Intestinal inflammation in the valproate mouse model of autism

Gut inflammation and autism.

Laughing or smirking? Wikipedia 

Words which still have the ability to furrow brows and precipitate eye rolling. Whatever your views on this topic, whether based on science or politics or both, there is no getting away from the evidence suggestive that in SOME cases of autism, issues with that deepest, darkest realm - the gut - do seem to be present.

Whether based on the presence of functional bowel issues (see here and here) or something rather more fundamental (see here), research continues to discover that the so-called second brain might have quite an important role to play in SOME cases of autism. This is not new news by the way (see here); the idea for which predates a certain [retracted] paper in 1998.

The recent paper from the laboratory of Paul Patterson (see here) suggesting that there may be issues with gut permeability (the so-called leaky gut) in offspring of a mouse model of maternal immune activation (MIA) during pregnancy was surprising to say the least. Whilst quite a lot of the media on this study went for the gut bacteria angle and bacteria potentially influencing behaviour (again, not necessarily new news), the forgotten angle of that paper was how immune activation in mother mice might be quite importantly linked to gut physiology of offspring.

As I see it, there's an important triad emerging in this area consisting of gut bacteria, gut barrier function and immune function potentially pertinent to lots of different issues and conditions. But what do I know?

It is again with mouse models and autism in mind, that I'm posting about the study from Caroline de Theije and colleagues* and their suggestion that offspring of the valproic acid (VPA) mouse model of autism might similar show 'gastrointestinal issues'. In particular: "VPA in utero- exposed male offspring showed epithelial cell loss and neutrophil infiltration in the intestinal tract".

The possible connection between foetal exposure to valproate and subsequent developmental outcomes has witnessed an explosion of interest this year (2013). Of course, the very fact that science has a VPA murine model of autism is testament to the fact that for quite a few years, there have been rumblings of a potentially important connection between the two factors. The recent data however, have led to some speculation which goes well beyond just correlation as per the paper by Harden**.

Back to the de Theije paper, and as follows a well-trodden research routine, it was a case of exposing pregnant mice (not, I hasten to add the usual BTBR dangermouse of autism) to either saline or more actively, valproic acid. Offspring mice were then studied both behaviourally and physiologically, upon which, intestinal issues of the inflammatory kind were detected in the VPA exposed mice. The authors conclude that: "gender-specific inflammatory conditions are present in the small intestines of VPA in utero- exposed mice and are accompanied by a disturbed serotonergic system in the brain as well as in the intestinal tract". Ergo, brain and gut seem to be implicated in the VPA murine model of autism, and boy mice seem to be the more fragile ones which some might seem as fitting in with the current data on the sex ratio of autism.

Similar to the MIA work, the VPA model with the gut in mind is at present solely focused on mouse models. Mouse models, in cold, hard scientific terms, tend to be good models to work with because well, they rely on mice not humans. Therein however, lies an issue: can a condition as complex and heterogeneous as autism really be recreated in mice? I'll leave the philosophers out there to ponder that question.

Bearing such a methodological issue in mind, the identification of something potentially going on gut-wise in the VPA model might actually turn out to be a useful finding. Assuming that someone is able to replicate these findings, one might begin to question what happens when said intestinal inflammation is treated in the VPA exposed offspring, and whether there may be any implications for intervention in humans for example, with autism in mind but also with conditions headed under the banner of foetal valproate syndrome***. I note in another paper from de Theije and colleagues**** there does seem to be some interest in the "gut-to-brain connection" with autism in mind so perhaps this is something already under consideration by the authors.

Perhaps even more speculatively, and with the recent Hsaio paper***** in mind, I should also ask the question of whether gut bacteria might be the next research target for the VPA mouse model of autism? Oh sorry, the authors have already thought of that******(what clever people).

Some music to close. I'm actually quite taken by the updated version of 'Dream a little dream' by Mr Williams & Ms Allen if the truth be known. Not that I'm implying that anyone outside of my brood should be dreaming about me...

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* de Theije CGM. et al. Intestinal inflammation in a murine model of autism spectrum disorders. Brain Behav Immun. 2013 Dec 6. pii: S0889-1591(13)00589-8.

** Harden CL. In Utero Valproate Exposure and Autism: Long Suspected, Finally Proven. Epilepsy Currents. 2013; 13: 282-284.

*** Kini U. Fetal valproate syndrome: a review. Paediatr Perinatal Drug Therapy. 2006; 7: 123-130.

**** de Theije CGM. et al. Pathways underlying the gut-to-brain connection in autism spectrum disorders as future targets for disease management. Eur J Pharmacol. 2011 Sep;668 Suppl 1:S70-80.

***** Hsiao EY. et al. Microbiota Modulate Behavioral and Physiological Abnormalities Associated with Neurodevelopmental Disorders. Cell. 2013 Dec 3. pii: S0092-8674(13)01473-6.

****** de Theije CGM. et al. Altered gut microbiota and activity in a murine model of autism spectrum disorders. Brain Behav Immun. 2013 Dec 11.

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de Theije CG, Koelink PJ, Korte-Bouws GA, Silva SL, Mechiel Korte S, Olivier B, Garssen J, & Kraneveld AD (2013). Intestinal inflammation in a murine model of autism spectrum disorders. Brain Behav Immun. DOI: 10.1016/j.bbi.2013.12.004