Decoding the interkingdom crosstalk between microbes and humans.
“Although the gut microbiota can communicate by endocrine and immune pathways, perhaps the fastest and most direct way for the microbiota to influence the brain is by hijacking vagus nerve signaling,” writes Christine Fulling and colleagues from APC Microbiome Ireland — the research center that pioneered the microbiota-gut-brain axis.
The vagus nerve is the main effector of the “rest-and-digest” nervous system — which is why it’s famous for its profound implications in wellness and health.
How the Vagus Nerve Works
The vagus nerve serves to transmit neural information that informs the brain of the state of other organs. It links many visceral organs — especially the gut— to the nucleus tractus solitarius (NTS) of the brainstem.
The information relayed to the NTS then projects to the forebrain areas involved in emotion and motivation — such as the amygdala, hypothalamus, substantia nigra, hippocampus, and ventral tegmental area. Cleave the vagus nerve and the activities of these brain regions go haywire.
Arguably the biggest influencer on the strength of vagal tone — meaning the activity of the vagus nerve — is the trillions of microbes that reside in the gut. Cut the vagus nerve connecting the gut to the brain and neuropsychiatric diseases will always develop. And this phenomenon has been well replicated in animals and humans since the beginning of the 21st century.
“The vagus nerve is able to sense the microbiota, to transfer this gut information to the central nervous system where it is integrated, and then to generate an adapted or inappropriate response,” writes Bruno Bonaz, Professor of Gastroenterology in the Grenoble Faculty of Medicine and Hospital, France and colleagues in the Frontiers of Neuroscience.
So how do gut microbes talk to the vagus nerve?
Calming Signals from GABA
Gamma-aminobutyric acid (GABA) is a neurochemical that calm the nerves. That’s why GABA is sold as a dietary supplement to lower stress and improve sleep.
Mice fed with Lactobacillus rhamnosus showed changes in GABA activities in some brain regions — the amygdala, hippocampus, and prefrontal cortex — in such a way that lowered their depressive and anxious behaviors. These behavioral benefits did not occur in mice whose vagus nerve was cut. Introduce L. rhamnosus into the mice gut, in turn, increased their vagal tone.
Likewise, feeding mice with Lactobacillus casei stimulated their vagus nerve while lowering their levels of stress hormones. Giving milk fermented with L. casei to stressed students also reduced their stress hormones compared to placebo milk.
GABA is a neurochemical — which means it interacts with neurons. The vagus nerve and its connections to the intestinal nerves have a lot of GABA receptors on their surface. And many Lactobacillus and Bifidobacterium species have enzymes that make GABA from dietary glutamate. This microbial GABA can, therefore, bind to the vagus nerve to send ‘calming’ signals to the GABA center in the brain.
Happy Signals from Serotonin
Serotonin is another neurochemical with many functions of which it’s most known for happiness. That’s why antidepressants commonly aim to restore serotonin levels in the brain, broadly speaking.
Supplementing mice with Lactobacillus helveticus increased growth factors and serotonin levels in their brain which cured them of depression. A 2019 study replicated this finding wherein L. helveticus increased serotonin receptors in the nucleus accumbens, “which plays an important role in stress resilience,” the authors stated. Indeed, those mice didn’t become depressed from repeated emotional stress from social defeat by bigger mice whereas control mice easily developed helplessness.
Following the same mechanism as above, certain L. helveticus and other Lactobacillus species produce serotonin at amounts equivalent to the human bloodstream. While serotonin is a larger neurochemical that doesn’t cross the blood-brain-barrier, it can interact with serotonin receptors on the intestinal and vagus nerves — to relay ‘happy’ and ‘resilience’ signals to the serotonin center in the brain.
Bonding Signals from Oxytocin
Oxytocin is the real name of the ‘love’ or ‘cuddle’ hormone. Because of its involvement in bonding, oxytocin is also responsible for social skills. Despite being a hormone that interacts with glands, oxytocin also has neurochemical properties — thus a neurohormone.
Autistic mice that received Lactobacillus reuteri completely recovered their social skills—but only if the vagus nerve was intact. This reversal of social deficits happened as a result of more abundance of oxytocin-receiving dopaminergic neurons in the brain.
“We discovered that L. reuteri promotes social behavior via the vagus nerve, a nerve that bi-directionally connects the gut and the brain and the oxytocin-dopamine reward system,” the authors stated. But how exactly L. reuteri talks to the vagus nerve, in this case, is not understood.
“L. reuteri emerges an intriguing non-invasive therapeutic alternative to persistently increase ‘‘endogenous’’ oxytocin levels in the brain,” the authors concluded in their 2019 paper printed in the prestigious journal, Neuron.
Anti-Inflammatory Signals from Butyrate
This mechanism is more indirect: Gut inflammation is known to decrease the vagal tone leading to a disharmonized communication between the brain and vagus nerve. And vagus nerve stimulation (a medical procedure), in turn, increases the vagal tone and reduces gut inflammation.
Aside from vagus nerve stimulation, butyrate can achieve the same effect owing to its potent anti-inflammatory effects that are systems-wide — from locally in the gut to 11 other distant organs including the brain.
Increased butyrate production from gut bacteria such as Faecalibacterium, Roseburia, Lactobacillus, and Bifidobacterium species would, thus, prevent gut inflammation and help the vagal tone to stay strong.
Putting it Together
“A dysregulated gut microbiota translates to a shift in the production of neuroactive metabolites and alters host neurotransmitter circuitry,” wrote a research review in the Frontiers of Neuroscience. How gut microbes affect the brain neurochemistry may occur via endocrinal, immune, and/or neural pathways — of which the vagus nerve is the quickest, as Fulling et al. also agreed.
“It is clear that in the context of microbiota at least what happens in vagus doesn’t stay in vagus but affects many aspects of emotionality and neurobiology,” continues Fulling and colleagues.
Following the importance of vagus nerve in brain health, Professor Bonaz advised that “monitoring and targeting vagal tone through vagus nerve stimulation, microbiota modulation (using prebiotics, probiotics, fecal microbiota transplantation, diet)… complementary medicine (hypnosis, meditation), cognitive-behavioral therapies, deep breathing, and moderate and sustainable physical activity would be of interest to restore a homeostatic microbiota-gut-brain axis.”
Aside from medical treatments like vagus nerve stimulation and psychotherapy, the other methods of keeping a healthy vagal tone Prof. Bonaz suggested are practical at our own means: Eat well, think well, breathe well and exercise well.
This article was originally published in Microbial Instincts.