Intestinal RORrt-generated Th17 cells control type 2 diabetes: A first antidiabetic target identified from the host to microbiota crosstalk

The recent discovery of the role played by gut microbiota on the control of metabolic disease opens novel routes for the identification of the causes of type 2 diabetes and obesity. This paradigm could explain the infiltration, by innate and adaptive immune cells, of the adipose tissue, liver, and islets of Langerhans which is responsible for the metabolic inflammation state that leads to impaired insulin action and secretion, and therefore, type 2 diabetes. The identification of the causal role of circulating lipopolysaccharides LPS and peptidoglycans in the development of metabolic inflammation, due to an increased intestinal permeability, led to the leaky gut hypothesis. In addition, whole live bacteria were found in metabolic tissues establishing a tissue microbiota which upon a fat-enriched diet becomes dysbiotic. The process of intestinal bacterial translocation was responsible for the onset of a leaky gut causal to the disease. The translocation of selective sets of intestinal bacteria to the blood could be identified. These blood bacterial 16SrRNA-DNA sequences are considered as biomarkers of the bacterial translocation process. An increased of the corresponding bacterial DNA concentration was predicting the occurrence of type 2 diabetes. Associated to the dysbiotic microbiota translocation, an impaired intestinal immune defense was identified as a cause of the selective leaky gut. The change in small intestine mucosal microbiota induced by a fat-enriched diet reduces the number of IL17-secreting CD4 T cells within the lamina propria of the intestine. This loss of IL17-secreting CD4 T cells is the consequence of an impaired capacity of intestinal antigen presenting cells to activate and trigger the expression of RORgt and the production of IL17 by CD4 T cells. Altogether, an impaired intestinal immune defense, notably the reduced differentiation of RORgt expressing IL17-producing CD4 T cells, favors the onset of a leaky gut leading to the translocation of bacterial factors and live bacteria towards tissues triggering metabolic inflammation; insulin resistance and type 2 diabetes. Hence, the triggering of intestinal defense surrounding RORgt pathway now appears as a potential target mechanism for the control of type 2 diabetes

The Gut Microbiota Regulates Intestinal CD4 T Cells Expressing RORγt and Controls Metabolic Disease

SummaryA high-fat diet (HFD) induces metabolic disease and low-grade metabolic inflammation in response to changes in the intestinal microbiota through as-yet-unknown mechanisms. Here, we show that a HFD-derived ileum microbiota is responsible for a decrease in Th17 cells of the lamina propria in axenic colonized mice. The HFD also changed the expression profiles of intestinal antigen-presenting cells and their ability to generate Th17 cells in vitro. Consistent with these data, the metabolic phenotype was mimicked in RORγt-deficient mice, which lack IL17 and IL22 function, and in the adoptive transfer experiment of T cells from RORγt-deficient mice into Rag1-deficient mice. We conclude that the microbiota of the ileum regulates Th17 cell homeostasis in the small intestine and determines the outcome of metabolic disease

Immuno-microbiota cross and talk: the new paradigm of metabolic diseases.

International audienceOver the last decades the rising occurrence of metabolic diseases throughout the world points to the failure of preventive and therapeutic strategies and of the corresponding molecular and physiological concepts. Therefore, a new paradigm needs to be elucidated. Very recently the intimate cross talk of the intestinal microbiota with the host immune system has opened new avenues. The large diversity of the intestinal microbes' genome, i.e. the metagenome, and the extreme plasticity of the immune system provide a unique balance which, when finely tuned, maintains a steady homeostasis. The discovery that a new microbiota repertoire is one of the causes responsible for the onset of metabolic disease suggests that the relationship with the immune system is impaired. Therefore, we here review the recent arguments that support the view that an alteration in the microbiota to host immune system balance leads to an increased translocation of bacterial antigens towards metabolically active tissues, and could result in a chronic inflammatory state and consequently impaired metabolic functions such as insulin resistance, hepatic fat deposition, insulin unresponsiveness, and excessive adipose tissue development. This imbalance could be at the onset of metabolic disease, and therefore the early treatment of the microbiota dysbiosis or immunomodulatory strategies should prevent and slow down the epidemic of metabolic diseases and hence the corresponding lethal cardiovascular consequences

Intestinal RORrt-generated Th17 cells control type 2 diabetes: A first antidiabetic target identified from the host to microbiota crosstalk: DOI: 10.14800/ics.1074

The recent discovery of the role played by gut microbiota on the control of metabolic disease opens novel routes for the identification of the causes of type 2 diabetes and obesity. This paradigm could explain the infiltration, by innate and adaptive immune cells, of the adipose tissue, liver, and islets of Langerhans which is responsible for the metabolic inflammation state that leads to impaired insulin action and secretion, and therefore, type 2 diabetes. The identification of the causal role of circulating lipopolysaccharides LPS and peptidoglycans in the development of metabolic inflammation, due to an increased intestinal permeability, led to the leaky gut hypothesis. In addition, whole live bacteria were found in metabolic tissues establishing a tissue microbiota which upon a fat-enriched diet becomes dysbiotic. The process of intestinal bacterial translocation was responsible for the onset of a leaky gut causal to the disease. The translocation of selective sets of intestinal bacteria to the blood could be identified. These blood bacterial 16SrRNA-DNA sequences are considered as biomarkers of the bacterial translocation process. An increased of the corresponding bacterial DNA concentration was predicting the occurrence of type 2 diabetes. Associated to the dysbiotic microbiota translocation, an impaired intestinal immune defense was identified as a cause of the selective leaky gut. The change in small intestine mucosal microbiota induced by a fat-enriched diet reduces the number of IL17-secreting CD4 T cells within the lamina propria of the intestine. This loss of IL17-secreting CD4 T cells is the consequence of an impaired capacity of intestinal antigen presenting cells to activate and trigger the expression of RORgt and the production of IL17 by CD4 T cells. Altogether, an impaired intestinal immune defense, notably the reduced differentiation of RORgt expressing IL17-producing CD4 T cells, favors the onset of a leaky gut leading to the translocation of bacterial factors and live bacteria towards tissues triggering metabolic inflammation; insulin resistance and type 2 diabetes. Hence, the triggering of intestinal defense surrounding RORgt pathway now appears as a potential target mechanism for the control of type 2 diabetes

