Direct and indirect mechanisms by which the gut microbiota influence host serotonin systems

Mounting evidence highlights the pivotal role of enteric microbes as a dynamic interface with the host. Indeed, the gut microbiota, located in the lumen of the gastrointestinal (GI) tract, influence many essential physiological processes that are evident in both healthy and pathological states. A key signaling molecule throughout the body is serotonin (5‐hydroxytryptamine; 5‐HT), which acts in the GI tract to regulate numerous gut functions including intestinal motility and secretion. The gut microbiota can modulate host 5‐HT systems both directly and indirectly. Direct actions of gut microbes, evidenced by studies using germ‐free animals or antibiotic administration, alter the expression of key 5‐HT‐related genes to promote 5‐HT biosynthesis. Indirectly, the gut microbiota produce numerous microbial metabolites, whose actions can influence host serotonergic systems in a variety of ways. This review summarizes the current knowledge regarding mechanisms by which gut bacteria act to regulate host 5‐HT and 5‐HT‐mediated gut functions, as well as implications for 5‐HT in the microbiota–gut–brain axis. Microbes can affect serotonin signaling in the gut through direct (A) and indirect (B‐E) mechanisms.