We have asked several scientists who gave presentations at the April 10-11 DAN! conference in Baltimore to share their research and perspectives from the meeting with you here on the blog. The following piece is from Dr. Alessio Fasano, M.D. Dr. Fasano is a Professor of Pediatrics and the Director of the Mucosal Biology Research Center at the University of Maryland. Dr. Fasano also leads the Center for Celiac Research, which includes a multidisciplinary team of gastroenterologists, pediatricians, dieticians and nurses who work together to develop individualized treatment plans for people with Celiac Disease.
The Intestine and ASD
The human intestine is a deceptively complex organ. It is lined by a single layer of cells exquisitely responsive to stimuli of innumerable variety, and is populated by a complex community of microbial partners, far more numerous than the cells of the intestine itself. Under normal circumstances, these intestinal cells form a tight, but selective barrier to “friends and foes”: microbes and most environmental substances are held at bay, but nutrients from the essential to the trivial are absorbed efficiently (1,2). Moreover, the tightness of the epithelial barrier is itself dynamic, though the mechanisms governing and effecting dynamic permeability are poorly understood. What is becoming increasingly clear is that an intestinal barrier defect (i.e., leaky gut) is associated with a large number of local and systemic disorders, including Autism Spectrum Disorders (ASD) (3).
Regulation of Intestinal Permeability
Intestinal permeability is mainly dependent on the functional state of intercellular tight junctions, sort of gates between neighboring cells that regulate trafficking of molecules and cells from the external environment into our body. To meet the diverse physiological challenges to which the intestinal epithelial barrier is subjected, these gates must be capable of rapid and coordinated responses. This requires the presence of a complex regulatory system that orchestrates the opening and closing of the gates between cells. While knowledge of the gates’ composition and assembly has progressed significantly during the past decade, relatively little is known about their regulation in health and disease in response to exposure to a variety of environmental stimuli. The discovery of zonulin, a molecule that reversibly modulates the gates’ opening, sheds light on how the intestinal barrier function is regulated in health and disease (4). The two major environmental stimuli triggering the production of zonulin in the small intestine are the presence of microorganisms (i.e., proximal bowel contamination) and exposure to gluten.
New evidence suggests that this exaggerated production of zonulin is responsible, at least in part, for the leaky gut causing abnormal passage of gluten and other “bad guys”, including casein, underneath the gut cell lining (2). This uncontrolled access of substances that do not belong to our body may lead to the onset of autoimmune and inflammatory diseases, including ASD, in genetically predisposed individuals (2). [Read more more about autoimmune disorders and autism]
ASD and Diet
ASD are heterogeneous neurodevelopmental disorders that affect approximately 1% of the general population (5). It is generally agreed that there are multiple causes for ASD, with both genetic and environmental components involved. Gastrointestinal (GI) symptoms are frequently experienced by subjects with ASD, but their prevalence, nature and, therefore, best treatments remain elusive (6,7). The most frequent GI symptoms experienced by subjects with ASD include constipation, gastroesophageal reflux, gastritis, intestinal inflammation (autistic entrocolitis), maldigestion, malabsorption, flatulence, abdominal pain or discomfort, lactose intolerance, enteric infections, among others. Of the almost 50 complementary and alternative treatments proposed for ASD, seven (antifungal therapy, chelation, enzymes, GI treatments, intestinal parasite therapy, nutritional supplements, and dietary options for autism) are specifically focused to the GI tract. It is worthwhile to note that in a recent informal survey conducted by the Autism Research Institute involving more than 27,000 parents of autistic kids, avoidance of gluten and/or casein were among the most frequent treatments implemented in their children, with a with a better:worse ratio of 30:1 and 32:1, respectively.
Intestine, Microbiome, and Leaky Gut
A possible unifying theory to “connect the dots” of all the factors mentioned above would link changes in the gut microorganism ecosystem with leaky gut, passage of digestion products of natural food such as bread and cow’s milk that would activate immune inflammatory cells that cause inflammation both in the intestine (autistic enterocolitis) and the brain (ASD). Alternative to the inflammatory hypothesis, it has been proposed that the defect in the intestinal barrier in ASD patients allows passage of neuroactive peptides of food origin (gliadorphin and casomorphins) into the blood and then into the cerebrospinal fluid to interfere directly with the function of the CNS. No matter which theory turns out to be correct, changes in the intestinal microbiome and the consequent leaky gut seem to be common denominators.
