbiome features in multimedicated individuals. Furthermore, the robust signatures identified using our framework provide new hypotheses for drug-host-microbiome interactions in cardiometabolic disease.

Hepatic expression of lipopolysaccharide-binding protein (Lbp) is induced by the gut microbiota through Myd88 and impairs glucose tolerance in mice independent of obesity.

OBJECTIVE: Gut-derived inflammatory factors can impair glucose homeostasis, but the underlying mechanisms are not fully understood. In this study, we investigated how hepatic gene expression is regulated by gut colonization status through myeloid differentiation primary response 88 (MYD88) and how one of the regulated genes, lipopolysaccharide-binding protein (Lbp), affects insulin signaling and systemic glucose homeostasis. METHODS: Liver transcriptomics analysis was conducted on four groups of mice fed a chow diet: conventionally raised (CONV-R) wild-type, germ-free (GF) wild-type, CONV-R Myd88 KO, and GF Myd88 KO. Primary hepatocytes were exposed to combinations of lipopolysaccharide (LPS), LBP, and the LBP-blocking peptide LBPK95A, and the effect on insulin signaling was determined. To assess how LBP affects glucose metabolism in vivo, two mouse models were applied: treatment with LBPK95A and hepatic knockdown of Lbp using CRISPR-CAS9. RESULTS: We showed that the colonization status regulates gene expression in the liver and that a subset of these genes, including Lbp, is regulated through MYD88. Furthermore, we demonstrated that LBP impairs insulin signaling in hepatocytes in the presence of low levels of LPS and that the effect of LBP is abolished by LBPK95A. We showed that both systemic pharmacological blocking of LBP by LBPK95A and CRISPR-CAS9-mediated downregulation of hepatic Lbp improve glucose homeostasis. CONCLUSIONS: Our results demonstrate that the gut microbiota regulates hepatic expression of Lbp through MYD88-dependent signaling. LBP potentiates LPS inhibition of insulin signaling in vitro and impairs systemic glucose homeostasis in vivo.

Gut microbiota of obese subjects with Prader-Willi syndrome is linked to metabolic health.

OBJECTIVE: The gut microbiota has been implicated in the aetiology of obesity and associated comorbidities. Patients with Prader-Willi syndrome (PWS) are obese but partly protected against insulin resistance. We hypothesised that the gut microbiota of PWS patients differs from that of non-genetically obese controls and correlate to metabolic health. Therefore, here we used PWS as a model to study the role of gut microbiota in the prevention of metabolic complications linked to obesity. DESIGN: We conducted a case-control study with 17 adult PWS patients and 17 obese subjects matched for body fat mass index, gender and age. The subjects were metabolically characterised and faecal microbiota was profiled by 16S ribosomal RNA gene sequencing. The patients' parents were used as a non-obese control group. Stool samples from two PWS patients and two obese controls were used for faecal microbiota transplantations in germ-free mice to examine the impact of the microbiota on glucose metabolism. RESULTS: The composition of the faecal microbiota in patients with PWS differed from that of obese controls, and was characterised by higher phylogenetic diversity and increased abundance of several taxa such as Akkermansia, Desulfovibrio and Archaea, and decreased abundance of Dorea. Microbial taxa prevalent in the PWS microbiota were associated with markers of insulin sensitivity. Improved insulin resistance of PWS was partly transmitted by faecal microbiota transplantations into germ-free mice. CONCLUSION: The gut microbiota of PWS patients is similar to that of their non-obese parents and might play a role for the protection of PWS patients from metabolic complications.

Dietary lipids, gut microbiota and lipid metabolism.

The gut microbiota is a central regulator of host metabolism. The composition and function of the gut microbiota is dynamic and affected by diet properties such as the amount and composition of lipids. Hence, dietary lipids may influence host physiology through interaction with the gut microbiota. Lipids affect the gut microbiota both as substrates for bacterial metabolic processes, and by inhibiting bacterial growth by toxic influence. The gut microbiota has been shown to affect lipid metabolism and lipid levels in blood and tissues, both in mice and humans. Furthermore, diseases linked to dyslipidemia, such as non-alcoholic liver disease and atherosclerosis, are associated with changes in gut microbiota profile. The influence of the gut microbiota on host lipid metabolism may be mediated through metabolites produced by the gut microbiota such as short-chain fatty acids, secondary bile acids and trimethylamine and by pro-inflammatory bacterially derived factors such as lipopolysaccharide. Here we will review the association between gut microbiota, dietary lipids and lipid metabolism.

