Have you experienced drowsiness after eating a large meal? Has an important presentation made your stomach turn? Seeing a special someone made you feel butterflies in your stomach? If you have (and you most likely have), then you know how strong the connection between the brain and the gut is.

Scientists have found that many chronic metabolic diseases, type 2 diabetes, mood disorders and even neurological diseases, such as Parkinson’s disease, Alzheimer’s disease, amyotrophic lateral sclerosis (ALS) and multiple sclerosis, are often associated with functional gastrointestinal disorders (1). The importance of the association between the gut and the brain is gaining momentum with each new study. However, the way HOW the signaling between these two integral parts of the body exactly works hasn’t been clear until recently.

It was thought for a long time that the only “communication channel” between the gut and the brain was the passive release of hormones stimulated by the consumed nutrients. Hormones entered the bloodstream and slowly notified the brain that the stomach is full of nutrients and calories. This rather slow and indirect way of passing messages takes from minutes to hours.

But now, a recent study (2) has elegantly proven that the gut can message the brain in seconds! Using a rabies virus enhanced with green fluorescence, the scientists traced a signal as it traveled from the intestines to the brainstem of mice, crossing from cell to cell in under 100 milliseconds – faster than the blink of an eye.

The researchers had also noticed that the sensory cells lining the gut were quite similar to the receptors in the nose and on the tongue (3). The effects, however, differ. In the mouth, the taste of fatty acids triggers signals to increase hunger, whereas in the small intestine, fatty acids trigger signals of satiety. This means that the discovered “gut feeling” might be considered as a sixth sense, a way of how the brain is being signaled when the stomach is full.

This new knowledge will help to understand the mechanism of appetite, develop new and more effective appetite suppressants and help those struggling with weight and problematic eating patterns.

REFERENCES
(1) Pellegrini C et al (2018) Interplay among gut microbiota, intestinal mucosal barrier and enteric neuro-immune system: a common path to neurodegenerative diseases? Acta Neuropathol 136:345. doi:10.1007/s00401-018-1856-5

(2) Kaelberer et al (2018) A gut-brain neural circuit for nutrient sensory transduction. Science 361(6408):eaat5236. doi:10.1126/science.aat5236

(3) Bohórquez and Liddle (2015) The gut connectome: making sense of what you eat. J Clin Invest 125(3):888–890. doi:10.1172/JCI81121

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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 not completely 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, led 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 suggests 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 in the barrier [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.

Gut_Microbes and Mental HealthSCFA’s are among the molecules having the privilege to cross the blood brain barrier and access the brain directly, 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 (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. However, they 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].

Other intestinal microbiota have been reported also to regulate 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 not until 2016 that a gut bacteria was identified as GABA consumer [5]. For example, decreased levels of bacterial GABA producers were identified in a human cohort of depressed individuals. Studies in mice reinforce these findings. 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 Central Nervous System.) 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 the human genome. 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 being explored.

Authors Prokopis Konstanti, MSc and Clara Belzer, PhD are working in the Department of Molecular Ecology, Laboratory of Microbiology, Wageningen University, Netherlands.

Footnotes

  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.

 

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