Buffington and Reber: Gut-Brain Interactions -- Annie Bryant


I really enjoyed learning about an area of neuroscience and microbiology that I don’t typically read about. The interaction between gut and brain has definitely been a hot topic in the last few years, and it’s exciting to see robust research published linking the two in development and manifestation of psychological disorders. At my last co-op, we started to work on a mouse model of Parkinson’s disease in which pathology-inducing alpha-synuclein is injected peripherally and travels (presumably via the vagus nerve) to the midbrain and cortex! This is in the context of findings that alpha synuclein aggregates can originate in the gut and induce aggregation in the cortex and midbrain.

I found the Buffington et al. paper much easier to follow and digest (no pun intended), and that’s likely at least in part why I preferred this one to the Reber et al. paper. The use of heat-killed bacteria was a great way to delineate vagus /gut interactions from immune response to the bacteria. It’s particularly interesting that L. reuteri only had rescuing effects on MHFD offspring when administered at 4 weeks, and not at 8 weeks. Autism does present very early in development and perhaps there is a critical window after which changes cannot be reversed (at least via this pathway). Alternatively, I wonder if the age of the mouse affects the ability of the bacteria to colonize in the gut microbiome after inoculation?

Their inclusion of LTP in the VTA ties in the aspect of reward and salience of social interactions, a circuit that is likely dysregulated in ASD and other social disorders. I liked the ideas they brought up in the conclusion about combining multiple types of probiotics to address different endophenotypes associated with ASD such as social deficits and perseveration. One thing I was unclear on was the section detailing oxytocin levels in the hypothalamus of MHFD offspring was the mechanism by which oxytocin levels actually decreased. Buffington et al. state that reduced oxytocin immunoreactivity in PVN neurons wasn’t due to an overall decrease in PVN neurons and leave it at that; is the change due to modulation of oxytocin transcription factors? Or perhaps due to post-translational modifications? Lastly, to directly identify a role for L. reuteri in modulating the social deficits in MHFD offspring, it would be interesting to see if knocking down L. reuteri in MRD offspring could elicit similar social endophenotypes.

The Reber paper was quite dense and went in several directions throughout, such that I think it could have been better suited as several papers that expanded on some really interesting results – such as the increased microglial density and changes to serotonin biosynthesis enzymes and transporters. However, the results do paint a clear picture that M. vaccae immunization reduces submissive responses to dominant mice in the CSC paradigm and increases microglia density in the mPFC, which is implicated in fear expression and is linked to the dorsal raphe nucleus, a major hub of serotonergic neurons. It’s important to note that (as the authors point out) Iba1 antibodies label both resting and activated microglia, and these microglial states exert significantly different effects on the immune environment. It would be really interesting to follow this finding further and use markers specific to activation like CD68.

One thing I noticed that Reber et al. don’t mention is that vehicle-treated mice in the CSC paradigm exhibited decreased submissive postures over the 15 days shown in Fig 1A, while M. vaccae-treated mice showed (reduced) consistent levels of submissive postures throughout the experiment. Over a longer time period, would vehicle-treated mice also exhibit similarly low frequency of submissive behaviors, perhaps indicating desensitization to the paradigm? It was also interesting that Buffington et al. used heat-killed bacteria (L. reuteri) as a negative control for their model, yet heat-killed bacteria (M. vaccae) effectively ameliorated social endophenotype deficits in the Reber et al. model.

Both Reber and Buffington highlight the role of environmental factors in inflammation and psychological symptoms. Reber et al. note that the prevalence of inflammatory diseases is increasing in urban locations, perhaps due to reduced exposure to soil-based exposure. Buffington et al. show that (in mice) offspring from a mother who consumed a high-fat diet during pregnancy are more susceptible to social and neurological impairment. These factors are particularly relevant for impoverished individuals in urban environments, who may not get exposed to bacteria in nature and who may not have access to healthy food options. Identifying causal relationships between gut microbiota deficiencies and social/learning disabilities can help elucidate alternative treatments and preventative measures.

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