Crosstalk Between Intestinal Serotonergic System and Pattern Recognition Receptors on the Microbiota-Gut-Brain Axis

Abstract

Disruption of the microbiota-gut-brain axis results in a wide range of pathologies that are affected, from the brain to the intestine. Gut hormones released by enteroendocrine cells to the gastrointestinal (GI) tract are important signaling molecules within this axis. In the search for the language that allows microbiota to communicate with the gut and the brain, serotonin seems to be the most important mediator. In recent years, serotonin has emerged as a key neurotransmitter in the gut-brain axis because it largely contributes to both GI and brain physiology. In addition, intestinal microbiota are crucial in serotonin signaling, which gives more relevance to the role of the serotonin as an important mediator in microbiota-host interactions. Despite the numerous investigations focused on the gut-brain axis and the pathologies associated, little is known regarding how serotonin can mediate in the microbiota-gut-brain axis. In this review, we will mainly discuss serotonergic system modulation by microbiota as a pathway of communication between intestinal microbes and the body on the microbiota-gut-brain axis, and we explore novel therapeutic approaches for GI diseases and mental disorders.

Keywords: 5-HT; NLRs; PRRs; TLRs; microorganisms; serotonin; tryptophan.

Figure 1

Schematic representation of brain and intestinal serotonergic systems: “ON/OFF” and signaling mechanisms. “ON” mechanism refers to the synthesis of 5-HT by enterochromaffin cells (EC) in the gut and serotonergic neurons both in the gut and in the central nervous system (CNS). Tryptophan (Trp) is catalyzed by the enzyme tryptophan hydroxylase (TPH), TPH1 in EC cells, and TPH2 in neurons, to synthesize 5-hydroxytryptophan (5-HTP), which is converted to 5-HT by aromatic amino acid decarboxylase (AADC). 5-HT is stored into vesicles through the vesicular monoamine transporter VMAT (VMAT1 in EC cells, and VMAT2 in neurons) and finally released into the extracellular space. 5-HT can bind to different serotonin receptors (5-HTR) or uptake into neurons, enterocytes, or platelets by the serotonin transporter (SERT), ending 5-HT effects (“OFF” mechanism). 5-HT is mostly stored in the dense (δ)-granules of platelets; however, the binding of plasma 5-HT to the platelet surface receptor 5-HT_2A initiates the mobilization of intracellular calcium stores for platelet activation, which promotes platelet degranulation, resulting in 5-HT release. Serotonin exerts its effects by signaling mechanisms through the 5-HT receptors located in postsynaptic and presynaptic neurons at CNS and intestinal serotonergic neurons, and in different cell types of gastrointestinal (GI) tract, but also in other systems such as the cardiovascular or immune system.

Figure 2

Serotonin (5-HT) communication pathways of the microbiota–gut–brain axis. Serotonin can modulate gastrointestinal (GI) and central nervous system (CNS) functions and is a key network for the gut–brain axis. Microorganisms produce tryptophan, and degrade tryptophan, affecting the central and intestinal 5-HT production. Intestinal microbiota modulate the synthesis of 5-HT and produce 5-HT independently of the host. Microbial associated molecular patterns from microorganisms (MAMPs) through toll-like receptors (TLRs) and nucleotide oligomerization domain (NOD)-like receptors (NLRs) affect directly the serotonergic system. TLR/NLR signaling seems to modulate the activity and the expression of serotonin transporter (SERT) and serotonin receptors (5-HTRs), as well as the 5-HT synthesis in the GI tract. However, this interconnection between TLRs/NLRs and serotonergic system exists in the CNS. In a feedback regulation, 5-HT affects pattern recognition receptor (PRR) expression. In addition, microbial metabolites, such as short chain fatty acids (SCFAs), can promote 5-HT synthesis by enterochromaffin (EC) cells and regulate SERT activity and expression. In the same way, these metabolites can migrate into the bloodstream to reach the brain, and some of them such as L-acetate can modulate the nervous serotonergic system, controlling the expression of 5-HT receptors.