The human gastrointestinal tract is inhabited by trillions of commensal bacteria collectively known as the gut microbiota. Our recognition of the significance of the complex interaction between the microbiota, and its host has grown dramatically over the past years. A balanced microbial community is a key regulator of the immune response, and metabolism of dietary components, which in turn, modulates several brain processes impacting mood and behavior. Consequently, it is likely that disruptions within the composition of the microbiota would remotely affect the mental state of the host. Here, we discuss how intestinal bacteria and their metabolites can orchestrate gut-associated neuroimmune mechanisms that influence mood and behavior leading to depression. In particular, we focus on microbiota-triggered gut inflammation and its implications in shifting the tryptophan metabolism towards kynurenine biosynthesis while disrupting the serotonergic signaling. We further investigate the gaps to be bridged in this exciting field of research in order to clarify our understanding of the multifaceted crosstalk in the microbiota–gut–brain interphase, bringing about novel, microbiota-targeted therapeutics for mental illnesses.

No abstract

Microbial conversion of dietary or drug substrates into small bioactive molecules represents a regulatory mechanism by which the gut microbiota alters intestinal physiology. Here, we show that a wide variety of gut bacteria can metabolize the dietary supplement and antidepressant 5-hydroxytryptophan (5-HTP) to 5-hydroxyindole (5-HI) via the tryptophanase (TnaA) enzyme. Oral administration of 5-HTP results in detection of 5-HI in fecal samples of healthy volunteers with interindividual variation. The production of 5-HI is inhibited upon pH reduction in in vitro studies. When administered orally in rats, 5-HI significantly accelerates the total gut transit time (TGTT). Deciphering the underlying mechanisms of action reveals that 5-HI accelerates gut contractility via activation of L-type calcium channels located on the colonic smooth muscle cells. Moreover, 5-HI stimulation of a cell line model of intestinal enterochromaffin cells results in significant increase in serotonin production. Together, our findings support a role for bacterial metabolism in altering gut motility and lay the foundation for microbiota-targeted interventions.

The human gastrointestinal tract is inhabited by trillions of commensal bacteria 11 collectively known as the gut microbiota. Our recognition of the significance of the complex 12 interaction between the microbiota, and its host has grown dramatically over the past years. A 13 balanced microbial community is a key regulator of the immune response, and metabolism of 14 dietary components, which in turn, modulates several brain processes impacting mood and 15 behavior. Consequently, it is likely that disruptions within the composition of the microbiota would 16 remotely affect the mental state of the host. Here, we discuss how intestinal bacteria and their 17 metabolites can orchestrate gut-associated neuroimmune mechanisms that influence mood and 18 behavior leading to depression. In particular, we focus on microbiota-triggered gut inflammation 19 and its implications in shifting the tryptophan metabolism towards kynurenine biosynthesis while 20 disrupting the serotonergic signaling. We further investigate the gaps to be bridged in this exciting 21 field of research in order to clarify our understanding of the multifaceted crosstalk in the microbiota-22 gut-brain interphase, bringing about a novel microbiota-targeted therapeutics for mental illnesses. 23 24 25 29 effects on the host immune development, metabolism and food preferences, brain development, 30 stress responses, pain and behavior [1][2][3][4][5]. Consequently, disruptions or alterations in this resilient 31 relationship is a significant factor in many diseases such as inflammatory gastrointestinal diseases, 32 and neuropsychiatric disorders, including depression [1,6-8]. 33 Depression is a severe neuropsychiatric disease with multiple comorbidities in play. According 34 to the World Health Organization (WHO), this long-standing mental disorder affects more than 300 35 million people of all ages worldwide [9]. Moreover, it is the leading cause of disability in modern 36 society, and approximately 1 million people suffering from depression commit suicide every year [9]. 37It is widely recognized now that depression is closely linked with inflammation, and disrupted 38 serotonergic systems throughout the human body, including the gut [10][11][12][13][14][15][16]. In fact, in a state of 39 inflammation, not only high levels of pro-inflammatory cytokines are produced but also altered 40 levels of neurotransmitters, such as serotonin, a derivative of tryptophan metabolism, are detected in 41 the gut [17][18][19]. The presence of vast majority of bodily serotonin and immune cells in the gut in 42 Preprints (www.preprints.org) | NOT PEER-REVIEWED | Posted: close proximity to the trillion of the gut-associated microbes implies the gut microbiota is likely to be 43 an orchestrator in this multi-faceted crosstalk between inflammation, serotonin, and depression, as 44 will be discussed in this review article. 45 Gastrointestinal inflammation and depression 46In a state of intestinal inflammation, the immune system responds by producing various pro-47 inflammatory ...

Intestinal microbiota and microbiota-derived metabolites play a key role in regulating the host physiology. Recently, we have identified a gut-bacterial metabolite, namely 5-hydroxyindole, as a potent stimulant of intestinal motility via its modulation of L-type voltage-gated calcium channels located on the intestinal smooth muscle cells. Dysregulation of L-type voltage-gated calcium channels is associated with various gastrointestinal motility disorders, including constipation, making L-type voltage-gated calcium channels an important target for drug development. Nonetheless, the majority of currently available drugs are associated with alteration of the gut microbiota. Using 16S rRNA sequencing this study shows that, when administered orally, 5-hydroxyindole has only marginal effects on the rat cecal microbiota. Molecular dynamics simulations propose potential-binding pockets of 5-hydroxyindole in the α1 subunit of the L-type voltage-gated calcium channels and when its stimulatory effect on the rat colonic contractility was compared to 16 different analogues, ex-vivo , 5-hydroxyindole stood as the most potent enhancer of the intestinal contractility. Overall, the present findings imply a potential role of microbiota-derived metabolites as candidate therapeutics for targeted treatment of slow intestinal motility-related disorders including constipation.