Elucidating the Effect of Short Chain Fatty Acids (SCFAs) on Metaflammation and Gut Microbiota Alteration in Diet Induced Type 2 Diabetes (T2D)

Abstract

Introduction: The gut microbiota-host interactions play a pivotal role in determining the health of an individual. Gut microbiota influence host metabolism and immune response mainly by its fermentation products such as Short Chain Fatty Acids (SCFAs). These SCFAs mainly acetate, propionate and butyrate regulate glucose and lipid metabolism by activation of SCFA receptors on liver, adipose tissue, brain and pancreas. In case of high fat diet (HFD) induced type 2 diabetes (T2D), the SCFA producing gut microbiota are reduced. Poor quality of diet and excess load of nutrients, in case of high fat diet consumption, leads to metabolic inflammation, metaflammation, and develop insulin resistance. In this study, we have tried to correlate dual role of SCFAs in metabolism as well as inflammation along with gut microbiota alteration and overall response in case of high fat diet induced diabetes. In most of the reports, only butyrate has been studied while acetate and propionate are given less attention. In this study, we have compared acetate, propionate and butyrate alone and in combination so that the best possible treatment could be identified. In most of the studies, levels of SCFAs in gut or circulation have been correlated with metabolic and immune state. Therefore, we hypothesized that orally administered major SCFAs i.e. acetate, propionate and butyrate individually and in combination would directly or indirectly alter gut microbial diversity, regulate liver carbohydrate and lipid metabolism as well as innate and adaptive immune response, in HFD induced T2D. Materials and Methods: To understand the effect of SCFAs, HFD was administered for four months till diabetes induction and SCFAs treatment was given for one month along with HFD diet in C57BL6 mice. At the end of study, physiological parameters, biological parameters, liver metabolism, SCFA receptor expression, systemic inflammation, T cell polarization in spleen and mesenteric lymph node and gut microbiota modulation was checked. Results and Discussion: HFD induced insulin resistance, altered liver metabolism along with alteration of gut microbiota. It also induced inflammatory Th1 and Th17 cells while suppressed Treg cells in spleen and lymph node as well as increased levels of inflammatory cytokines while decreased levels of anti-inflammatory cytokines in blood. Butyrate as well as propionate in combination with acetate or butyrate improved insulin sensitivity and metabolism in liver. SCFAs mainly butyrate, acetate + propionate and propionate + butyrate improved Treg population in spleen and lymph node that suppresses the Th1 and Th17 cells and thus reduced inflammation by down regulation of inflammatory cytokines in circulation. HFD administration altered gut microbiota and reduced good bacteria i.e. Bifidobacterium, Lactobacillus and iv Eubacterium while higher number of Bifidobacteria and butyrate producers were found in acetate + propionate, acetate + butyrate and propionate + butyrate administered group of animals. Acetate + propionate, propionate, acetate and acetate + butyrate also boosted the growth of Akkermansia muciniphila. Abundance of Lactobacillus spp. were improved due to treatment with acetate, propionate, acetate + propionate and acetate + butyrate. Conclusion: In conclusion, High fat diet induces type 2 diabetes via reducing the beneficial microbiota, increasing inflammation and developing insulin resistance while SCFAs (mainly Propionate in combination with Acetate or Butyrate) modulate the gut microbiota in healthy manner, reduce inflammation, induce insulin sensitivity and regulate liver metabolism to maintain energy and immune homeostasis.