Monday, 5 August 2013

Leaky gut and autism: the story so far

Gut or intestinal hyperpermeability a.k.a leaky gut has been a point of some contention when it comes to a complicated set of conditions like the autisms.

Describing the process and mechanism of disruption to the quite delicate barrier which separates our intestinal contents from the wider environment and functions of the body, mention leaky gut to some people and you'll get some pretty peculiar looks. Allied perhaps unfairly to the realm of complementary and alternative medicine (CAM), leaky gut in some circles has not received great press in its attempts to offer an explanation for lots of different (chronic) conditions including autism.
Rumplestiltskin @ Wikipedia 

With autism specifically in mind, leaky gut seemingly encompasses all the most controversial elements about the condition: (i) involvement of the gastrointestinal (GI) tract, (ii) discussions about its possible link with food and diet (more to come on that), and (iii) other variables including who and from where the message about leaky gut originates from.

That and portraying autism as potentially being more than the sum of just the brain as being involved in the presentation of its behavioural characteristics and you have all the required elements in place to push leaky gut into the nether regions of autism research discussions. 

In this mega-post I'm going to ask that you put any prejudice aside for a short while as I intend to have a close look at the [limited] peer-reviewed and almost peer-reviewed evidence mentioning leaky gut and autism. I'll say now that I'm not going to offer some shining recommendation for leaky gut as being a core part of all cases of autism or even that it is a primary part of presentation; the available evidence does not point to that. Instead I'm going to put forward a view that leaky gut might, just might, be a part of some of the complexity of autism, some autism, and where present might offer some interesting leads into underlying pathology and/or intervention.

What is leaky gut?
OK, I should have probably mentioned this before but the name leaky gut is a bit of a misnomer when it comes to describing what might be going on in our deepest, darkest recesses. Everyone has some degree of leaky gut or gut permeability; if not, how would we be able to absorb nutrients from food for example. It's perhaps more pertinent to talk about excess gut permeability or gut hyperpermeability as describing the scenario more accurately.

The basic tenet of leaky gut, sorry gut hyperpermeability, is that the normally 'fairly porous to a certain degree' gut barrier is for whatever reason more permeable and porous than it should be and as a result various 'chemicals' (yep the misuse of that word again) and other material including bacteria and friends, are able to make a journey into the gut membrane and perhaps beyond.

OK so what's the problem with that I hear you ask? Well, the gut barrier is there for a reason and part of that reason is so that our immune system for example, does not get to meet certain biochemicals and bacteria in certain places of the body and do what it is designed to do, mount an immune response against them as part of its protection duties. Think bacterial translocation* - gut bacteria appearing in places other than the gut - as one example. Actually the immune system is only part of the proposed issue here which anyone who has an interest in autism research history and the opioid-excess theory** will know and the suggestion that dietary peptides are able to traverse this barrier and in some shape or form activate opiate receptors. Speculation at least; but if you read my training post on coeliac (celiac) disease, you'll know that gluten peptides can move into at least one part of the gut barrier for whatever reason.

Leaky gut and medicine
Taking aspirin affects the permeability of the gut. No really, it's true as per papers like this one***. Drinking alcohol affects gut permeability too****. What these and other papers demonstrate is that gut permeability is a dynamic process which is very much affected by environmental conditions such as what medicines we take and what we eat and drink. Would you believe me if I told you that taking something like melatonin might also affect gut permeability too (at least in rats)? Albeit in the opposite direction from aspirin and alcohol.

It's also been known for quite a few years that various conditions manifest issues with gut permeability as per the example of the inflammatory bowel diseases (IBDs)***** (open-access). Indeed, various other conditions with an autoimmune element to them have been a real point of discussion with gut hyperpermeability in mind, as per the chatter about type 1 diabetes****** for example.

I'm going to come on to autism shortly, but various other suggestions have been made linking leaky gut to disease and ill-health. One of them - Chronic Fatigue Syndrome (CFS) - has been talked about a few times with this permeability issue in mind on other blogs I'm linked to (see here). Indeed the name Dr Michael Maes carries quite an impressive array of articles on leaky gut and bacterial translocation in relation to all manner of conditions and indeed, some clues as to what intervention might also be able to do*******.

Leaky gut and autism
To save me typing the whole thing out again, I've talked about leaky gut and autism previously on another site (see here). The gist of that article detailed the main papers making up the autism and leaky gut scene to date: D'Eufemia and colleagues******** and their initial intestinal permeability results, Robertson and colleagues********* saying not so fast albeit including participants who were on dietary intervention and de Magistris and colleagues********** (see full-text here) who agreeing with D'Eufemia also suggested that gut permeability might be influenced by the use of a gluten- and casein-free (GFCF) diet so potentially also answering the whys of the Robertson findings.

