(1) The gut microbiota influences the host‘s glucose metabolism and hormone production via the production of several metabolites. Three-way interaction between the gut microbiota, glucose metabolism, and the immune system. In addition, we propose whether, based on current evidence, modulation of inflammation via the intestinal microbiota could form a target for novel therapies to reduce the current diabetes pandemic. In this review, we extensively address the tripartite interaction between the gut microbiota, the mammalian immune system and glucometabolic pathways ( Figure 1). In accordance, the gut microbiota has been appointed as driver of metainflammation observed in obesity and T2D, which are also characterized by an altered gut microbiota composition ( 6– 8). Although this property is critical for human health, it can also have detrimental consequences. The intestinal microbiota, the collective community of microorganisms in the gastrointestinal tract, plays a critical role in human metabolism, in part by acting as an immunomodulator. While a vast body of research has provided detailed insight into regulation of glucose homeostasis by inflammatory pathways, the upstream triggers of these pathways have remained elusive for a long time. As such, metainflammation has been linked to both impaired insulin action and secretion ( 5). In recent decades, chronic low-grade “metabolic” inflammation (local and systemic), also called metainflammation, has been identified to contribute to the development of insulin resistance and progression to T2D. Hyperglycemia has been extensively linked to the detrimental micro- and macrovascular complications typically observed in humans with T2D ( 4). When pancreatic beta cells fail to meet the increased insulin demand, hyperglycemia develops ( 3). In early stages of insulin resistance, the pancreas can compensate for impaired peripheral insulin action by increasing insulin production. Insulin is produced by the beta cells of the endocrine pancreas. This results in reduced insulin-stimulated glucose disposal, impaired insulin-induced suppression of hepatic glucose production and lipolysis rates, respectively ( 2). T2D is typically preceded by insulin resistance a condition in which the actions of insulin on peripheral tissues including skeletal muscle, liver, and adipose, are impaired. In 2019, it was estimated that 463 million people were suffering from diabetes worldwide these numbers are expected to continue to rise toward 578 million patients in 2030 ( 1). Type 2 diabetes (T2D) incidence, which is in large driven by the obesity pandemic, is increasing with alarming rates. 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. ![]() ![]() Lastly, we will critically discuss clinical studies that focus on the interaction between gut microbiota and the immune system in metabolic disease. Next, we will give a detailed view on how gut microbial changes have been implicated in low-grade inflammation. First, we will summarize major findings about immunological and gut microbial changes in these metabolic diseases. 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. 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. ![]() The underlying mechanisms as to how intestinal microbiota may contribute to T2D are only partly understood. The gut microbiota has been linked to the development of obesity and type 2 diabetes (T2D).
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