The gut microbiota has been linked to the development of obesity and type 2 diabetes (T2D). The underlying mechanisms as to how intestinal microbiota may contribute to T2D are only partly understood. It becomes progressively clear that T2D is characterized by a chronic state of low-grade inflammation, which has been linked to the development of insulin resistance. Here, we review the current evidence that intestinal microbiota, and the metabolites they produce, could drive the development of insulin resistance in obesity and T2D, possibly by initiating an inflammatory response. First, we will summarize major findings about immunological and gut microbial changes in these metabolic diseases. Next, we will give a detailed view on how gut microbial changes have been implicated in low-grade inflammation. Lastly, we will critically discuss clinical studies that focus on the interaction between gut microbiota and the immune system in metabolic disease. Overall, there is strong evidence that the tripartite interaction between gut microbiota, host immune system and metabolism is a critical partaker in the pathophysiology of obesity and T2D.

ObjectiveBariatric surgery improves glucose metabolism. Recent data suggest that faecal microbiota transplantation (FMT) using faeces from postbariatric surgery diet-induced obese mice in germ-free mice improves glucose metabolism and intestinal homeostasis. We here investigated whether allogenic FMT using faeces from post-Roux-en-Y gastric bypass donors (RYGB-D) compared with using faeces from metabolic syndrome donors (METS-D) has short-term effects on glucose metabolism, intestinal transit time and adipose tissue inflammation in treatment-naïve, obese, insulin-resistant male subjects.DesignSubjects with metabolic syndrome (n=22) received allogenic FMT either from RYGB-D or METS-D. Hepatic and peripheral insulin sensitivity as well as lipolysis were measured at baseline and 2 weeks after FMT by hyperinsulinaemic euglycaemic stable isotope (2H2-glucose and 2H5-glycerol) clamp. Secondary outcome parameters were changes in resting energy expenditure, intestinal transit time, faecal short-chain fatty acids (SCFA) and bile acids, and inflammatory markers in subcutaneous adipose tissue related to intestinal microbiota composition. Faecal SCFA, bile acids, glycaemic control and inflammatory parameters were also evaluated at 8 weeks.ResultsWe observed a significant decrease in insulin sensitivity 2 weeks after allogenic METS-D FMT (median rate of glucose disappearance: from 40.6 to 34.0 µmol/kg/min; p<0.01). Moreover, a trend (p=0.052) towards faster intestinal transit time following RYGB-D FMT was seen. Finally, we observed changes in faecal bile acids (increased lithocholic, deoxycholic and (iso)lithocholic acid after METS-D FMT), inflammatory markers (decreased adipose tissue chemokine ligand 2 (CCL2) gene expression and plasma CCL2 after RYGB-D FMT) and changes in several intestinal microbiota taxa.ConclusionAllogenic FMT using METS-D decreases insulin sensitivity in metabolic syndrome recipients when compared with using post-RYGB-D. Further research is needed to delineate the role of donor characteristics in FMT efficacy in human insulin-resistant subjects.Trial registration numberNTR4327.

ObjectiveEnvironmental factors driving the development of type 1 diabetes (T1D) are still largely unknown. Both animal and human studies have shown an association between altered fecal microbiota composition, impaired production of short-chain fatty acids (SCFA) and T1D onset. However, observational evidence on SCFA and fecal and oral microbiota in adults with longstanding T1D vs healthy controls (HC) is lacking.Research design and methodsWe included 53 T1D patients without complications or medication and 50 HC matched for age, sex and BMI. Oral and fecal microbiota, fecal and plasma SCFA levels, markers of intestinal inflammation (fecal IgA and calprotectin) and markers of low-grade systemic inflammation were measured.ResultsOral microbiota were markedly different in T1D (eg abundance of Streptococci) compared to HC. Fecal analysis showed decreased butyrate producing species in T1D and less butyryl-CoA transferase genes. Also, plasma levels of acetate and propionate were lower in T1D, with similar fecal SCFA. Finally, fecal strains Christensenella and Subdoligranulum correlated with glycemic control, inflammatory parameters and SCFA.ConclusionsWe conclude that T1D patients harbor a different amount of intestinal SCFA (butyrate) producers and different plasma acetate and propionate levels. Future research should disentangle cause and effect and whether supplementation of SCFA-producing bacteria or SCFA alone can have disease-modifying effects in T1D.

ObjectiveThe twin pandemics of obesity and Type 2 diabetes (T2D) are a global challenge for health care systems. Changes in the environment, behavior, diet, and lifestyle during the last decades are considered the major causes. A Western diet, which is rich in saturated fat and simple sugars, may lead to changes in gut microbial composition and physiology, which have recently been linked to the development of metabolic diseases.MethodsWe will discuss evidence that demonstrates the influence of the small and large intestinal microbiota on weight regulation and the development of insulin resistance, based on literature search.ResultsAltered large intestinal microbial composition may promote obesity by increasing energy harvest through specialized gut microbes. In both large and small intestine, microbial alterations may increase gut permeability that facilitates the translocation of whole bacteria or endotoxic bacterial components into metabolic active tissues. Moreover, changed microbial communities may affect the production of satiety-inducing signals. Finally, bacterial metabolic products, such as short chain fatty acids (SCFAs) and their relative ratios, may be causal in disturbed immune and metabolic signaling, notably in the small intestine where the surface is large. The function of these organs (adipose tissue, brain, liver, muscle, pancreas) may be disturbed by the induction of low-grade inflammation, contributing to insulin resistance.ConclusionsInterventions aimed to restoring gut microbial homeostasis, such as ingestion of specific fibers or therapeutic microbes, are promising strategies to reduce insulin resistance and the related metabolic abnormalities in obesity, metabolic syndrome, and type 2 diabetes. This article is part of a special issue on microbiota.