Pharmacologic and Nonpharmacologic Therapies for the Gut Microbiota in Type 2 Diabetes.

The gut microbiota is an important regulator of host metabolism. Metagenome analyses have demonstrated that the gut microbiota differs between patients with type 2 diabetes and healthy subjects, and several studies have shown that impaired glucose metabolism is associated with decreased levels of butyrate-producing bacteria. Gut microbiota-produced metabolites, such as short-chain fatty acids, amino acid derivatives and secondary bile acids, participate in metabolic and immunologic processes and, hence, pose putative links between the gut microbiota and glucose homeostasis. Strategies to prevent and treat type 2 diabetes through manipulation of the gut microbiota are being developed. These include replacement of the gut microbiota by fecal transplantation, consumption of fibres to promote the function and growth of beneficial bacteria and treatment with probiotic bacterial strains. Furthermore, it has been shown that many drugs, including drugs used for treatment of diabetes, have major impacts on gut microbiota and, thereby, potentially on glucose metabolism. In particular, the commonly used drug metformin has been shown to influence the functional capacity of the gut microbiota, and recent evidence indicates that this may contribute to the antidiabetes effect of metformin.

Liver-specific RORα deletion does not affect the metabolic susceptibility to western style diet feeding.

OBJECTIVES: The nuclear receptor superfamily is a potential target for the development of new treatments for obesity and metabolic diseases. Increasing evidence has pointed towards the retinoic acid-related orphan receptor-alpha (RORα) as an important nuclear receptor involved in several biological processes. RORα full body knockout mice display improved metabolic phenotypes on both chow and high fat (60% fat, 20% carbohydrate) diets, but also have severe behavioral abnormalities. Here we investigated the effect of hepatic RORα by generating mice with liver-specific RORα deletion to elucidate the role of this nuclear receptor on host metabolism. METHODS: 8 week-old mice with liver-specific RORα deletion and littermate controls were fed either chow or western-style diets (40% fat, 40% carbohydrate) for 12 weeks. Metabolic phenotyping was performed at the end of the dietary intervention. RESULTS: Here, we show that hepatic RORα deletion does not affect the metabolic susceptibility to either chow or western-style diet in terms of glucose metabolism and adiposity. CONCLUSIONS: Our data indicate that liver deletion of RORα does not have a pivotal role in the regulation of hepatic glucose and lipid metabolism on chow or western-style diet.

Impact of Gut Microbiota and Diet on the Development of Atherosclerosis in Apoe-/- Mice.

Objective- To investigate the effect of gut microbiota and diet on atherogenesis. Approach and Results- Here, we investigated the interaction between the gut microbiota and diet on atherosclerosis by feeding germ-free or conventionally raised Apoe-/- mice chow or Western diet alone or supplemented with choline (which is metabolized by the gut microbiota and host enzymes to trimethylamine N-oxide) for 12 weeks. We observed smaller aortic lesions and lower plasma cholesterol levels in conventionally raised mice compared with germ-free mice on a chow diet; these differences were not observed in mice on a Western diet. Choline supplementation increased plasma trimethylamine N-oxide levels in conventionally raised mice but not in germ-free mice. However, this treatment did not affect the size of aortic lesions or plasma cholesterol levels. Gut microbiota composition was analyzed by sequencing of 16S rRNA genes. As expected, the global community structure and relative abundance of many taxa differed between mice fed chow or a Western diet. Choline supplementation had minor effects on the community structure although the relative abundance of some taxa belonging to Clostridiales was altered. Conclusions- In conclusion, the impact of the gut microbiota on atherosclerosis is dietary dependent and is associated with plasma cholesterol levels. Furthermore, the microbiota was required for trimethylamine N-oxide production from dietary choline, but this process could not be linked to increased atherosclerosis in this model.

Aberrant intestinal microbiota in individuals with prediabetes.

