The Microbiome and Mental Illness: An Old Story that is Too Far From its Happy Ending

I just finished reading an article from 2018 on mental health and the microbiome that describes some of where we are now, knowledge-wise, and where we need to be before psychobiotics become a treatment norm.[i]  There were multiple pieces of information in it which were either new to me, or worth repeating.

The history lover in me very much enjoyed the first section which points out that while we are currently undergoing a medical revolution in terms of biome research, in actuality, the link between the gut and health was recognized as early as the 4^th century, when a Chinese physician, Ge Hong,  treated severe diarrhea using  fecal microbiota transplant (except that he administered the concoction orally…which must have been special for the patient!).  In terms of recognizing the relationship of these bacteria to the brain, back in 1908, a paper was published which suggested that “…health could be enhanced and ‘senility’ delayed by manipulating the intestinal microbiome with host-friendly bacteria.”  Yes…unfortunately for all of us, science moves painfully slowly sometimes!  Here is a cheerful statistic though:  “Links between microbiota and pathophysiology triggered an explosion of interest in this field, with 85% of the over 10,000 PubMed publications on ‘intestinal microbiota’ arising in the last 5 years, currently averaging about 5 new publications per day.”  It’s no wonder that I am constantly feeling overwhelmed, bringing you the latest and greatest!  Sorry folks, but no…I do not have time to read and write about 35 papers every week!

Some highlights of current evidence pointing to the microbiome/mental illness connection:

1. As my regular readers know, there is plenty of experimental evidence that the gut bacteria influence the brain and behavior.  15 years ago, one of the earliest studies in this modern era of biome research showed that “…germ-free mice lacking intestinal and other microbiota display maladaptive and exaggerated responses to stress that can be normalized by probiotic-induced intestinal recolonization.”  The article goes on to say that, “…germ-free mice show that gut microbiota are essential for development of neuronal circuits underlying motor control, anxiety behavior, and social responses.”  I actually remember when that first study came out.  It is research like this, of course, that provided the fodder for much of the work currently being done on autism and the microbiome.
2. The article gives really interesting examples of the commutation pathways between the gut and brain.
   • For example, the probiotic Lactobacillus rhamnosus can send signals directly to the brain via the vagus nerve and in mouse studies, can decrease stress-induced anxiety and depression, and lower cortisol (stress hormone) levels. If the vagus nerve connection between the gut and brain is cut,  the probiotic has no effect.
   • The intestinal microbiota, as you know, produce much of our neurotransmitters. “Specific examples include generation of GABA by members of the Lactobacilli and Bifidobacteria families, dopamine and noradrenalin by members of the Bacillus family…” Also, remember that short-chain fatty acids have profound physiological effects, on both the gut and the brain.  While we know SCFAs can cross the blood-brain barrier (the tight cell membrane that protects the brain from the rest of the body), how much this actually happens is as yet unknown.  We do know though that SCFAs help maintain the integrity of this barrier which is unbelievably important in terms of keeping toxins, germs, etc. out of the brain.  Obviously, if this barrier becomes compromised, the effects on the brain (and thus behavior and mental health) can be profound.
   • You already know this, as I’ve written about it many, many times before, but would be remiss if I didn’t emphasize it once again: “Intestinal microbiota influence the generation, maturation, and function of numerous immune cells, which in turn, modify the balance and metabolic activity of intestinal microbes.”

 

In terms of our current knowledge of how to achieve and maintain the health of the biome (and thus, the brain), 4 key points that merit repeating:

1.  To me, is one of the scariest phenomena we have yet discovered is how biome depletion is passed down from generation to generation: “…recent experimental data indicate that chronic consumption of high fat/low fiber diets across generations in mice progressively decreases intestinal microbiome diversity, and that this pattern becomes irreversible even when fiber is reintroduced.”  This paper is over a year old though and in the time between its publication and now, this has also been shown in humans, as I wrote about here.
2. I have also (probably too frequently…I’m getting boring!) written about the crucial importance of diet in terms of what we are discovering about its relationship to the advent of disease: “…highly processed, lower quality foods that decrease microbial diversity and disrupt pathogen/commensal balance are linked to increased risk for mental disorders and clinical studies show significant inverse relationships between symptoms of mental illness and metrics of diet quality.”  As I wrote about just last week, way  more research is needed in this area, but as this paper states, “…a diet rick in diverse and seasonal plant-based products is in keeping with most general dietary guidelines and would likely foster a more diverse and resilient microbiome.”
3. Probiotics: “B.longum reduces depression and increases quality of life in IBS patients…Other randomized trials confirm beneficial effects of probiotics on mood; and a recent placebo-controlled trial showed that L.casei reduces physiologic responses to stress while increasing intestinal microbial diversity.”  I’ve stated about a million times before that WAY more research is needed in this field, and many studies show contradictory results because of a lack of consistency in methodology, and so forth.  Still…we have made a start.
4. There are some randomized human trials using prebiotics. For example, one shows that the prebiotic fiber galactooligosaccharide (GOS) decreases the stress response improved emotional affect in healthy volunteers.

In the conclusion, the authors point out that one of the many things we still don’t know all too often is what is cause and what is effect, “…when dysbiosis causes disease rather than accompanying it…”   So in spite of the fact that there are five papers per day on average being published, and the evidence connecting bacterial microbiome alterations to mental illness continues to mount, we know a minute fraction of what we need to know before biome manipulation becomes the medical norm.

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[i] Bruce-Keller, A, Salbaum, JM, Berthoud, H-B. Harnessing gut microbes for mental health: getting from here to there.  Biological Psychiatry. 2018. 83(3):214-223.  doi:10.1016/j.biopsych.2017.08.014.