Gut Microbiota as a Trigger for Metabolic Inflammation in Obesity and Type 2 Diabetes

Torsten P M Scheithauer, Elena Rampanelli, Max Nieuwdorp, Bruce A Vallance, C Bruce Verchere, Daniël H van Raalte, Hilde Herrema, Torsten P M Scheithauer, Elena Rampanelli, Max Nieuwdorp, Bruce A Vallance, C Bruce Verchere, Daniël H van Raalte, Hilde Herrema

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.

Keywords: diabetes; metabolism; metainflammation; microbiota; obesity.

Copyright © 2020 Scheithauer, Rampanelli, Nieuwdorp, Vallance, Verchere, van Raalte and Herrema.

Figures

Figure 1
Figure 1
Three-way interaction between the gut microbiota, glucose metabolism, and the immune system. (1) The gut microbiota influences the host‘s glucose metabolism and hormone production via the production of several metabolites. Hyperglycemia increases gut permeability and thereby translocation of bacterial components into the circulation. In turn, bacterial translocation is fueling a (pro) inflammatory response of the immune system. Under normal conditions, the gut microbiota is training the immune system via several bacterial components and metabolites. (2) The immune system is shaping and controlling gut microbiota to keep a symbiotic relationship between host and microbiota. Further, it prevents bacterial translocation via promoting gut integrity. Bacterial translocation may lead to inflammation in several tissues and consequential loss of function (e.g., beta-cell dysfunction, insulin resistance and fatty liver disease). (3) The glucose metabolism can induce a pro-inflammatory response of the immune system through interplay of metabolic and inflammatory pathways (immunometabolism). Thereby, all three factors affect each other and may drive metabolic diseases.
Figure 2
Figure 2
Inflammation influences beta cell function and insulin sensitivity. (1) A westernized diet induces insulin resistance and a pro-inflammatory immune response in metabolic active tissues. T cells (Th1 via IFN-γ and CD8+ T cells) have been discussed a secondary mediator that led to the attraction of macrophages, which are the main source of several pro-inflammatory cytokines. (2) An active pro-inflammatory response in those tissues enhances and deteriorates the extend of the insulin resistance via several inflammatory mediators (TNF, IL-6, and IL-1β), mainly secreted from M1 macrophages. Several downstream molecules (JNK, IKK, and SOCS3) interfere with the insulin signaling. Inhibition of those pro-inflammatory pathways led to improvement of insulin sensitivity and glucose tolerance (e.g., pharmacological treatments such as anakinra, gevokizumab, and aspirin). Anti-inflammatory cytokines such as IL-10 (expressed by various immune cell types, but mainly M2 macrophages) and adiponectin (from adipocytes) can resolve inflammation and improve insulin sensitivity. (3) Chronic high concentrations of pro-inflammatory cytokines lead to alpha cell expansion and beta cell dysfunction in pancreatic islets, which drives the progression toward T2D in obese subjects. Th, T helper cell; IFN, interferon; CD, cluster of differentiation; TNF, tumor necrosis factor; IL, interleukin; JNK, c-Jun N-terminal kinases; IKK, IκB kinase; SOCS, suppressor of cytokine signaling; GLUT, glucose transporter; IR, insulin receptor; IRS, insulin response substrate; MCP, monocyte chemoattractant protein 1.
Figure 3
Figure 3
Alterations in the obese and diabetic gut microbiota. (1) Under healthy conditions (lean), the gut microbiota lives in symbiosis and provides the host with several beneficial functions. For example, it produces short chain fatty acids (SCFAs) that are used as an energy source and have effects on several host tissues. However, several bacteria are able to induce an inflammatory response and can even breach the intestinal barrier, which has to be prevented by a proper immune response. (2) The gut microbiota in metabolic diseases is often described as “dysbiotic,” meaning that there is an expansion of normally underrepresented bacteria (in particular opportunistic pathogens) and a lower diversity. A disturbed intestinal immune response and a westernized diet is discussed as causes. Further, a westernized diet induces a “leakiness” of the gut. Parts of (opportunistic) bacteria are able to cross the intestinal barrier and induce a pro-inflammatory response in the host. Lastly, people with obesity show an increased energy harvest by the gut microbiota and a different SCFAs profile as lean people, which might have deleterious consequences for the host health.
Figure 4
Figure 4
