Thursday, 5 December 2013

Leaky mice guts, bacteria and autism (part 2)

So, leaky gut, the gut microbiota and the immune system in relation to autism then? Maybe not so 'on the fringe' as you might have thought.

Readers are asked to consider this entry an extension of the post I published last year (see here) talking about some very interesting research coming out of the laboratory of Prof. Paul Patterson at CalTech. If you need any sort of background, Prof. Patterson and his team have for quite a while been investigating the concept of maternal immune activation (MIA) in relation to autism and schizophrenia risk and the notion that maternal infection during pregnancy might have the ability to impact on offspring outcomes*. At least in mice.

The mice will play @ Wikipedia 
In my previous post, the interest was in a report on a report on a report given at the Society for Neuroscience (2012) meeting which appeared to detail the presence of gut hyperpermeability (yep, the so-called leaky gut) in offspring of the maternal immune activated (MIA) mouse model.

Indeed, the various members of the Patterson lab also suggested that said issues with increased gut permeability might also be 'modified' by the introduction of Bacteroides fragilis via a proposed effect on the the levels of a uremic compound called 4-ethylphenylsulfate.

With the publication by Elaine Hsiao and colleagues** this initial report has now seen the peer-reviewed light of day as was hinted at in a recent piece on gut bacteria potentially guiding "the workings of our minds" and on Prof. Patterson's blog.

As perhaps would be expected, there are few other details to discuss about the paper outside of what has already been seen. We know that the work included pregnant mice who were immune challenged by a mock virus. We know a little more about the types of mouse behaviours that were observed as a result of being a MIA offspring and which seemed to be affected by the introduction of B. fragilis. And we know some more details about the effect of feeding B. fragilis on 4-ethylphenylsulfate levels. Actually, there are two pretty good interpretations of the study on the SFARI site (here) and the Autism Speaks site (here).

We still also know that this was a study of mice and not humans and that questions remain about how and why gut bacteria seemed to affect gut permeability and the relationship to presented behaviours. These points certainly merit me repeating my oft-cited caveat on this blog about not giving medical or clinical advice.

Still, this work (if and when replicated) potentially represents another turning point when it comes to our understanding about the autisms. It further suggests autism, some types of autism, might not just soley be a 'brain-based' condition*** but rather a more multi-organ condition. Indeed, if we're talking about that 'gut-brain axis' which has been banded about for a good few years now with autism in mind, the mouse findings imply that altering parameters in the gut may very well have an impact on presented behaviour as per the interest in dietary intervention and autism for example (see here).

Indeed with my own professional interest in food and autism in mind, I'm also wondering whether some of the behavioural effects noted from a dietary change in cases of autism might actually reflect dietary changes impacting on the types of bacteria predominating in the gut as per other findings and the recent revelations from Martinez-Medina and colleagues****. I might add that this does not exclude a more direct effect on barrier integrity also and indeed, my still waiting for someone to publish on levels of [General] zonulin when it comes to autism.

The Hsiao study also provides a potentially important tie-up between the triad which is gut bacteria, gut permeability and immune function in relation to cases of autism. Yes, there are still big gaps in our knowledge about how these systems fit together, but what we are starting to realise is that there is an intricate relationship between them which might be even more profound than we've ever realised.

A game-changer paper?

[Update: January 2014. The PhD thesis of Elaine Hsiao is now available to view open-access with all data pertaining to this and other studies].


* Garay PA. et al. Maternal immune activation causes age- and region-specific changes in brain cytokines in offspring throughout development. Brain Behav Immun. 2013 Jul;31:54-68.

** Hsiao EY. et al. Microbiota Modulate Behavioral and Physiological Abnormalities Associated with Neurodevelopmental Disorders. Cell. 2013. 5 December.

*** Coury DL. et al. Gastrointestinal Conditions in Children With Autism Spectrum Disorder: Developing a Research Agenda. Pediatrics. 2012; 130: S160-S168.

**** Martinez-Medina M. et al. Western diet induces dysbiosis with increased E coli in CEABAC10 mice, alters host barrier function favouring AIEC colonisation. Gut 2014; 63: 116-124.

------------ Elaine Y. Hsiao, Sara W. McBride, Sophia Hsien, Gil Sharon, Embriette R. Hyde, Tyler McCue, Julian A. Codelli, Janet Chow, Sarah E. Reisman, Joseph F. Petrosino, Paul H. Pattersons, & Sarkis K. Mazmania (2013). Microbiota Modulate Behavioral and Physiological Abnormalities Associated with Neurodevelopmental Disorders Cell DOI: 10.1016/j.cell.2013.11.024