Gut-Brain Interactions: Buffington et al, Reber et al 2016

April 13 Papers (Buffington et. al, Reber et. al)

I found this week’s papers to be quite novel in that they both proposed potential treatments for neurodevelopmental or psychiatric disorders that target bacterial or microbial abnormalities and how these give rise to certain behavioral and physical symptoms associated with the disorders. I thought this was a very unusual yet interesting approach, and as I have not previously studied the gut-brain axis, these papers offered me a fresh perspective on researching psychiatric and neurodevelopmental disorders. They were also unconventional in their focus of the physical symptoms that often accompany mental disorders, as this is not something that I have seen many other papers touch upon very much. Particularly, I was surprised by the Reber et al paper’s focus on the link between psychiatric disorders and inflammation in organs other than the brain, such as the colon, and the Buffington et al paper’s description of a relationship between neurodevelopmental disorders and gastrointestinal problems. I wonder just how common these comorbidities are and why they’re not common knowledge or discussed very often.

The Buffington paper examined how maternal obesity induced by a high-fat diet (MHFD) alters the gut microbial ecology in offspring, and how this in turn is linked to deficiencies in social behaviors and other symptoms typical of Autism Spectrum Disorder (ASD). The study identified one particular commensal strain in the gut, L. reuteri, which was decreased in the offspring of obese mothers, and claimed that this strain is responsible for maintaining oxytocin levels and enabling Long Term Potentiation (LTP) in dopamine (DA) neurons in the ventral tegmental area (VTA). Reduced oxytocin levels and LTP as a result of decreased L. reuteri in the gut then leads to the aforementioned social behavioral deficits. The results concluded that treatment with L. reuteri can reverse these physical abnormalities and related behavioral symptoms, and suggested certain probiotics could help treat neurodevelopmental disorders such as ASD.

I was very surprised at the idea of treating neurodevelopmental disorders with probiotics, although I can see the logic behind this after reading the paper. This made me wonder whether hormonal treatments targeting oxytocin or other hormones proven to be associated with clinical symptomatology could also be a potential avenue of treatment. I’m not sure, however, whether such treatments could effectively target specific brain regions (in this case, raising oxytocin levels only in the VTA) or what other limitations might be associated with treatments of this sort. Importantly, there seemed to be a specific developmental period during which these interventions were effective, which would limit the population that would be good candidates for these treatments. For example, those diagnosed later in life might not benefit from these treatments.

Going off of this, I wondered if the reason why the study found that treatment with L. reuteri rescued only social but not other behavioral endophenotypes associated with ASD was because the experiment missed the developmental window during which L. reuteri treatment could have reversed other non-social behavioral abnormalities, such as repetitive behavior. That is, if L. reuteri treatment was only effective in rescuing social behaviors when applied at four weeks but not eight weeks, could it have been effective in reversing disadvantageous repetitive behaviors if applied at two or three weeks? Perhaps the earlier the intervention takes place, the more behavioral symptoms can be reversed. 

Furthermore, the fact that only some, but not all of patients with ASD suffer from dysbiosis of the gut microbiota raises the question of how these social deficits can be explained in those with normal gut microbial ecology. Is it possible that microbial ecology could also be altered but imperceptibly so in those patients, and that even unobservable alterations could still have negative effects on oxytocin levels and LTP in the VTA, leading to behavioral symptoms? The paper also mentioned that the abundance of another Lactobacillus species named L. johnsonii was also reduced in the gut microbiota of MHFD offspring, but that treatment with L. johnsonii failed to rescue social behaviors. What then, if any, are the negative effects stemming from reduced amounts of L. johnsonii? Can this species be linked to other symptoms of ASD, like maybe the aforementioned non-social behavioral abnormalities that L. reuteri treatment could not reverse?

This paper left me with a number of other questions. For instance, I asked myself whether the altered gut microbial ecology seen in MHFD offspring would then result in similar abnormalities in the gut microbiome of their offspring in turn. I would have also liked to know more about the relationship between oxytocin and dopamine in processing social cues. Additionally, how would the results have differed if female mice had been studied, or if the social tests had not been conducted only with age and sex-matched mice? Lastly, as we have discussed other weeks, I think it is important to consider the validity of this (or any) mouse model of ASD, and how accurate of a representation of human ASD it is. 

The Reber paper claimed that immunization with a heat-killed preparation of the environmental bacterium Mycobacterium vaccae could help prevent anxiety and affective disorders and certain medical comorbidities like inflammatory symptoms and exaggerated autoimmunity. As I stated at the beginning of this reflection, I think this is a very novel and unusual approach to treating psychiatric disorders, and one that should certainly be investigated further in the future. However, this method seems to serve mostly for prevention of these disorders and medical symptoms instead of treatment after they have already presented themselves. While still valuable, I wonder what methods would be used to determine who is most at risk for these disorders and who this preventative treatment would be most beneficial for. Would risk be determined by genetic factors like parental diagnoses of certain disorders, environmental factors like exposure to trauma that could lead to stress-related symptoms, or a mix of both?

Moreover, the paper stated that repeated immunization would be necessary in adults to make the immunoregulatory effects last. Would this then be a chronic treatment that patients would have to keep up with their whole lives, or would it be more akin to vaccinations which require two or three doses but that then grant people immunity for life, like the MMR or HPV vaccines? Are there any developmental windows during which this treatment is most (or solely) effective, as was the case for the probiotic treatment suggested in the Buffington paper?

Finally, the Reber paper mentioned that L. reuteri has shown to increase testosterone in mice, a fact that as far as I can remember was not mentioned in the Buffington paper despite its strong focus on L. reuteri. Is it possible that the increase in testosterone also influenced the changes in social behavioral symptoms seen in mice after treatment? Experimenters are often reluctant to study female mice because of variabilities in mood or behavior due to their estrous cycle, but changes in testosterone in male mice also have an effect on their mood and behavior.