Intestinal hyperpermeability—or leaky gut—is increasingly being recognized as a very real clinical finding for a host of different conditions. With autism spectrum disorders in mind, research is starting to ask some interesting questions about its involvement in the gut-brain axis.
I first heard about leaky gut when starting my research career looking at autism back in 1996. My initial reaction was, I have to admit, less than impressive as “stories” about autism, some cases of autism, being potentially linked to the inner workings of the gastrointestinal (GI) tract started to surface. Everything I had been taught about autism up to that point was brain and genes. Autism was genetic and everything about autism was located in the master control center floating in the skull.
Beyond the “autism gene” model
The research that has emerged in the intervening years has, however, challenged quite a few of these very widely held beliefs. Opinions on the nature of autism have moved away from the “autism gene” model to seemingly embracing the heterogeneity and diversity that make up the condition and talking about genetic fragility, some role for environment (however you want to define this) and indeed the possibility that our genome may not necessarily be our destiny (see my previous post on epigenetics). This all happening alongside a growing realization that autism—or rather the autisms (note the plural)—can and does predispose a person to quite a lot of increased risk for all manner of comorbidity including epilepsy and seizure disorder, psychiatric comorbidity (particularly in later life) and yes, somatic comorbidity—including that rooted in the gut. Said comorbidity also variably impacting on the quality of a person’s life and indeed potentially also on their symptom presentation.
Trawling back through the research literature on autism, one does pick up little clues and snippets of information that the GI tract is not necessarily a new place to look when autism has been diagnosed. Mary Goodwin and colleagues  way back in 1971 talked about the gut-brain axis—in their case “malabsorption and cerebral dysfunction” and how there may be a connection between what goes on in the GI tract and brain functions. A few years earlier, the late Curt Dohan had been talking about similar things with schizophrenia in mind .
Ever since, a growing body of research has been amassing on how both functional GI dysfunction and more serious GI pathology can and do occur in some cases of autism [3, 4]. In among such work ideas began to emerge about food proteins and peptides, opioid-like activity and some overlap noted with the presentation of autistic behaviours . Indeed this crossing into my area of research interest on gluten- and casein-free diets and autism [6, 7].
Bearing in mind the description of such GI dysfunction in cases of autism, attention has focused on the physiological effects over and above any connection to behavioural and cognitive symptoms. As per other conditions like celiac disease or the inflammatory bowel diseases, the net effect of symptoms like inflammation on the very delicate barrier that separates our intestinal contents from the body (and immune system) at large have started to be questioned with autism in mind. The GI barrier is a world within a world; functioning to help us absorb the vital nutrition from our food intake whilst at the same time keeping our transported waste and other things away from other areas of the body prior to its eventual evacuation to the next world.
Coincidental to my education about autism starting in earnest in 1996, this was the year that Patricia D’Eufemia and colleagues published a seminal paper on gut hyperpermeability—leaky gut—in relation to autism . Based on the most traditional method for ascertaining gut permeability, the lactulose:mannitol test (comprising of two different sugars given orally and output measured in urine), D’Eufemia reported altered intestinal permeability in nearly half of her participants, compared with none of the controls examined. The absolute numbers of children with autism examined were low, but this was some of the first evidence for leaky gut moving out of the complementary medicine shadows.
To quite a few people including me, a finding like that reported by D’Eufemia and colleagues present in nearly half of their participant group was important and worthy of much greater investigation. It is therefore surprising that given such a simple test to administer without the invasion of taking blood or plasma or other biofluids outside collecting urine, the next peer-reviewed published foray into leaky gut research in autism came 12 years later with a study from Robertson and colleagues . Call me an old cynic, but there seemed to be a severe lack of research interest in leaky gut and autism in the intervening period.
Having said all that, the findings reported by Robertson and colleagues were not great news for leaky gut and autism as they reported no significant differences in gut permeability in their small cohort. So back into the autism research wilderness went leaky gut to join such interesting areas as sulfation and the hugely statistically significant results produced by Dr. Rosemary Waring previously of the University of Birmingham (UK).
Back from the wilderness
That was until the publication of results by Laura de Magistris and colleagues  in 2010. During a very well executed study, de Magistris reported on the presence of abnormal intestinal permeability (leaky gut) in over a third of her cohort of children diagnosed with autism (36.7%). She also reported abnormal intestinal permeability as being present in over 20% of first degree relatives too. Perhaps just as interesting were the findings following use of a gluten- and casein-free diet in her cohort: those on such diets were found to have less permeability than those not following the diet. She concluded: “The results obtained support the leaky gut hypothesis and indicate that measuring IPT could help to identify a subgroup of patients with autism who could benefit from a gluten-free diet. The IPT alterations found in first-degree relatives suggest the presence of an intestinal (tight-junction linked) hereditary factor in the families of subjects with autism”. Something for everyone there including the earlier Robertson paper which it seems did not exclude participants who were already following a gluten-free diet.