AIMS/HYPOTHESIS: Individuals with type 2 diabetes have aberrant intestinal microbiota. However, recent studies suggest that metformin alters the composition and functional potential of gut microbiota, thereby interfering with the diabetes-related microbial signatures. We tested whether specific gut microbiota profiles are associated with prediabetes (defined as fasting plasma glucose of 6.1-7.0 mmol/l or HbA1c of 42-48 mmol/mol [6.0-6.5%]) and a range of clinical biomarkers of poor metabolic health. METHODS: In the present case-control study, we analysed the gut microbiota of 134 Danish adults with prediabetes, overweight, insulin resistance, dyslipidaemia and low-grade inflammation and 134 age- and sex-matched individuals with normal glucose regulation. RESULTS: We found that five bacterial genera and 36 operational taxonomic units (OTUs) were differentially abundant between individuals with prediabetes and those with normal glucose regulation. At the genus level, the abundance of Clostridium was decreased (mean log2 fold change -0.64 (SEM 0.23), p adj = 0.0497), whereas the abundances of Dorea, [Ruminococcus], Sutterella and Streptococcus were increased (mean log2 fold change 0.51 (SEM 0.12), p adj = 5 × 10-4; 0.51 (SEM 0.11), p adj = 1 × 10-4; 0.60 (SEM 0.21), p adj = 0.0497; and 0.92 (SEM 0.21), p adj = 4 × 10-4, respectively). The two OTUs that differed the most were a member of the order Clostridiales (OTU 146564) and Akkermansia muciniphila, which both displayed lower abundance among individuals with prediabetes (mean log2 fold change -1.74 (SEM 0.41), p adj = 2 × 10-3 and -1.65 (SEM 0.34), p adj = 4 × 10-4, respectively). Faecal transfer from donors with prediabetes or screen-detected, drug-naive type 2 diabetes to germfree Swiss Webster or conventional C57BL/6 J mice did not induce impaired glucose regulation in recipient mice. CONCLUSIONS/INTERPRETATION: Collectively, our data show that individuals with prediabetes have aberrant intestinal microbiota characterised by a decreased abundance of the genus Clostridium and the mucin-degrading bacterium A. muciniphila. Our findings are comparable to observations in overt chronic diseases characterised by low-grade inflammation.

Host-microbiota interaction induces bi-phasic inflammation and glucose intolerance in mice.

OBJECTIVE: Gut microbiota modulates adiposity and glucose metabolism in humans and mice. Here we investigated how colonization of germ-free (GF) mice affects kinetics of adiposity and glucose metabolism. METHODS: Adiposity and glucose metabolism were evaluated at different time points in ex-GF and antibiotic treated mice after colonization with gut microbiota from a conventionally raised (CONV-R) mouse. Mouse physiology, microbiome configuration, serum cytokine levels, and gene expression for inflammatory markers were performed in different tissues. RESULTS: Colonization resulted in a bi-phasic glucose impairment: the first phase occurring within 3 days of colonization (early phase) and the second 14-28 days after colonization (delayed phase). The early phase co-occurred with an inflammatory response and was independent of adiposity, while the delayed phase was mostly ascribed to adipose tissue expansion and inflammation. Importantly, re-colonization of antibiotic treated mice displays only the delayed phase of glucose impairment and adiposity, suggesting that the early phase may be unique to colonization of the immature GF mice gut. CONCLUSIONS: Our results provide new insights on host-microbiota interaction during colonization of GF mice and the resulting effects on adiposity and glucose metabolism in a time resolved fashion.

Metformin alters the gut microbiome of individuals with treatment-naive type 2 diabetes, contributing to the therapeutic effects of the drug.

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.

Microbiota-induced obesity requires farnesoid X receptor.

