Is there more to that gut feeling? How the gut biome influences the brain


The intestines contain a large number of highly diverse bacteria, which form their own ecosystem. This gut “microbiome” is now recognized to be an organ unto itself, and maintaining the balance and diversity of these intestinal bacteria is vital to human health. 

Gut microbial composition and function are found to be modulated by diet, and nutrients made available to the host depend to a large extent on microbial metabolism.

We know that many of the microbiota exist in a largely symbiotic relationship with their hosts. The micro-ecosystem serves the host in several ways:

  • Metabolizing complex lipids and polysaccharides
  • Neutralizing drugs and carcinogens
  • Modulating intestinal motility
  • Resistance against pathogens

Moreover, recent research indicates that the influence of our microbiome extends to our mental health, too!

Though a lot of the findings in the microbiome research space are currently based on animal research data, there is potential for trials in humans that will elucidate how the gut and the brain are interlinked, paving the way for innovative treatments for neuropsychiatric disorders. Key elements of current research are described in this article. 

The gut-brain axis

Neurobiologist John F. Cryan and team demonstrated in 2009 that separating very young rat pups from their mothers' induced stress that could lead to long-term changes in the pups’ microbiomes. Further investigation showed that supplementing the pups’ diets with a specific probiotic bacterium reduced stress-induced hormone release as well as anxiety/depression-related behavior.  The reduction in stress-induced anxiety and depression-like behavior was seen along with changes in the expression of a neurotransmitter, gamma-aminobutyric acid (GABA),  in the brain of mice given the probiotic supplement. In the brain, GABA acts as a brain cell, reducing the “firing” of neurons and keeping neural networks in optimal shape.

In another study, supplementing with a different probiotic, in this case, Bifidobacterium longum NCC3001, normalized anxiety-like behavior in mice with infectious colitis. 

Interestingly, the neurochemical and behavioral effects from these studies were not found in comparator groups of mice where the vagus nerve had been cut. This points to the vagus as an important communication pathway between the gut microbiome and the brain. Thus, the gut-brain axis is, in reality, a “microbiota-gut-vagus-brain axis.”

 

Why Vagus?

The vagus nerve is one of the twelve major nerves that directly connect the body to the brain.  It is like a two-way information superhighway connecting several body parts, including the gut, to the medulla oblongata region of the brain. This vital sensory pathway is made up of approximately 80% afferent fibers that relay signals from peripheral organs, including a section of the gut from the esophagus upto mid-colon, to the central nervous system. Visceral afferent input can modulate cognition, emotion, and behavior

In simpler words, the myriad “connections” of the vagus nerve are the conduits to “inform” the brain how our body is feeling and what it is experiencing. You know that “meh” feeling? The vagus may very well be behind it!

Psychobiotics

Psychobiotics have been in physicians’ cadre of treatments since the early 1900s. For instance, neurologists putting epileptic kids on a specific low-carb, high fat, high protein diet (now familiar to us as a ketogenic diet) is an old hat. This diet was shown to decrease the number of epileptic seizures, but not much was known on why exactly it worked.

Recent findings in mice indicate that it is the gut microbiome that brings about this anti-epileptic seizure effect of a ketogenic diet. The neuroprotective effects of a ketogenic diet can be attributed to the change in the gut microbiota brought about by a steady ketogenic diet. The gut microbiome was found to be integral to conferring protection against acute, electrically induced seizures and spontaneous tonic-clonic seizures in mouse models.

In contrast, mice treated with antibiotics that kill gut bacteria and alter the composition and balance of the microbiome did not receive this protective effect. Similarly, germ-free mice models also missed out on the neuroprotective benefits of the ketogenic diet.

Cooperative interactions observed in this study between two diet-associated bacteria that regulate levels of circulating dietary metabolites, brain neurotransmitters, and seizure incidence in mice, further reinforce a link between the gut and the brain. 

 

The way ahead

 

Opinion on the relationships among gut microbial metabolism, mental health, and wellness is quite divided at this point. Some researchers maintain that since the gut microbiome-brain connection has largely been investigated in animal models, the reproducibility of results in humans cannot be guaranteed.

Others maintain that animal studies are a legitimate starting point and that this is just the beginning. Regardless, more research is needed for any therapies to take shape - laboratory mice are homogeneous whereas human populations are heterogeneous and more complex. 


The Flemish Gut Flora Project studied samples from over a thousand participants. DNA sequencing helped researchers identify specific groups of microorganisms that either positively or negatively correlated with mental health in humans.

Populations of gut bacteria belonging to the genera Coprococcus and Dialester were found to be consistently reduced when depression was a factor. This correlation may be linked to the genes these bacteria carry, which code for butyrate - a short-chain fatty acid with antidepressant properties.

However, it remains unclear whether those bacterial genes are actively expressed and producing butyrate. Furthermore, either butyrate or its metabolites would still have two barriers to cross -the gut and the brain - to be effective. Nonetheless, it is a promising start to what could turn out to be game-changing research. 

References:

  1. https://medlineplus.gov/ency/article/007165.htm
  2. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6523821/
  3. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6723551/
  4. https://go.aws/2X1K5X6
  5. https://www.pnas.org/content/108/38/16050
  6. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3413724/
  7. https://bit.ly/2R4bzr8
  8. http://dx.doi.org/10.1038/s41564-018-0337-x

Author: Ranjan Sinha


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