CD8+CD28- regulatory T lymphocytes prevent experimental inflammatory bowel disease in mice.

BACKGROUND & AIMS: Immune responses to innocuous intestinal antigens appear tightly controlled by regulatory T lymphocytes. While CD4+ T lymphocytes have recently attracted the most attention, CD8+ regulatory T-cell populations are also believed to play an important role in control of mucosal immunity. However, CD8+ regulatory T-cell function has mainly been studied in vitro and no direct in vivo evidence exists that they can control mucosal immune responses. We investigated the capacity of CD8+CD28- T cells to prevent experimental inflammatory bowel disease (IBD) in mice. METHODS: CD8+CD28- regulatory T cells were isolated from unmanipulated mice and tested for their capacity to inhibit T-cell activation in allogeneic mixed lymphocyte cultures in vitro and to prevent IBD induced by injection of CD4+CD45RB(high) cells into syngeneic immunodeficient RAG-2 mutant mice. RESULTS: CD8+CD28- T lymphocytes inhibited proliferation and interferon gamma production by CD4+ responder T cells in vitro. CD8+CD28- regulatory T cells freshly isolated from spleen or gut efficiently prevented IBD induced by transfer of colitogenic T cells into immunodeficient hosts. Regulatory CD8+CD28- T cells incapable of producing interleukin-10 did not prevent colitis. Moreover, IBD induced with colitogenic T cells incapable of responding to transforming growth factor beta could not be prevented with CD8+CD28- regulatory T cells. CD8+CD28+ T cells did not inhibit in vitro or in vivo immune responses. CONCLUSIONS: Our findings show that naturally occurring CD8+CD28- regulatory T lymphocytes can prevent experimental IBD in mice and suggest that these cells may play an important role in control of mucosal immunity

Camu-Camu Reduces Obesity and Improves Diabetic Profiles of Obese and Diabetic Mice: A Dose-Ranging Study

Overweight, obesity, and their comorbidities are currently considered a major public health concern. Today considerable efforts are still needed to develop efficient strategies able to attenuate the burden of these diseases. Nutritional interventions, some with plant extracts, present promising health benefits. In this study, we evaluated the action of Camu-Camu (Myrciaria dubia), an Amazonian fruit rich in polyphenols and vitamin C, on the prevention of obesity and associated disorders in mice and the abundance of Akkermansia muciniphila in both cecum and feces. Methods: We investigated the dose-response effects of Camu-Camu extract (CCE) in the context of high-fat-diet (HFD)-induced obesity. After 5 weeks of supplementation, we demonstrated that the two doses of CCE differently improved glucose and lipid homeostasis. The lowest CCE dose (62.5 mg/kg) preferentially decreased non-HDL cholesterol and free fatty acids (FFA) and increased the abundance of A. muciniphila without affecting liver metabolism, while only the highest dose of CCE (200 mg/kg) prevented excessive body weight gain, fat mass gain, and hepatic steatosis. Both doses decreased fasting hyperglycemia induced by HFD. In conclusion, the use of plant extracts, and particularly CCE, may represent an additional option in the support of weight management strategies and glucose homeostasis alteration by mechanisms likely independent from the modulation of A. muciniphila abundance

Triggering the adaptive immune system with commensal gut bacteria protects against insulin resistance and dysglycemia

Objective: To demonstrate that glycemia and insulin resistance are controlled by a mechanism involving the adaptive immune system and gut microbiota crosstalk. Methods: We triggered the immune system with microbial extracts specifically from the intestinal ileum contents of HFD-diabetic mice by the process of immunization. 35 days later, immunized mice were fed a HFD for up to two months in order to challenge the development of metabolic features. The immune responses were quantified. Eventually, adoptive transfer of immune cells from the microbiota-immunized mice to naïve mice was performed to demonstrate the causality of the microbiota-stimulated adaptive immune system on the development of metabolic disease. The gut microbiota of the immunized HFD-fed mice was characterized in order to demonstrate whether the manipulation of the microbiota to immune system interaction reverses the causal deleterious effect of gut microbiota dysbiosis on metabolic disease. Results: Subcutaneous injection (immunization procedure) of ileum microbial extracts prevented hyperglycemia and insulin resistance in a dose-dependent manner in response to a HFD. The immunization enhanced the proliferation of CD4 and CD8 T cells in lymphoid organs, also increased cytokine production and antibody secretion. As a mechanism explaining the metabolic improvement, the immunization procedure reversed gut microbiota dysbiosis. Finally, adoptive transfer of immune cells from immunized mice improved metabolic features in response to HFD. Conclusions: Glycemia and insulin sensitivity can be regulated by triggering the adaptive immunity to microbiota interaction. This reduces the gut microbiota dysbiosis induced by a fat-enriched diet. Keywords: Gut microbiota and metabolic diseases, Immunity, Insulin resistanc