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.