The Gluten Free Diet
Given the fact that ASD is a complex and heterogeneous condition, it is instrumental to stratify children affected by autism to identify subgroups that can benefit of specific therapeutic interventions, like a gluten free diet. Therefore, it would be highly desirable to develop specific biomarkers to help identify who would benefit the most by implementing specific interventions, including the gluten free diet. The ingestion by genetically susceptible individuals of gluten from wheat and of similar proteins present in barley and rye can cause immune reaction leading to small bowel inflammation. It is the interplay between genes and the environmental triggers that leads to this inflammation. This inflammatory process is initially driven by special immune cells called neutrophils (a type of white blood cell), soldiers that are called immediately into the gut to fight the uncontrolled passage of invaders through the gates stuck open because of gluten-dependent zonulin release. Once neutrophils intercept the invader, they try to eliminate it by causing inflammation that is not necessarily limited to the gut, since these “armed” immune cells can subsequently migrate in other tissues and organs, including skin, liver, joints, heart, and brain, causing inflammation also in the organs where they migrated. Therefore, the strict avoidance of gluten-containing grains is the best approach to avoid these inflammatory processes that can be responsible of specific clinical outcomes, including ASD, in a subgroup of individuals genetically at risk to react to gluten.
Alternative Therapeutic Strategies
Alternative therapeutic strategies to a gluten-free diet include the oral use of the zonulin inhibitor larazotide and probiotics. Larazotide, a sort of wax that blocks the hole in which the zonulin key locks in to open the gates in between intestinal cells, has already been successfully explored in an animal model of autoimmunity and, more recently and preliminarily, in celiac disease patients through double-blind, randomized, placebo-controlled human clinical trials (2). Probiotics are “good bacteria” typically found in dairy products like yogurt and are claimed to have several beneficial effects related to their capability of either reducing the risk or treating disease (8). Although the safety of probiotics naturally present in yogurt has never been in question, the more recent use of probiotics, like lactobacilli or bifidobacteria, delivered in high numbers to consumers with potentially compromised health has raised the question of safety. The safety of these probiotics has been reviewed by qualified experts in the field. The general conclusion is that the potential of physiological harm of lactobacilli and bifidobacteria is quite low. While the initial use of probiotics was based on anecdotal reports of their beneficial effects, we have more recently witnessed a series of more rigorously designed clinical trials documenting the potential use of probiotics for the treatment of a variety of pediatric disorders, including enteric infectious diseases, allergic and atopic disorders, and intestinal inflammatory diseases. The two most studied probiotics are lactobacillus GG and bifidobacteria BB12, and there have been a large number of studies with these organisms in the pediatric population, whit consistent good safety data (ie., lack of side effects) but mixed efficacy (8). The inconsistent positive therapeutic results may be related to the fact that each probiotic organism has different effects, and, therefore, they cannot be used indiscriminately for each disorder. Indeed, different conditions may be triggered by different microbiota composition and, therefore, may require different probiotics to be effectively treated. By performing more detailed studies to link gut microbiota composition to certain conditions, such as ASD, we will be able to decipher the host-microbe cross-talk and, therefore, we will be able to customize probiotic treatment for specific conditions (i.e.; personalized medicine).
All the aforementioned therapeutic strategies are viable interventions and, therefore, it would be desirable to perform well-designed multi-center studies to stratify children with ASD to establish which subgroup of patients would benefit of these treatments. This approach will allow customizing treatments to maximize the chance of success by targeting the subpopulation of ASD children that would benefit the most from a gluten free diet, the use of larazotide, or to choose the proper probiotic(s) to re-establish a healthy gut ecosystem capable to decrease or completely ameliorate the clinical presentations of ASD.
- Fasano A. Pathological and therapeutical implications of macromolecule passage through the tight junction. In Tight Junctions. Boca Raton, FL: CRC Press, Inc., 2001, p. 697-722.
- Fasano A. Physiological, pathological, and therapeutic implications of zonulin-mediated intestinal barrier modulation: living life on the edge of the wall. Am J Pathol.173:1243-52, 2008.
- White JF. Intestinal pathophysiology in Autism. Exp Biol Med 228:639–649, 2003.
- Wang W, Uzzau S, Goldblum SE, Fasano A. Human zonulin, a potential modulator of intestinal tight junctions. J Cell Sci 2000;113:4435-4440.
- Prevalence of autism spectrum disorders – Autism and Developmental Disabilities Monitoring Network, United States, 2006.Autism and Developmental Disabilities Monitoring Network Surveillance Year 2006 Principal Investigators; Centers for Disease Control and Prevention (CDC). MMWR Surveill Summ. 2009;58:1-20.
- Buie T, Campbell DB, Fuchs GJ, III, et al Evaluation, Diagnosis, and Treatment of Gastrointestinal Disorders in Individuals With ASDs: A Consensus Report. Pediatrics 2010;125;S1-S18.
- Buie T, Fuchs GJ, III, Furuta GT, Kooros K, Levy J, Lewis JD, Wershil BK, Winter H. Recommendations for Evaluation and Treatment of Common Gastrointestinal Problems in Children With ASDs. Pediatrics 2010;125;S19-S29
- Guarner F Prebiotics, probiotics and helminths: the ‘natural’ solution? Dig Dis. 2009;27:412-7. .