There is also the conference presentation by Paul Patterson and colleagues (see here) on leaky gut in his offspring mouse model of maternal immune activation (which itself has seen some research action lately) but let's wait until that sees the peer-reviewed light of day. Oh and we have the next installment from de Magistris and colleagues (see here) which will have a post of its own soon [hint: leaky gut remains present in some people on the autism spectrum].

As per my introducing leaky gut with autoimmunity in mind, you might also be able to see how gut permeability issues could potentially be present in cases of autism which also include autoimmune comorbidity for example. So IBDs for example (see here) or coeliac disease (see here) or even type 1 diabetes (see here) might all elevate risk of abnormal gut permeability if present.

Based on this accumulated work alongside other speculations as a function of things like immune reactivity to gluten peptides for example (see here) there is a favourable base to gut hyperpermeability being a feature of autism in anything up to a third of cases. Indeed, outside of the direct measurement of gut permeability, other papers have also mentioned leaky gut in their text; for example as an explanation for those antibodies to Sutterella bacteria found in some cases of autism (see here).

More to see
I've not specifically mentioned about how one goes about assessing gut permeability because that in itself offers a number of potential routes worthy of a post of its own (lactulose:mannitol, PEG, etc.). Nor have I talked about where permeability is greatest in the gut in relation to autism or the issue of what type of permeability might exist (transcellular vs. paracellular). And as for other potential players in gut permeability such as [general] zonulin (see here) and the continuing saga of whether dietary intervention might 'affect' permeability*********** (no medical advice given or intended) or indeed other interventions .... we wait to see what future research offers about these factors specifically with autism in mind.

So after all that, still think leaky gut in autism is a load of old tosh?

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* Berg RD. Bacterial translocation from the gastrointestinal tract. Adv Exp Med Biol. 1999;473:11-30.

** Shattock P. & Whiteley P. Biochemical aspects in autism spectrum disorders: updating the opioid-excess theory and presenting new opportunities for biomedical intervention. Expert Opin Ther Targets. 2002 Apr;6(2):175-83.

*** Lambert GP. et al. Effect of aspirin dose on gastrointestinal permeability. Int J Sports Med. 2012 Jun;33(6):421-5. doi: 10.1055/s-0032-1301892.

**** Worthington BS. et al. Effect of daily ethanol ingestion on intestinal permeability to macromolecules. Am J Dig Dis. 1978; 23: 23-32.

***** Gerova VA. et al. Increased intestinal permeability in inflammatory bowel diseases assessed by iohexol test. World J Gastroenterol. 2011 May 7; 17(17): 2211–2215.

****** Vaarala O. Leaking gut in type 1 diabetes. Curr Opin Gastroenterol. 2008 Nov;24(6):701-6. doi: 10.1097/MOG.0b013e32830e6d98.

******* Maes M. & Leunis JC. Normalization of leaky gut in chronic fatigue syndrome (CFS) is accompanied by a clinical improvement: effects of age, duration of illness and the translocation of LPS from gram-negative bacteria. Neuro Endocrinol Lett. 2008 Dec;29(6):902-10.

******** D'Eufemia P. et al. Abnormal intestinal permeability in children with autism. Acta Paediatr. 1996 Sep;85(9):1076-9.

********* Robertson MA. et al. Intestinal permeability and glucagon-like peptide-2 in children with autism: a controlled pilot study. J Autism Dev Disord. 2008 Jul;38(6):1066-71. doi: 10.1007/s10803-007-0482-1.

********** de Magistris L. et al. Alterations of the intestinal barrier in patients with autism spectrum disorders and in their first-degree relatives. J Pediatr Gastroenterol Nutr. 2010 Oct;51(4):418-24. doi: 10.1097/MPG.0b013e3181dcc4a5.

*********** Sildorf SM. et al. Remission without insulin therapy on gluten-free diet in a 6-year old boy with type 1 diabetes mellitus. BMJ Case Rep. 2012 Jun 21;2012. pii: bcr0220125878. doi: 10.1136/bcr.02.2012.5878.

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ResearchBlogging.org de Magistris L, Familiari V, Pascotto A, Sapone A, Frolli A, Iardino P, Carteni M, De Rosa M, Francavilla R, Riegler G, Militerni R, & Bravaccio C (2010). Alterations of the intestinal barrier in patients with autism spectrum disorders and in their first-degree relatives. Journal of pediatric gastroenterology and nutrition, 51 (4), 418-24 PMID: 20683204