The messy science behind The Autism Enigma

Last Monday, the Australian current affairs program Four Corners featured a Canadian documentary entitled The Autism Enigma (it’s still currently available on iView in Australia). The main thrust of the program was that autism is caused by harmful bacteria in the gut. Not surprisingly, the program caused quite a stir, prompting responses from various members of the Australian autism research community. Critics argued that it over-simplified the problem of autism, ignored alternative explanations, promoted interventions that weren’t evidence-based, and offered false hope to parents.

Not knowing very much about this area of research, I’ve since been reading around some of the studies that were mentioned in the program.

Trailer for the Canadian showing of The Autism Enigma

The vancomycin trial

One of the key studies featured in The Autism Enigma was a pilot study of antibiotic treatment in 11 autistic children, conducted by Dr Richard Sandler and colleagues, and published in the Journal of Child Neurology in 2000.

The “index case” at the beginning of the paper describes Andy Bolte, one of the boys featured in the program. Andy appeared to be developing normally but regressed severely at 18 months. Andy’s mother Ellen suspected that the regression was caused by antibiotic treatment for an ear infection. This, she hypothesized, had wiped out many of the bacteria in his gut, allowing harmful Clostridia bacteria to thrive. Andy was given Vancomycin, a more powerful antibiotic that can target Clostridia, and his symptoms improved temporarily. But when he finished the course of Vancomycin, he regressed again.

The Sandler study set out to determine whether other autistic children would also respond to Vancomycin. The researchers deliberately recruited kids with a similar developmental history to Andy (see Table 1 of the paper). This makes sense but already means that we’re talking about a subgroup of autistic kids - not autistic kids in general. The children all had regressive autism and in each case the onset of autism symptoms followed treatment with antibiotics and diarrhoea. While it’s tempting to assume that the antibiotics must have caused the regressions, it’s also important to remember that many kids around that age will be given antibiotics, and that diarrhoea is a common side-effect of antibiotics. 

Professor Sydney Finegold was a co-author of the study and one of the central characters in The Autism Enigma. As he stated in the program, the results indicated that “80% of the children improved”. However, it’s not quite that straightforward. The 80% figure comes from a video analysis in which 10 of the 11 children were taped before and during treatment. The tapes were given to a child psychologist, who was asked “Does the child appear better overall in one tape over the other?” 8 of the 10 children were rated as showing better behaviour during treatment than before.

To reduce any bias, the psychologist rating the tapes was not told which ones were made before or during treatment. However, bias might have crept in elsewhere, for example in choosing when to tape the kids’ behaviour. It’s also worth bearing in mind that autistic kids are often pretty anxious in a new environment around unfamiliar people so, all else being equal, you’d expect them to show better behaviour on the second visit. Finally, the question the psychologists were asked doesn’t tell us in what sense the kids were better. It certainly doesn’t allow us to conclude that they were less autistic.

So the study results were promising, but far from compelling or conclusive. No study is perfect, but these are the kinds of concerns that you’d expect to be addressed in a follow-up study. As far as I can tell, there has been no such follow up – Finegold’s review certainly doesn’t mention one. The program hinted at ethical concerns about the use of Vancomycin (particularly as the benefits weren’t permanent), but in the absence of replication and with the limitations of the original study, we have to be very cautious.

Number Twos

In 2002, Finegold and colleagues published an analysis of stool (poo) samples from 11 autistic children (presumably these are the same children tested in the Sadler et al study but that’s not entirely clear). Their main finding was an increased level of clostridia in the samples, compared to non-autistic children. According to The Autism Enigma, “several researchers have replicated [this] finding”. However, I could only find one independent replication - a 2006 study by Parracho et al. [PDF].

Other studies haven’t replicated the findings. In a more recent paper, Finegold et al 2010 reported that clostridia actually accounted for significantly less of the gut bacteria in severely autistic kids, compared with non-autistic control children. Instead, they found an increase in Desulfovibrio bacteria. Finegold now argues that this is a more fruitful line of enquiry. In fact, there was a point in The Autism Enigma when Finegold, discussing the impact of antibiotics said “…the organisms that tend to persist are Clostriddia…” and then the audio was cut mid-sentence. My guess is that he went on to mention other bacteria but the program-makers didn’t want to complicate their simple narrative.

I’m not in a position to comment on the technical aspects of the studies. However, even to a non-expert, an obvious limitation of these studies is that they have only 8 or 10 control children. This makes it very difficult to be sure what is “normal”, particularly given the emphasis on bacteria being found in autistic children but never in controls. One recent Australian study [PDF] took a different approach, comparing 28 autistic children to a much larger sample collected as part of other research studies. They found relatively little evidence of bacterial abnormalities - and only 1 out of the 28 children with autism had clostridium counts that were outside the normal range. Similarly, several studies have pointed to “abnormalities” of gut bacteria in the stool samples of non-autistic siblings of autistic children. This could be interpreted in many different ways, but clearly complicates any story linking bacteria to autism.