But the news about leaky gut and autism does not stop there. More recently, preliminary, not-as-yet published results have been presented by Paul Patterson and colleagues in relation to his group’s mouse model studies of maternal immune activation and the onward effects to offspring . A report on their findings  suggests that alongside behavioural findings, offspring also “show a host of abnormalities in the gut. They have unusually permeable intestinal membranes, for instance, which may allow metabolites of gut bacteria to leak into the bloodstream”. Perhaps even more exciting is the news that administration of a probiotic “blocked leaky gut” in the mice being studied noting that this was unpublished research carried out in mice not humans.
Of course there is still some way to go in terms of investigations into leaky gut and autism. The precise mechanism of how leaky gut comes about is still unknown and whether applying findings from other conditions relating to molecules like zonulin  may yet have some interest for the condition in cases of autism. Likewise, the link between leaky gut and bacterial translocation—gut bacteria promoting an antibody response—potentially identified in other studies of autism  remains an area of intense importance onward to the known issues associated with immune function in cases of autism.
So, after a slow start, maybe the time has come for leaky gut to take a proper turn on the autism research stage?
 Malabsorption and cerebral dysfunction: a multivariate and comparative study of autistic children. Goodwin MS, Cowen MA, Goodwin TC. J Autism Child Schizophr. 1971 Jan-Mar;1(1):48-62
 Relapsed schizophrenics: more rapid improvement on a milk- and cereal-free diet. Dohan FC, Grasberger JC, LowellFM, JohnstonHT Jr, Arbegast AW. Br J Psychiatry. 1969 May;115(522):595-6
 The prevalence of gastrointestinal problems in children across the United Stateswith autism spectrum disorders from families with multiple affected members. Wang LW, Tancredi DJ, Thomas DW. J Dev Behav Pediatr. 2011 Jun;32(5):351-60
 Panenteric IBD-like disease in a patient with regressive autism shown for the first time by the wireless capsule enteroscopy: another piece in the jigsaw of this gut-brain syndrome? Balzola F, Barbon V, Repici A, Rizzetto M, Clauser D, Gandione M, Sapino A. Am J Gastroenterol. 2005 Apr;100(4):979-81
 Can the pathophysiology of autism be explained by the nature of the discovered urine peptides? Reichelt KL, Knivsberg AM. Nutr Neurosci. 2003 Feb;6(1):19-28
 Biochemical aspects in autism spectrum disorders: updating the opioid-excess theory and presenting new opportunities for biomedical intervention. Shattock P, Whiteley P. Expert Opin Ther Targets. 2002 Apr;6(2):175-83
 The ScanBrit randomised, controlled, single-blind study of a gluten- and casein-free dietary intervention for children with autism spectrum disorders. Whiteley P, Haracopos D, Knivsberg AM, Reichelt KL, Parlar S, Jacobsen J, Seim A, Pedersen L, Schondel M, Shattock P. Nutr Neurosci. 2010 Apr;13(2):87-100
 Abnormal intestinal permeability in children with autism. D’Eufemia P, Celli M, Finocchiaro R, Pacifico L, Viozzi L, Zaccagnini M, Cardi E, Giardini O. Acta Paediatr. 1996 Sep;85(9):1076-9
 Intestinal permeability and glucagon-like peptide-2 in children with autism: a controlled pilot study. Robertson MA, Sigalet DL, Holst JJ, Meddings JB, Wood J, Sharkey KA. J Autism Dev Disord. 2008 Jul;38(6):1066-71
 Alterations of the intestinal barrier in patients with autism spectrum disorders and in their first-degree relatives. 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. J Pediatr Gastroenterol Nutr. 2010 Oct;51(4):418-24
 Maternal immune activation yields offspring displaying mouse versions of the three core symptoms of autism. MalkovaNV, Yu CZ, Hsiao EY, MooreMJ, Patterson PH. Brain Behav Immun. 2012 May;26(4):607-16
 Hughes V. Probiotic curbs autism features in mouse model. http://sfari.org/news-and-opinion/conference-news/2012/society-for-neuroscience-2012/probiotic-curbs-autism-features-in-mouse-model [accessed22/10/12]
 Intestinal permeability and its regulation by zonulin: diagnostic and therapeutic implications. Fasano A. Clin Gastroenterol Hepatol. 2012 Oct;10(10):1096-100
 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. Williams BL, Hornig M, Parekh T, Lipkin WI. MBio. 2012 Jan 10;3(1). pii: e00261-11