Abstract
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.
Highlights
Type 2 diabetes (T2D) incidence, which is in large driven by the obesity pandemic, is increasing with alarming rates
Summary of relevant findings that are discussed in this review. hsCRP, highly sensitive C-reactive peptide; HOMA-IR, homeostatic model assessment for insulin resistance; LBP, lipopolysaccharide binding protein; TNF, tumor necrosis factor; IL, interleukin; NAFLD, Non-alcoholic fatty liver disease; DIO, diet induced obesity; MCP-1, Monocyte chemoattractant protein-1; SCFAs, short fain fatty acids; LPS, lipopolysaccharide; CLS, crown-like structure; FMT, fecal microbiota transplantation. ♂, male participants; ♀, female participants; Arrows, treatment leads to up or down regulation
Expansion and infiltration of pro-inflammatory immune cells is present in several metabolic active tissues during the development of T2D [21, 92]
Summary
Type 2 diabetes (T2D) incidence, which is in large driven by the obesity pandemic, is increasing with alarming rates. MCP1 overexpression in adipose tissue increased macrophage infiltration and mediated insulin resistance, whereas MCP1 knock out in combination with high fat diet feeding augmented development of insulin resistance compared to wild type mice [38] This observation was not observed in another study [39], higher chemokine production in obese adipose tissue has been associated with infiltration of immune cells and development of insulin resistance. Cytotoxic ILCs kill adipose tissue macrophages to maintain homeostasis [53] This is impaired under high fat diet conditions leading to an increase of pro-inflammatory macrophages in the adipose tissue of obese mice and humans. The intertwined relation between metabolic disorders and low-grade inflammation has been coined “metainflammation.” This illustrates that, in contrast to an instrumental acute inflammatory response to pathogens and tissue damage, chronic low-grade inflammation as observed in obesity and T2D has detrimental consequences for human metabolism
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