Prokopis Konstanti is a PhD candidate focusing on the molecular analysis of microbial communities, the role of microbes in human physiology and the gut-brain axis in the group of Molecular Ecology at the Laboratory of Microbiology at the Wageningen University (the Netherlands).
Recently, the idea that gastrointestinal microbiota are able to affect host behaviour is gaining momentum and it is based on studies conducted with animal models but also in humans with neurological disorders. However, the mechanisms that underlay this complex interplay between gut, brain and microbiota are incompletely understood. Here we discuss recent findings on how microbial products could potentially affect the gut-brain axis.
Intestinal microbiota, grow through the fermentation of undigested carbohydrates that end up in the large intestine. It was shown that absence of microbes or disruption of the microbiota, lead to increased populations of impaired microglia cells in mice. Microglia cells, are the primary effector cells for immune signalling to the central nervous system. The presence of a complex microbiota community, was shown to be essential for proper microglia maturation and function [1].
The main products of microbial fermentation in the gut are; acetate, propionate and butyrate collectively known as short chain fatty acids(SCFA’s). Their beneficial role in human physiology have been well described and recently evidence suggest that these molecules are able to cross blood brain barrier [2]. Moreover, gut microbiota have been associated with the brain barrier integrity. Mice raised in absence of bacteria are reported to have reduced brain barrier integrity. Once colonized with either a butyrate or an acetate/propionate producing bacteria, significant improvements were reported [3]. Notably the integrity of the blood-brain barrier from the germ free mice was able to be restored through the oral administration of butyrate. SCFA’s are among the molecules having the privilege to cross the blood brain barrier and access brain, their role should be studied in detail.
Recent studies also demonstrate that gut microbes regulate levels of intestinal neurotransmitters. The enteric nervous system interacts with a plethora of neurotransmitters and more than 30 have been identified so far. Actually, the bulk of serotonin production ~90%, a neurotransmitter associated with mood and appetite is located in the gut. Specialized cells known as enterochromaffin cells are the main serotonin producers in the gut. In the absence of intestinal microbiota gastrointestinal serotonin levels are depleted but can be restored by the addition of a specific spore forming consortium of intestinal bacteria. Specific bacterial metabolites have been reported to mediate this effect [4].
Except from serotonin, the intestinal microbiota have been reported to regulate also the levels of the GABA neurotransmitter. Reduced levels of GABA have been associated with anxiety, panic disorder and depression. Bacterial GABA producers have been known to exist for years but it was until 2016 that a gut bacteria was identified as GABA consumer [5]. In line, decreased levels of bacterial GABA producers were identified in a human cohort of depressed individuals. Studies in mice reinforce these findings, as intervention with the lactic acid bacteria Lactobacillus rhamnosus (JB-1) in healthy mice, reduced anxiety related symptoms accompanied by a reduction in the mRNA expression of GABA receptors in the CNS. Lactic acid producing bacteria have also been reported to produce GABA in several food products such as kimchi, fermented fish and cheese [6].
Collectively, our gut microbiota encodes for ~100 times more genes than humans. The potential for some of these microbial genes to produce compounds able to interact with the nervous system and regulate critical pathways implicated in the gut brain axis is realistic and worth’s to be explored.
Authors Prokopis Konstanti and Clara Belzer are working in the Department of Molecular Ecology, Laboratory of Microbiology, Wageningen University, Netherlands.
1. Erny, D., et al., Host microbiota constantly control maturation and function of microglia in the CNS. Nature neuroscience, 2015. 18(7): p. 965-977.
2. Joseph, J., et al., Modified Mediterranean Diet for Enrichment of Short Chain Fatty Acids: Potential Adjunctive Therapeutic to Target Immune and Metabolic Dysfunction in Schizophrenia? Frontiers in Neuroscience, 2017. 11(155).
3. Braniste, V., et al., The gut microbiota influences blood-brain barrier permeability in mice. Science translational medicine, 2014. 6(263): p. 263ra158-263ra158.
4. Yano, J.M., et al., Indigenous bacteria from the gut microbiota regulate host serotonin biosynthesis. Cell, 2015. 161(2): p. 264-276.
5. P. Strandwitz, K.K., D. Dietrich, D. McDonald, T. Ramadhar, E. J. Stewart, R. Knight, J. Clardy, K. Lewis; , Gaba Modulating Bacteria of the Human Gut Microbiome. 2016.
6. Dhakal, R., V.K. Bajpai, and K.-H. Baek, Production of gaba (γ – Aminobutyric acid) by microorganisms: a review. Brazilian Journal of Microbiology, 2012. 43(4): p. 1230-1241.