Finally, we shouldn’t confuse correlation with causation. Even if there really are abnormalities of gut bacteria in kids with autism, they could simply be a consequence of their often altered diet. As The Autism Enigma points out, many autistic kids will only eat a restricted set of foods - and many will also eat things they’re not supposed to (Andy Bolte ate ashes and paint). Some parents administer probiotics or will enforce gluten or casein free diets. In their 2002 paper, Finegold et al. acknowledge that “we are not aware of any studies that have indicated whether such a diet influences the makeup of the bowel flora” (admittedly there may be recent studies that do indicate). Similarly, Parracho et al. (2006) noted “an association between high clostridial counts and individuals consuming probiotics”. It’s difficult to know what’s cause and effect, but The Autism Enigma only considered one possibility - the bacteria came first.

Rats on acid 

Setting those concerns aside, the theory put forward in The Autism Enigma was that autism is caused by propionic acid, a common food preservative that also happens to be a bi-product of clostridia. According to the narrator, “Once in the brain it changes brain cells to become like those of autistic people”.

The program featured a study by Dr Derrick MacFabe and colleagues in which rats were administered propionic acid and immediately started behaving strangely. They became less social, ignoring one another, and also started hunching up their backs as they ran. Viewers were invited to make the connection to social aversion and toe-walking of autistic kids.

Animal research can play an important role in understanding the causes of autism, but results always need to be treated with caution. Often they don’t translate to humans - and it’s difficult to know whether atypical rat behaviour really is equivalent to atypical human behaviour. Given that autism affects so many aspects of cognition and behaviour, it’s very easy to find some aspect of experimentally-induced behaviour that could be described as “autistic-like”.

One other point of note. In the program we were simply told that the propionic acid was “given to the rats in small doses”. I’d naively assumed that the rats were given it in their water but, in fact, it was injected directly into their brains. MacFabe states that propionic acid can easily get to the brain from the gut, but we still need to know whether the amount reaching the brain via the gut is equivalent to the amount being pumped directly into the rats’ brains. As the saying goes, the dose makes the poison. Indeed, the fact that propionic acid is found in lots of food products suggests that our brains are already exposed to it at some level.

Gut feelings 

If nothing else, The Autism Enigma serves an important purpose in highlighting gastro intestinal issues that affect some individuals with autism. They’re clearly part of the bigger autism picture and might provide clues to the origins of autism in at least some cases. But even to a non-expert like me, there are legitimate concerns about the research on which The Autism Enigma relied and, in particular, the strengths of conclusions that can be drawn from those studies. The science is still at a very preliminary stage and, at best, is relevant to only a subset of the autism population. Admittedly, Kerry O’Brien, who introduced the documentary to Australian viewers, was at pains to emphasise the controversial nature of the research, but nothing he said explained why the research was controversial. The net effect was to caricature the researchers involved as maverick outsiders.

This I think is a shame. My reaction from reading the papers is that research on gut bacteria in autism is similar in many ways to what might be considered more mainstream areas of autism science. It struggles with the same complexities and many of the same criticisms apply. Over-generalization of conclusions; a tendency to confuse correlation with cause; sample sizes that are way too small; evidence that is consistent in vague descriptive way but completely contradictory when you get up close. We could be talking about psychological research, genetics, neuroimaging, behavioural intervention research. Progress is being made but these are all still developing fields of science.

The difficulty, as one father stated at the beginning of the program, is that “Parents can’t wait for science to catch up.” As The Autism Enigma showed, there are plenty of people, well-meaning or otherwise, who are prepared to fill that gap. The problem is not so much false hope as false certainty.

References

Finegold SM, Downes J, & Summanen PH (2012). Microbiology of regressive autism. Anaerobe, 18 (2), 260-2 PMID: 22202440 Full Text

Finegold SM, Molitoris D, Song Y, Liu C, Vaisanen M-L, Bolte E, et al. (2002). Gastro-intestinal microflora studies in late-onset autism. Clinical Infectious Disease, 35, Suppl.1:S6-16. Full Text

MacFabe DF, Rodriguez-Capote K, Hoffman JE, Franklin AE, Mohammed-Asef Y, Taylor AR, et al. (2008). A novel rodent model of autism: intraventricular infusions of propionic acid increase locomotor activity and induce neuroinflammation and oxidative stress in discrete regions of adult rat brain. Am J Biochem Biotech, 4, 146-166. Full Text

Sandler RH, Finegold SM, Bolte ER, Buchanan CP, Maxwell AP, Väisänen ML, Nelson MN, Wexler HM (2000). Short-term benefit from oral vancomycin treatment of regressive-onset autism. Journal of Child Neurolology, 15, 429-35.  Full Text

Related posts

• Theories of autism: Lessons from Dr House
• Conference report: BioAutism 2012

Further reading

• Andrew Whitehouse: ABC's Four Corners and the messy truth of autism
• Elisa Hill: Can a gut bacteria imbalance really cause autism?