Gastrointestinal

Autism and Gut Dysfunction: Going to the Source

Patrick Hanaway, MD

Autism is expanding in its incidence in all industrialized countries. This multi-factorial process is an example of the importance of subtle gene-environment interactions and their impact on the regulation (or dysregulation) of the immune system. It is necessary to evaluate the role of the gastrointestinal tract and the development of late-onset autism, as Dr. Baker, Dr. Rimland, Dr. Pangborn, and the DAN! WorkGroup have highlighted. The gastrointestinal tract is the principal interface between humans and the environment and is the home to 70% of the immune system. This immune system is dynamically educated over the first few years of life by the presence of and interaction with commensal flora [beneficial micro-organisms] in the gut. .

There has been a great deal of discussion of genetic predisposition for autism. While research on genetic predisposition as a risk factor is useful to help us understand the pathophysiology of disease, it does not fully explain the increasing incidence of autism over the past 20-30 years. Our genetic structures have not changed during this time period. Therefore, we must look to the environmental changes that have impacted the immune system most directly and target treatment at that level. Empirically, this is what the DAN! practitioners have been doing for the last 10 years.

The interaction of the body (through the epidermal, respiratory , oro-pharyngeal, and gastrointestinal interfaces) and the myriad microbes in the environment provides benefits to both parties. Evidence demonstrates that bacteria have co-evolved to support digestion, absorption, metabolism, and development of the immune system.

Interactions of commensal intestinal bacteria and the immune system are of mutual benefit throughout life. This mutual co-existence gives bacteria a stable habitat that is rich in nutrients; humans get heat from the metabolism of indigestible compounds; we use SCF As ( short chain fatty acids), especially n-butyrate and Vitamin K in our metabolic pathways; and commensal microflora compete with pathogens in our intestine for space and resources.1 In addition, the commensal flora shapes both the mucosal and ..2 systemic Immune system.

Colonization of gut flora begins immediately after birth and is nearly complete after – one week of life, but quantity and species vary markedly over the first six months of life.3 More than 500 species have been noted, each with numerous strains identified by molecular probes. Overall, the number of bacteria present in the fastrointestinal lumen are IO-fold greater than the number of cells in the human body, with more than 100 times the human genome’s DNA content! Studies demonstrate that bacteria differentially colonize the neonatal, infant, and child gastrointestinal tract based upon a number of environmental factors including: the mode of delivery (Cesarean section or vaginal delivery), hygiene measures, environmental contaminants, maternal flora, age at birth, and type of feeding. 5

Mammalian evolution has kept us in close contact with relatively harmless microorganisms over a LONG period of time. In fact, it is clear that our innate immune system has evolved to recognize these ‘old friends’ as harmless. However, in afiluent countries, we may not have the necessary ‘friends’ present to consistently stimulate the maturation of regulatory T cells (T reg). This may require changes in bacterial exposure to reconstitute the proper gastrointestinal environment and strengthen/ balance our immune system.

The fluctuating balance of contrasting T-Helper cells (aka TeffectoJ provides a simple construct to understand immune system imbalance.6 THI cells stimulate cell mediated immunity, while TH2 cells stimulate antibody formation. The ‘hygiene hypothesis’ has emphasized the TH2-domination present in infancy, highlighting the increased incidence of allergies as support for the hypothesis. However, it is now apparent that modern living conditions lead to defective maturation of regulatory T cells (T reg) and regulatory antigen presenting cells -those cells that say “don’t attack”. Thus, T effector / T reg balance is a much more crucial factor than TH1I TH2 balance.7 Such immune dysregulation can help us to understand the current increase in both allergies (THI) and auto-immune diseases (TH2). In fact, Ashwood’s excellent reviews describes avast array of immune dysfunction proven within the autism spectrum disorders, that include alterations in both TH1 and TH2 mediated processes.

