Indole, a Signaling Molecule Produced by the Gut Microbiota, Negatively Impacts Emotional Behaviors in Rats

Abstract

Gut microbiota produces a wide and diverse array of metabolites that are an integral part of the host metabolome. The emergence of the gut microbiome-brain axis concept has prompted investigations on the role of gut microbiota dysbioses in the pathophysiology of brain diseases. Specifically, the search for microbe-related metabolomic signatures in human patients and animal models of psychiatric disorders has pointed out the importance of the microbial metabolism of aromatic amino acids. Here, we investigated the effect of indole on brain and behavior in rats. Indole is produced by gut microbiota from tryptophan, through the tryptophanase enzyme encoded by the tnaA gene. First, we mimicked an acute and high overproduction of indole by injecting this compound in the cecum of conventional rats. This treatment led to a dramatic decrease of motor activity. The neurodepressant oxidized derivatives of indole, oxindole and isatin, accumulated in the brain. In addition, increase in eye blinking frequency and in c-Fos protein expression in the dorsal vagal complex denoted a vagus nerve activation. Second, we mimicked a chronic and moderate overproduction of indole by colonizing germ-free rats with the indole-producing bacterial species Escherichia coli. We compared emotional behaviors of these rats with those of germ-free rats colonized with a genetically-engineered counterpart strain unable to produce indole. Rats overproducing indole displayed higher helplessness in the tail suspension test, and enhanced anxiety-like behavior in the novelty, elevated plus maze and open-field tests. Vagus nerve activation was suggested by an increase in eye blinking frequency. However, unlike the conventional rats dosed with a high amount of indole, the motor activity was not altered and neither oxindole nor isatin could be detected in the brain. Further studies are required for a comprehensive understanding of the mechanisms supporting indole effects on emotional behaviors. As our findings suggest that people whose gut microbiota is highly prone to produce indole could be more likely to develop anxiety and mood disorders, we addressed the issue of the inter-individual variability of indole producing potential in humans. An in silico investigation of metagenomic data focused on the tnaA gene products definitively proved this inter-individual variability.

Effects of regulating gut microbiota on the serotonin metabolism in the chronic unpredictable mild stress rat model

“…The current data point to a strong link between intestinal inflammation, disruption of serotonin signaling and the consequent alteration in gut motility, and development of depression. Presently, there were some studies, which implied another mechanism by the creation of the neuro‐suppressive indole‐derivatives; alternative probable mechanism might be through stimulation of the vagal afferent fibers . Overall, additional studies are necessary for a complete understanding of the interaction of this bacterial organism and depression.…”

“…[50][51][52][53] There have been various preceding studies with focus on the effects of the "microbiota-gut-brain axis". 54,55 To search the role of Figure 7). The result suggested that frontal Cortex 5-HT exhibited negative associations with the ratio of Firmicutes in total gut microbiota, which suggested there might be a negative feedback mechanism between gut microbiota and neurotransmitter.…”

Role of Microbiota and Tryptophan Metabolites in the Remote Effect of Intestinal Inflammation on Brain and Depression

“…, which is unable to produce indole, only rats colonized with wild-type strain showed anxiety-like behavior suggesting that indole and its metabolites might play a role in developing depression [136]. This study implies a direct mechanism by which the gut microbiota can influence the brain, and result in a state of depression, in this case via the production of the neurosuppressive indole-derivatives; oxindole and isatin, which are products of gut epithelial or hepatic xenobiotic metabolizing enzymes ( Figure 1D).…”

Plasma and Fecal Metabolite Profiles in Autism Spectrum Disorder

“…Some metabolites are closely linked with neurological disorders, either to positive or negative outcomes (92,93). Several examples have been reported of gut metabolites entering circulation and directly affecting the brain, as well as cases where metabolites stimulate pathways in the gut, immune, or autonomic nervous system and exert changes to the brain and to behavior (94)(95)(96)(97). Comprehensive metabolic profiling in humans and animal models provides insight into the molecular status of disease and how genetic factors and environmental risks interact.…”