Gut Microbial Metabolites of Aromatic Amino Acids as Signals in Host–Microbe Interplay

The gut microbiome converts AAAs to a collection of signaling metabolites that impact the host as well as the microbiome. Microbial AAA metabolites regulate biological processes, such as intestinal epithelial cell homeostasis, immune cell response, and neuronal excitability, thereby mediating host–gut microbiome crosstalk at local and systems levels. The role of microbial AAA metabolites has been explored in different physiological and disease settings, and the relevance of these compounds as important integrators of environmental, immune, and neural system signals continues to emerge. Targeting AAA metabolism has shown therapeutic promise in animal models of disease, such as inflammatory bowel disease (IBD) and multiple sclerosis (MS). Deciphering the key bacterial sources and signaling mechanisms of AAA metabolites could enable the rational design of microbial and metabolite-based therapeutics. Gut microbial metabolism is intimately coupled with host health and disease. Aromatic amino acid (AAA) catabolism by the gut microbiome yields numerous metabolites that may regulate immune, metabolic, and neuronal responses at local and distant sites. Such a chemical dialog between host cells and the gut microbiome is shaped by environmental cues, and may become dysregulated in gastrointestinal and systems diseases. Increasing knowledge of the bacterial pathway and signaling basis may shed additional light on metabolic host–microbiome crosstalk that remains untapped for drug discovery. Here, we update our understanding of microbial AAA metabolism and its impacts on host physiology and disease. We also consider open questions related to therapeutically mining these signaling metabolites and how recent concepts and tools may drive this area forward. Gut microbial metabolism is intimately coupled with host health and disease. Aromatic amino acid (AAA) catabolism by the gut microbiome yields numerous metabolites that may regulate immune, metabolic, and neuronal responses at local and distant sites. Such a chemical dialog between host cells and the gut microbiome is shaped by environmental cues, and may become dysregulated in gastrointestinal and systems diseases. Increasing knowledge of the bacterial pathway and signaling basis may shed additional light on metabolic host–microbiome crosstalk that remains untapped for drug discovery. Here, we update our understanding of microbial AAA metabolism and its impacts on host physiology and disease. We also consider open questions related to therapeutically mining these signaling metabolites and how recent concepts and tools may drive this area forward. amino acids that include an aromatic ring, including tryptophan (Trp), phenylalanine (Phe), and tyrosine (Tyr). Trp and Phe are essential amino acids for animals since they are not synthesized in the human body. Tyr is semi-essential since it can be synthesized from Phe. an amino acid that is required for a stage of growth but cannot be synthesized de novo by the organism or manufactured in sufficient quantities and, thus, must be supplied from diet. mice that are only colonized by a known, defined set of microorganisms, which enables mechanistic understanding of certain microbes in host phenotype. a nonspecific chronic recurrent intestinal inflammatory disease, including ulcerative colitis and Crohn's disease. IBD is recently regarded as an abnormal immune response and chronic intestinal inflammation caused by genetic factors, environmental factors, ad complex interactions between the intestinal flora and the host immune system. describes the bidirectional signaling between gut, its resident microbiome, and the brain that underlies the functional crosstalk of gut and brain in physiology and disease. The signaling mechanism of this axis is yet to be fully revealed, and largely involves hormonal, immune, and neuronal routes. conversion of primary bile acids (e.g., cholate and chenodeoxycholate) by anaerobic bacteria in the colon generates several modified bile acids, including deoxycholate (DCA), ursodeoxycholate (UDCA), and lithocholate (LCA). These secondary bile acids are either passively absorbed from the colon or excreted in the feces. fatty acids with fewer than six carbon atoms. They are mainly produced during fermentation of the soluble dietary fiber by microbes residing in the colon. a class of GPCRs that were initially discovered in 2001; also referred to as trace amine receptors. There are nine subfamilies (TAAR1–9) identified in mammalian species.