What We Know So Far about the Metabolite-Mediated Microbiota-Intestinal Immunity Dialogue and How to Hear the Sound of This Crosstalk

Abstract

Trillions of microorganisms, termed the “microbiota”, reside in the mammalian gastrointestinal tract, and collectively participate in regulating the host phenotype. It is now clear that the gut microbiota, metabolites, and intestinal immune function are correlated, and that alterations of the complex and dynamic host-microbiota interactions can have deep consequences for host health. However, the mechanisms by which the immune system regulates the microbiota and by which the microbiota shapes host immunity are still not fully understood. This article discusses the contribution of metabolites in the crosstalk between gut microbiota and immune cells. The identification of key metabolites having a causal effect on immune responses and of the mechanisms involved can contribute to a deeper insight into host-microorganism relationships. This will allow a better understanding of the correlation between dysbiosis, microbial-based dysmetabolism, and pathogenesis, thus creating opportunities to develop microbiota-based therapeutics to improve human health. In particular, we systematically review the role of soluble and membrane-bound microbial metabolites in modulating host immunity in the gut, and of immune cells-derived metabolites affecting the microbiota, while discussing evidence of the bidirectional impact of this crosstalk. Furthermore, we discuss the potential strategies to hear the sound of such metabolite-mediated crosstalk.

Altered Fecal Metabolomics and Potential Biomarkers of Psoriatic Arthritis Differing From Rheumatoid Arthritis

“…We noticed that many metabolites (N-palmitoyl-sphinganine, phytosphingosine, dihydrosphingosine and serine) in sphingolipid metabolism pathway were altered in PsA. Sphingolipids, produced by both the host and specific bacteria, participate in specific signaling pathways of physiologic cellular functions by acting as signaling molecules or regulating the function of downstream signal molecules ( 16 , 48 ). In the intestine, host sphingolipids have been thought to act directly or indirectly as inflammatory mediators ( 49 ).…”

“…These vitamins were both produced and secreted by intestinal microbes and exhibited anti-inflammatory and antioxidant activities ( 33 , 54 ). Nicotinic acid is the precursor of nicotinamide adenine dinucleotide (NAD), which plays an important role in various biological processes, namely, cell metabolism, inflammatory response, aging regulation, and cell death ( 16 ). VB3 directly activates G Protein-Coupled Receptor 109A (GPCR109A), which is one of the receptor for short chain fatty acid (SCFA).…”

“…It is well known that bile acids, such as cholic acid and deoxycholic acid, are signal molecules produced by the decomposition of cholesterol through the interaction between the host and the intestinal flora, which activate bile acid activated receptors (BARs) to regulate liver lipid and glucose metabolic homeostasis and energy metabolism (34)(35)(36)(37). Furthermore, in intestinal macrophages, G protein-coupled bile acid receptor 1 (GPBAR1) and Farnesoid-X-receptor (FXR) are highly expressed, which also occurs in innate immunity such as dendritic cells and natural killer cells (16,35). Additionally, secondary bile acids, namely, lithocholic acid and deoxycholic acid, have been reported to protect the intestinal barrier (38,39).…”

“…With the rise of new technologies for the analysis of genome, transcription, protein, metabolomics, and others, new approaches have been provided for the study of pathogenesis ( 16 ). The intestinal microbiome may affect distant sites except the intestine through immunomodulation, such as the joints ( 17 ).…”

“…The intestinal microbiome may affect distant sites except the intestine through immunomodulation, such as the joints ( 17 ). Recent studies have shown that metabolites in the gut play a fundamental role in the evolutionary relationship between symbiotic microorganisms and their hosts ( 16 , 18 ). Metabolite profiles provide functional readings of microbial activity and can be used as intermediate phenotypes to mediate interactions between human and microorganism ( 19 ).…”