OBJECTIVE: The gut microbiota has been implicated as an environmental factor that modulates obesity, and recent evidence suggests that microbiota-mediated changes in bile acid profiles and signalling through the bile acid nuclear receptor farnesoid X receptor (FXR) contribute to impaired host metabolism. Here we investigated if the gut microbiota modulates obesity and associated phenotypes through FXR. DESIGN: We fed germ-free (GF) and conventionally raised (CONV-R) wild-type and Fxr-/- mice a high-fat diet (HFD) for 10 weeks. We monitored weight gain and glucose metabolism and analysed the gut microbiota and bile acid composition, beta-cell mass, accumulation of macrophages in adipose tissue, liver steatosis, and expression of target genes in adipose tissue and liver. We also transferred the microbiota of wild-type and Fxr-deficient mice to GF wild-type mice. RESULTS: The gut microbiota promoted weight gain and hepatic steatosis in an FXR-dependent manner, and the bile acid profiles and composition of faecal microbiota differed between Fxr-/- and wild-type mice. The obese phenotype in colonised wild-type mice was associated with increased beta-cell mass, increased adipose inflammation, increased steatosis and expression of genes involved in lipid uptake. By transferring the caecal microbiota from HFD-fed Fxr-/- and wild-type mice into GF mice, we showed that the obesity phenotype was transferable. CONCLUSIONS: Our results indicate that the gut microbiota promotes diet-induced obesity and associated phenotypes through FXR, and that FXR may contribute to increased adiposity by altering the microbiota composition.

Interaction between dietary lipids and gut microbiota regulates hepatic cholesterol metabolism.

The gut microbiota influences many aspects of host metabolism. We have previously shown that the presence of a gut microbiota remodels lipid composition. Here we investigated how interaction between gut microbiota and dietary lipids regulates lipid composition in the liver and plasma, and gene expression in the liver. Germ-free and conventionally raised mice were fed a lard or fish oil diet for 11 weeks. We performed lipidomics analysis of the liver and serum and microarray analysis of the liver. As expected, most of the variation in the lipidomics dataset was induced by the diet, and abundance of most lipid classes differed between mice fed lard and fish oil. However, the gut microbiota also affected lipid composition. The gut microbiota increased hepatic levels of cholesterol and cholesteryl esters in mice fed lard, but not in mice fed fish oil. Serum levels of cholesterol and cholesteryl esters were not affected by the gut microbiota. Genes encoding enzymes involved in cholesterol biosynthesis were downregulated by the gut microbiota in mice fed lard and were expressed at a low level in mice fed fish oil independent of microbial status. In summary, we show that gut microbiota-induced regulation of hepatic cholesterol metabolism is dependent on dietary lipid composition.

Crosstalk between Gut Microbiota and Dietary Lipids Aggravates WAT Inflammation through TLR Signaling.

Dietary lipids may influence the abundance of circulating inflammatory microbial factors. Hence, inflammation in white adipose tissue (WAT) induced by dietary lipids may be partly dependent on their interaction with the gut microbiota. Here, we show that mice fed lard for 11 weeks have increased Toll-like receptor (TLR) activation and WAT inflammation and reduced insulin sensitivity compared with mice fed fish oil and that phenotypic differences between the dietary groups can be partly attributed to differences in microbiota composition. Trif(-/-) and Myd88(-/-) mice are protected against lard-induced WAT inflammation and impaired insulin sensitivity. Experiments in germ-free mice show that an interaction between gut microbiota and saturated lipids promotes WAT inflammation independent of adiposity. Finally, we demonstrate that the chemokine CCL2 contributes to microbiota-induced WAT inflammation in lard-fed mice. These results indicate that gut microbiota exacerbates metabolic inflammation through TLR signaling upon challenge with a diet rich in saturated lipids.

Intestinal epithelial MyD88 is a sensor switching host metabolism towards obesity according to nutritional status.

Obesity is associated with a cluster of metabolic disorders, low-grade inflammation and altered gut microbiota. Whether host metabolism is controlled by intestinal innate immune system and the gut microbiota is unknown. Here we report that inducible intestinal epithelial cell-specific deletion of MyD88 partially protects against diet-induced obesity, diabetes and inflammation. This is associated with increased energy expenditure, an improved glucose homeostasis, reduced hepatic steatosis, fat mass and inflammation. Protection is transferred following gut microbiota transplantation to germ-free recipients. We also demonstrate that intestinal epithelial MyD88 deletion increases anti-inflammatory endocannabinoids, restores antimicrobial peptides production and increases intestinal regulatory T cells during diet-induced obesity. Targeting MyD88 after the onset of obesity reduces fat mass and inflammation. Our work thus identifies intestinal epithelial MyD88 as a sensor changing host metabolism according to the nutritional status and we show that targeting intestinal epithelial MyD88 constitutes a putative therapeutic target for obesity and related disorders.