The dialogue between host and bacteria at the mucosal interface plays an important part in development of a competent immune system. Microbial colonization of the gastrointestinal tract affects the composition of gut-associated lymphoid tissue. Many diverse interactions between microbes, epithelium and gut-associated lymphoid tissue are involved in creating the memory of the immune system. For instance, commensal flora are intimately involved in the development of oral tolerance, part of the body’s acceptance of something as self.9 The ability to recognize food particles and commensal bacteria are critical for educating the adaptive immune system properly.

The innate immune system discriminates between potential pathogens from commensal bacteria by using a number of pattern recognition receptors (PRRs ). Mammalian cells

express a series of toll-like receptors (11..Rs ), which recognize bacterial and microbial structures, including DNA.}o When infection or pathogens are present, the inflammatory response can increase intestinal permeability. This allows for increased sampling of gut flora by the immune system -a physiologic process of checks and balances. In the presence of an alteration of the gut flora, or immune dysregulation, or agenetic predisposition, there is a sustained chronic inflammation and release of calprotectin from neutrophils (i.e. white blood cells).}} The inflammatory response of the intestinal epithelial cells to pathogenic and altered gut flora can lead to increases in intestinal permeability .

Significant permeability changes in the gut mucosa can have profound effects on anatomic and immunologic barriers to disease.}2 Altered intestinal permeability, also known as ‘leaky gut’, can lead to increased inflammatory cytokine production and a propagation of inflammation within the intestine.lJ There is a great deal of evidence linking increased intestinal permeability with multiorgan system failure, systemic disease, and immune dysfunction.14 The role of increased intestinal permeability and immune dysfunction has been confirmed with autistic children,15 including those who did not have gastrointestinal symptoms! 16

Here we have the context for understanding the important work that Horvath, Perman, Wakefield, Buie, Krigsman and others have done on validating research on immune dysfunction and gastrointestinal disease in autism. 17,18,19,20 In addition, there is also a role for toxic metal exposure affecting immune system development. For instance, aluminum is an important adjuvant used in vaccines to stimulate the innate immune system21 and mercury has multiple mechanisms by which it can modulate the immune system, including disruption of the cytokine network.22

Each of these factors emphasizes the critical role that the gastrointestinal tract plays in the development of autism. In order to effectively move forward with adequate and targeted treatment, it is necessary to understand the SOURCE of the underlying problem(s). We have underscored concerns with: pathogenic infection and dysbiosis, increased intestinal permeability , and inflammation as noted by elevated fecal calprotectin. Additional gastrointestinal factors of concern include: maldigestion and upper gut dysfunction, hypochlorhydria and disaccharidase deficiency (e.g., lactase), pancreatic insufficiency, food allergies, cow milk allergy, celiac disease, and malabsorption (especially B vitamins). Critical diagnostic tools include: comprehensive stool analysis, intestinal permeability, and food antigens. In addition, evaluations of neurotransmitters, oxidative stress, heavy metal toxicity, methylation/detoxification pathways and genomic risk factors help us to more clearly define the root of the problem. This diagnostic process helps to then effectively guide therapy.

The role of diet and foods as pre-biotics (the food source for friendly bacteria) must also be considered in this process. Ultimately, the use of dietary changes to bring balance back to the gastrointestinal tract will be critical to refining the milieu and returning to a commensal flora of’ old friends. ‘ In many ways, the face of autism has been one in which these children have become the ‘canary in a coal mine.’ We observe rapidly increasing incidence of other gastrointestinal disorders, including: Inflammatory bowel disease, irritable bowel syndrome, recurrent abdominal pain, and gastro-esophageal reflux disease. ‘ Researchers again focus on genetic predisposition and delve deeply into -immune dysregulation, but the role of diet and changes in the gastrointestinal milieu have been overlooked” The treatment strategies for these diseases will have similar approaches.

The correct gastrointestinal environment helps to re-set the mucosal immune system. Correction of inflammation and altered intestinal permeability will reduce the oxidative stress and neuroactive compounds, decrease the demand on methylation, and provide a supportive environment for balance and healing to occur. In autism and in life, let us first remember to ‘Mind the Gut.’

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