The Microbiome and the Basal Ganglia in …The Case of the Leaky Gut?

I recently read an article looking at the effects of bacterial microbiome alterations on particular circuits in the brain (the thalamo-cortico-basal ganglia)  that are associated with compulsive behavior, addiction, altered sensations and motor output.[i]  What struck me is how closely related seemingly unrelated disorders actually are, from a biological point of view.  That is: while autism, Parkinson’s disease (PD), addiction/substance abuse and compulsive behaviors on the surface have nothing to do with each other, it turns out that on a brain level, they actually have a whole lot in common.

This review paper focused on the basal ganglia, a group of structures found deep in the central brain,  near the base (brain stem) that include the substantia nigra, the part of the brain affected in Parkinson’s disease:  “The contributions of the basal ganglia to movement are complex and still not completely understood. In fact, the basal ganglia probably have multiple movement-related functions, ranging from choosing actions that are likely to lead to positive consequences to avoiding things that might be aversive. But the basal ganglia are most often linked to the initiation and execution of movements. One popular hypothesis suggests that the basal ganglia act to facilitate desired movements and inhibit unwanted and/or competing movements.”[ii]

The key to all this is that the basal ganglia are located near the blood-brain barrier, which becomes permeable in conditions of systemic inflammation:  “…toxins produced by the microbiota have differential access to different brain regions depending on the permeability of the blood-brain barrier.”  For example, “Regions of the basal ganglia are situated near the blood-brain barrier that are particularly leaky in PD patients.”

Remember that the same tight cell junctions found in the epithelial lining of the gut (which should prevent undigested food, bacteria and their metabolites, etc. from making their way directly into the blood stream) are also found in the blood-brain barrier.  If this becomes “leaky,” these substances can make their way into the brain causing an inflammatory response.  You can read more about this phenomenon in this post.

I’ve written about the connection of PD to the gut bacteria pretty extensively on this blog (here and here, as just two examples) so I won’t go into much detail on this today.  I’ll just mention one particularly interesting study this paper describes.  Mice that are genetically prone to developing PD are protected from the disease if raised in a germ-free environment.  If colonized though with the fecal microbiome from normal control mice or healthy humans, the mice developed a movement disorder.  If these mice are colonized with the microbiome of humans with PD, that movement disorder is markedly worse.  To date though, there is no definitive description of the PD microbiome.  Studies have had conflicting results.

In terms of autism, the basal ganglia have long been looked at as the potential area responsible for repetitive behaviors and tics.  Research has shown that increasing the intestinal load of lipopolysaccharides (toxic metabolites from a type of gut bacteria) increases repetitive behaviors.  Again, I have written before about the autism-Clostridia connection (for example, here).

Repetitive and compulsive behaviors are not only a hallmark of autism, but of other “compulsive” disorders as well, including some cases of obesity, i.e. compulsive eating:  “Obese individuals exhibit significant comorbidity with obsessive-compulsive disorder along with several neurobiological markers of addiction…”  The gut microbiota also appear to be heavily involved in the development of compulsive substance abuse:  “Recent work has found that the gut microbiota both influences and is influenced by the effects of psychostimulant drugs and may contribute to compulsive substance use.”  For example, in an animal model, depleting the normal microbiome using antibiotics led to an increased sensitivity to the behavioral effects of cocaine.”  The animals treated with antibiotics reacted to the drug at doses that had no effect on control animals.  The current theory is that alterations to the gut microbiome alter neurotransmitter receptor expression, including to dopamine, which is very much responsible for  reward and goal-directed behaviors (motivation).

We know that the microbiota, “…actively maintain normal basal ganglia physiology” and “…may affect basal ganglia function and behavioral output.”  Accumulating evidence points to “…wholesale depletion and modification of gut microbiota either ameliorating or worsening disease state in animal models of PD, obesity, and cocaine addiction.”  Certainly, the recent successful clinical trial on fecal microbiota transplant and autism suggest that the gut microbiome play an enormous role in the development of this condition.   This article suggests that, “One potential core mechanism may be increases in gut permeability, which may be mediated by several dysbiotic changes in gut microbiota.”  One suspect bacterial type is Prevotella, which maintains gut barrier integrity (i.e. protects against leaky gut).  It is sometimes found at lower levels in people with PD and autism, but there are conflicting data.  An overgrowth of Proteobacteria, which increases intestinal permeability, is also on the short suspect list, as this is seen in PD, autism, obesity and cocaine addiction.  Again though, definitive proof is lacking.

That said, the current, prevailing hypothesis is that, “…changes in bacterial composition, likely interacts with several environmental and genetic risk factors to precipitate specific disease outcomes…Increases in gut barrier dysfunction may alter other gut microbial communication pathways to the brain…”  Remember this post from earlier this year, re:  a potential treatment for leaky gut?  As time goes on, the crucial importance of a treatment becomes more and more evident.

p.s.  As I was about to post this, I noticed a new article on Parkinson’s News Today entitled, “Review Addresses Problems in Studies of the Gut Microbiome in Parkinson’s.”[iii]  To sum it up, as mentioned in the article I discussed today, differing methodologies have led to inconsistent results and as of now, there is no confirmed “PD microbiome” that has been established that could be used to diagnose or guide future treatment options.  This paragraph struck me as particular noteworthy, in light of what I’ve written above:  “While the researchers noted that, ‘several findings, such as an increase of Verrucomicrobiaceae and Akkermansia, and a decrease of  Prevotellaceae were robustly replicated,’ other findings were inconsistent or even directly contradictory. For example, some studies reported increased numbers of the bacterial groups Lactobacillaceae and Bacteroidetes in people with Parkinson’s, while others found the opposite.”  So low levels of Prevotella in those with PD, which maintain gut barrier function, actually does appear to be pretty accepted at this point.  Interesting, huh?

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[i] Fields, CT, Sampson, TR, Bruce-Keller, AJ, Kiraly, DD, Hsiao, EY, de Vries, GJ. Defining dysbiosis in disorders of movement and motivation. The Journal of Neuorscience. 2018;38(44):9414-9422.

[ii] https://www.neuroscientificallychallenged.com/blog/what-are-basal-ganglia

[iii] https://parkinsonsnewstoday.com/2019/11/13/review-addresses-problems-in-studies-of-the-gut-microbiome-in-parkinsons/