The contribution of gut bacterial metabolites in the human immune signaling pathway of non-communicable diseases

Abstract

The interaction disorder between gut microbiota and its host has been documented in different non-communicable diseases (NCDs) such as metabolic syndrome, neurodegenerative disease, and autoimmune disease. The majority of these altered interactions arise through metabolic cross-talk between gut microbiota and host immune system, inducing a low-grade chronic inflammation that characterizes all NCDs. In this review, we discuss the contribution of bacterial metabolites to immune signaling pathways involved in NCDs. We then review recent advances that aid to rationally design microbial therapeutics. A deeper understanding of these intersections between host and gut microbiota metabolism using metabolomics-based system biology platform promises to reveal the fundamental mechanisms that drive metabolic predispositions to disease and suggest new avenues to use microbial therapeutic opportunities for NCDs treatment and prevention. Abbreviations: NCDs: non-communicable disease, IBD: inflammatory bowel disease, IL: interleukin, T2D: type 2 diabetes, SCFAs: short-chain fatty acids, HDAC: histone deacetylases, GPCR: G-protein coupled receptors, 5-HT: 5-hydroxytryptamine receptor signaling, DCs: dendritic cells, IECs: intestinal epithelial cells, T-reg: T regulatory cell, NF-κB: nuclear factor κB, TNF-α: tumor necrosis factor alpha, Th: T helper cell, CNS: central nervous system, ECs: enterochromaffin cells, NSAIDs: non-steroidal anti-inflammatory drugs, AhR: aryl hydrocarbon receptor, IDO: indoleamine 2,3-dioxygenase, QUIN: quinolinic acid, PC: phosphatidylcholine, TMA: trimethylamine, TMAO: trimethylamine N-oxide, CVD: cardiovascular disease, NASH: nonalcoholic steatohepatitis, BAs: bile acids, FXR: farnesoid X receptor, CDCA: chenodeoxycholic acid, DCA: deoxycholic acid, LCA: lithocholic acid, UDCA: ursodeoxycholic acid, CB: cannabinoid receptor, COBRA: constraint-based reconstruction and analysis.

Keywords: Bacterial metabolites; gut microbiota; immune signaling; metabolomics; non-communicable diseases; system biology.

Figure 1.

Immune signaling pathway activated by Short-Chain Fatty Acids. SCFAs act on immune cells mainly through two pathways: activation of G-protein coupled receptors (GPCRs) such as GPCR 41, GPCR 43, and GPCR 109 and inhibition of histone deacetylase (HDAC). AC: acetylate; HAT: histone acetylase

Figure 2.

Overview of the different ways microbes degrade tryptophan in the human gut. Tryptophan metabolites regulate various host processes through their function as signaling molecules. In the gut, tryptophan can undergo several possible chemical alterations: the direct transformation of tryptophan by the gut microbiota into several molecules, such as indole and its derivatives, and indirectly through the kynurenine pathway and the serotonin pathway. Various tryptophan catabolites are ligands for the aryl hydrocarbon receptor (AhR) expressed on intestinal immune cells and thereby alter innate and adaptive immune responses. AhR ligands are denoted with a red asterisk. Pro-inflammatory factors (NF-κB, TNF-α and interferon gamma) upregulate indoleamine 2,3-dioxygenase (IDO) expression, whereas anti-inflammatory factors such as IL-4 inhibit its expression. IDP: indole propionic acid; IDS, indoxyl sulfate, IDA: indoxyl acetic acid

Figure 3.

Anti- inflammatory and pro-inflammatory immune modulation by bacterial metabolites. Microbial-associated metabolites affect multiple facets of the immune response such as neutrophil (NФ) chemotaxis and cytokine secretion by macrophages (MФ), dendritic cells (DC), and T-regulatory cells (T-reg). Based on the immune response, secreted cytokines can suppress or activate the NF-κB pathway. NF-κB is a major transcription factor that regulates expression of pro-inflammatory genes responsible for both the innate and adaptive immune response and inflammation such as TNF-α, IL-6, IL-8, and IL-1β

Figure 4.

Integrated omics/systems biology/animal model approach to elucidate host-microbiota interactions in inflammation. Combining the results of the gnotobiotic and the metabolite- based approaches yields a set of bacteria capable of causally effecting an immune phenotype by potentially distinct mechanisms. These strains may be used together as rationally designed microbial therapeutics