No clinically meaningful differences: gut bacteria and autism?

Who's stool? @Wikipedia

I've been in heavy gut microbiome reading mode these past few days as a result of helping to write some overview material on the topic (and various other -omics) for some collaborations. Autism spectrum disorders have not been a specific focus for most of the work, but I've been drawing heavily on the collected research so far as per the Lipkin Sutterella findings and the Aussie Akkermansia muciniphila observations.

It was with great interest therefore that I read the abstract to the paper by Gondalia and colleagues* and quote: "Results did not indicate clinically meaningful differences between groups. The data do not support the hypothesis that the gastrointestinal microbiota of children with ASD plays a role in the symptomatology of ASD." Strong words indeed from a study based on just over a hundred participants.

So with a little more detail:

• The paper originates from the Swinburne Autism Bio-Research Initiative (SABRI) and a few names attached to autism research that I've come across before, including David Austin who last year published some correlative research suggesting a link between Pink disease and autism** (full-text) (see media on the paper here).
• Pyrosequencing of (stool) samples was completed for 23 children with autism (no gastrointestinal (GI) dysfunction), 28 children with autism (accompanied by GI dysfunction) and neurotypical siblings (n=53). Keep in mind that neurotypical siblings bit for now.
• Results: the dominant phyla in descending order were "Firmicutes (70%), Bacteroidetes (20%) and Proteobacteria (4%)" with no "clinically meaningful differences between groups".

I'm going to try and remain objective about these findings. Science is science and even though I might be less than most predisposed to the view that "other explanations for the gastrointestinal dysfunction in this population should be considered including elevated anxiety and self-restricted diets", despite the recent paper by Micah Mazurek linking gut problems to anxiety, that's the author's take on their results and it should be respected. The Aussie group did look at endophenotypes within the autism spectrum based on comorbidity and did take into account various SES variables. Fair do's to them.

A few factors however potentially intersect with the current findings:

• If we've learned anything from the first results to come from the Human Microbiome Project (HMP) and related research, it's that there's probably more uniting us in bacterial terms, than divides us. By saying this I'm not saying that we are identical when it comes to bacteria, but rather like our genome (and epigenome) and indeed our brain gene maps, the similarities across populations probably outweigh the differences. From this perspective, I don't think such general results are too unexpected.
• When undertaking controlled studies, it's always wise to see who and what controls are used. For this study, the control group was comprised solely of asymptomatic siblings. There was no external non-family control group (age and sex matched), just a group who probably lived with, ate similar food to, drank similar fluids to, etc and were genetically similar to the target participants. In this respect, I'm taken back to quite a bit of the other research on gut bacteria and autism, where most significant differences seem to be reported compared with external controls. So as per this study by Helena Parracho and colleagues*** (full-text) and of course, the Wang study**** (full-text) on short chain fatty acids and A.muciniphila. Note also in both these studies the suggestion of more similarities than differences between participants with autism and their sibling controls. 
• The current findings are based on stool analysis; something which this group have published on previously with autism in mind***** (full-text). I'm perfectly happy to accept that stool analysis is a viable (non-invasive) route to speculating on gut bacteria in different groups, mindful however that different bacteria can populate different parts of the gut and that genetic regulation by bacteria can differ in different parts of the (mouse) gut. Probably the only study done so far looking at bacteria derived from biopsy samples in autism, and therefore reflective of the different areas of the gut, is the Brent Williams / Ian Lipkin Sutterella study****** (full-text) and I 'aint going to argue with their results following their recent XMRV de-discovery.

I hope this post hasn't turned into a rant. I for one am happy to see that gut bacteria and indeed the whole microbiome area is starting to receive some research interest with autism in mind. Accepting that Australia has recently been introduced to the 'Autism Enigma' programme (Jon Brock talked about it in a recent post), there is perhaps quite a bit of chatter Down Under about the ins and outs of gut bacteria with autism in mind. It is coincidental that this paper appears when it does from where it does.

I'm not quite ready to give up on the possibility of a gut bacterial role to some cases of autism. One cannot simply assume that the previous research carried out in this area is null and void on the basis of one study. Even if those little beasties are not a central facet to the condition and apply only to a specific sub-group of those on the spectrum, gut bacteria are just too important to health to just push out of the autism research agenda for now as per another great word by a familiar name:  pharmacometabonomics - gut bacteria affecting drug metabolism (see here*******).

Speaking of Down Under....

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* Gondalia SV. et al. Molecular characterisation of gastrointestinal microbiota of children with autism (with and without gastrointestinal dysfunction) and their neurotypical siblings. Autism Research. September 2012.

** Shandley K. & Austin DW. Ancestry of pink disease (infantile acrodynia) identified as a risk factor for autism spectrum disorders. Journal of Toxicology & Environmental Health A. 2011; 74: 1185-1194.

*** Parracho H. et al. Differences between the gut microflora of children with autistic spectrum disorders and that of healthy children. Journal of Medical Microbiology. 2005; 54: 987-991.

**** Wang L. et al. Low relative abundances of the mucolytic bacterium Akkermansia muciniphila and Bifidobacterium spp. in feces of children with autism. Appl Environ Microbiol. 2011; 77: 6718-6721.

***** Gondalia SV. et al. Faecal microbiota of individuals with autism spectrum disorder. Electronic Journal of Applied Psychology. 2010; 6: 24-29.

****** Williams BL. et al. Application of novel PCR-based methods for detection, quantitation, and phylogenetic characterization of Sutterella species in intestinal biopsy samples from children with autism and gastrointestinal disturbances. mBio. 2012; 3: e00261-11.

******* Clayton TA. et al. Pharmacometabonomic identification of a significant host-microbiome metabolic interaction affecting human drug metabolism. PNAS. August 2009.

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Gondalia SV, Palombo EA, Knowles SR, Cox SB, Meyer D, & Austin DW (2012). Molecular Characterisation of Gastrointestinal Microbiota of Children With Autism (With and Without Gastrointestinal Dysfunction) and Their Neurotypical Siblings. Autism research : official journal of the International Society for Autism Research PMID: 22997101