The intestinal barrier is disturbed in people with obesity and diabetes. (1) A high fiber diet supports intestinal barrier function by improving intestinal tight junction expression and immune cell function. Antigen presenting cells (e.g., dendritic cells) are probing the intestinal environment, present the antigens to T and B cells, which may lead into immune tolerance or an inflammatory response (cytokine and antibody expression). (2) The intestinal integrity is affected in people with metabolic syndrome. They have a thinner mucus layer, which leads to penetration of opportunistic bacteria; lower levels of IgA positive B cells and a lower IgA secretion, which may end into microbial alterations (outgrowth of opportunistic pathogens). A westernized diet decreases intestinal tight junction expression, which results into translocation of bacteria and pathogen associated molecular patterns (PAMPs). High glucose levels (hyperglycemia) reduces tight junction expression via GLUT2, promoting bacterial translocation in people with diabetes. PAMPs in the periphery induce inflammation in several other tissues such as the adipose tissue, where macrophages proliferate and accumulate. In particular, adipose tissue macrophages are responsible for low grade inflammation (high pro-inflammatory cytokine levels and less anti-inflammatory cytokines).
Figure 5
Figure 5
Molecular mechanism involved in microbiota promoted metainflammation. (1) The acute inflammation has to be resolved to avoid chronic inflammation that can induce tissue damage. Genetic and environmental factors can disturb this system leading to a chronic (low-grade) inflammation. Several of following pathways are disturbed during obesity and diabetes: (2) Tolle like receptors (TLRs) and their adapter molecules are important for recognizing bacterial components. Activation triggers different inflammasomes to initiate an inflammatory response. Similarly, interleukin (IL) 36 leads to the activation of the inflammasomes and a pro-inflammatory response that can be inhibited by the endogenous IL-36 antagonist. (3) Inflammasomes consists of different proteins: NACHT, LRR, and PYD domains-containing protein (NLRP), Apoptosis-associated speck like protein containing a caspase recruitment domain (ASC), and pro-caspase. Upon activation they can mature IL-1β and IL-18. NLRP12 has dual roles: It acts pro-inflammatory response via maturation of IL-1β and anti-inflammatory by inhibiting down-stream signals of several TLRs. NLRP6 is important for the maturation of IL-18 and antimicrobial protein expression in the intestine. Its activity can be increased by the microbial metabolites taurine and decreased by Spermidine as well as Histamine. It is important for maintaining a gut symbiosis and intestinal barrier function. NLRP3 activity can be increased during lipid accumulation. Further, hexokinases can detect intracellular particles of Gram positive bacteria and activate NLRP3, which leads to the maturation of the pro-inflammatory acting IL-1β. (4) Pro-inflammatory signals can increase the intracellular enzyme indoleamine 2,3-dioxygenase (IDO), which in turn metabolizes tryptophan to kynurenine. Kynurenine can activate the transcription factor Aryl hydrocarbon receptor (AhR), which induces the release of IL-22. IL-22 is important for the intestinal barrier function, which can be promoted via IL-23. Obesity interferes with that response, but the exact mechanism is not clear. (5) Nucleotide-binding oligomerization domain-containing protein (NOD) 1 can be activated by bacterial diaminopimelic acid (DAP). DAP can be cleaved by intestinal Lyzozyme (lyz) 1 enzymes from bacterial peptidoglycans. NOD1 has dual roles: It induces insulin resistance and insulin trafficking in beta cells. NOD2 can be activated by bacterial muramyl dipeptide (MDP). NOD2 inhibits the development of insulin resistance.
Figure 6
Figure 6
Microbial metabolites that affect glucose tolerance and inflammation. (1) A high fiber consumption has several beneficial effects on the gut microbiota and host health. They are degraded by the gut microbiota in short chain fatty acids such as butyrate, propionate, and acetate. SCFAs can be taken up by the enterocytes, used as an energy source or bound to free fatty acid receptors to stimulate varies responses (e.g., GLP-1 release from intestinal L-cells). Intracellularly, it can stimulate epigenetic changes via histone deacetylase (HDAC). It supports the expansion of beneficial bacteria and keeps opportunistic pathogens in control, improves glucose and appetite control, supports intestinal barrier integrity and induces an anti-inflammatory immune response in intestinal as well as systemic tissue sides. (2) Primary bile acids (pBA) are produced in the liver from cholesterol and secreted into the intestine via the gall bladder. There, they can change the gut microbiota and are transformed by bacteria to secondary bile acids (sBA). Bile acids can activate intestinal and systemic TGR5 as well as FXR, which increases the energy expenditure, lower inflammation and improves glucose tolerance. (3) A westernized diet, which is usually rich in saturated lipids, can disturb the branched chain amino acid (BCAA) catabolism of the host, which in turn inhibits the insulin signaling. (4) Further, a westernized diet is commonly rich in choline and carnitine, which the gut microbiota can metabolize to trimethylamine (TMA). After intestinal uptake, the liver transforms TMA into Trimethylamine N-oxide (TMAO) via flavin-containing monooxygenase (FMO). TMAO inhibits bile acid synthesis, reverse cholesterol transport (RCT), induce macrophage foam cell formation and inflammation via NLRP3. That in turn leads to cardiovascular complications.

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