Today’s post will cover some of the research concerning the connection between gut dysbiosis and autism spectrum disorders (ASDs).
ASDs are a group of developmental disabilities that cause a whole host of challenges in afflicted children. Among these are difficulties with social interaction, communication, behavior and movement.
Males are approximately four times more likely to develop ASDs, and eleven times more likely to develop Asperger’s than females.
Diagnoses of autism spectrum disorders typically occurs before the age of three. According to the Centers for Disease Control, the prevalence of autism in 2012 was 20 per 1,000 children in the United States. This figure is up from 2008 when occurrence was reported as 11 in 1,000 kids.
Debates rage as to how much of this increase can be attributed to actual development of these disorders in contrast to more frequent diagnosis. I suspect a bit of both.
Health practitioners, parents and school personnel are far more aware of ASDs than they used to be, so it would follow that children presenting with these disorders are more likely to be diagnosed than in the past. The criteria for diagnosing autism have also been broadened. However, I don’t think anyone would seriously doubt that the prevalence of these disorders has also increased over the last few decades.
Like all diseases, there is a genetic component involved. Nevertheless, there is no definitive proof that genes can independently explain the onset of autism, let alone its varied manifestations.
A number of observers have noted the common finding of gastrointestinal distress in those with these disorders. It is not unusual for many parents to report bloating, unpleasant gas and unusual bowel movements in these children.
Food allergies are also extremely common in this group, as are food cravings. Some of the common dietary changes made by parents of autistic children is elimination of gluten and dairy from the diet. While many report improvement in symptoms, others see no difference.
Many of you know that I consider gut dysbiosis an important contributor to mental disabilities like chronic depression and anxiety. There is no reason to believe it’s any different in ASDs, although the exact mechanisms of action may be different.
The argument for implicating gut dysbiosis as a major, if not the major, cause for autism springs from some curious observations:
The inability to properly digest food has been documented in those with ASDs. One study of 22 autistic children showed impaired digestion of carbohydrates, specifically mono- and disaccharides. (1)
In these kids, genes that encode for glucose, galactose and fructose transporters, which are required to shuttle these sugars across the gut wall, were found to be lower in comparison to controls. Of the five genes responsible for the expression of these transporters, 93.3% of the autistic children lacked at least one of them.
The reason for this finding, I suspect, is due to rapid turnover of gut epithelial cells in the small intestine. Cells of the brush border are born in the crypts, or the base of the hair-like structures or villi lining the small intestine. These cells migrate to the tops of the villi as they mature to in turn be replaced by new cells taking their place from below.
The development and maturation of these cells is under the influence of beneficial gut bacteria. One of the many functions of the lactobacillus bacteria that call this part of the digestive tract home is to regulate epithelial cell turnover. Their absence or depletion would be expected to have a decidedly negative impact on these cells, including the expression of carbohydrate transporters, as well as the secretion of brush-border enzymes necessary for proper digestion.
The inability to adequately digest mono- and disaccharides would have a number of downstream consequences for these children. Glucose deprivation would be expected to impair the maintenance of the mucus layer of the digestive tract that serves as an important physical barrier against the contents of the gut lumen. I explained the importance of this barrier here.
Another manifestation of glucose deficiency would be impaired thyroid function via the initiation of euthyroid sick syndrome. This would negatively react back on intestinal health by reducing motility.
Recurring peristalsis is necessary to prevent potentially pathogenic bacteria from migrating from the colon into the illeum and jejunum of the small intestine. I covered how low thyroid function would increase the risk of contracting small intestinal bacterial overgrowth (SIBO) in this post. SIBO always impairs the proper digestion of food.
That said, I seriously doubt that malabsorption of carbohydrates is the only macronutrient affected in these children. Reduced thyroid function caused by glucose malabsorption would also impair the digestion of protein by reducing the production of hydrochloric acid in the stomach. This in turn would lead to some level of protein malabsorption as it is doubtful that protein-cleaving enzymes secreted from both the pancreas and the small intestine would entirely compensate, especially in the presence of an impaired brush border. Low hydrochloric acid levels would also predispose to developing SIBO by compromising gastric-barrier function.
It’s also highly likely that lipases and bile, essential for the breakdown and digestion of fat, are also secreted in less than optimal amounts. Fatty stools (steatorrhea) are another commonly seen symptom in those with autism.
It should go without saying that the improper digestion of all macronutrients—fat, protein and carbohydrate—will result in nutritional deficiencies in vitamins and minerals. How severe these deficiencies are depends entirely on the severity of malabsorption.
Abnormal gut flora
This same study also found gut flora populations that were significantly different in composition to those found in healthy controls. This isn’t the only study that’s discovered these abnormalities.
However, unlike previous studies this one assessed microbial composition via biopsies of the gut wall, not stool analysis. The reliance on stool samples to determine what is going on either in the small or large intestine has serious limitations that many who charge for these tests would rather you not know about lest it cut into their income stream.
What appears in feces typically has very little relation to what is attached to the gut wall. And since what is adhering to the gut wall is of far more importance when it comes to accurately diagnosing gut dysbiosis, this is no minor matter.
The reality is that many pathogens form biofilms. The bacteria contained in these biofilms are not likely to make it into passing food or feces. Therefore, relying solely on what bacteria shows up in a stool sample to assess gut health is liable to lead many a researcher and clinician astray.
Another notable problem with stool testing is displacement. What do I mean by this?
Suppose you begin taking an effective probiotic supplemented with a prebiotic. Assuming these beneficial bacteria begin displacing pathogens from the gut wall, Klebsiella and Clostridium for example, these pathogenic organisms will be newly incorporated into feces.
Any stool sample analyzed when this shift is occurring will show high levels of both Klebsiella and Clostridium. An inexperienced clinician could jump to the conclusion that the probiotics and prebiotics are “feeding” and causing a bloom of pathogenic species when in fact the opposite is occurring.
Likewise, when someone claims they have excellent gut flora because their stool tests show high levels of bifidobacteria and lactobaccillus I question this conclusion. It could very well be the case that the reason stools contain high counts of these beneficial organisms is precisely because they are being crowded out by pathogens. Remember, whenever bacteria are displaced they’ve got to go somewhere and that somewhere is feces.
By directly sampling the mucosal layer of the gut wall via biopsies, these researchers avoided these confounding issues. Their results showed a dramatic decline in Bacteroidetes bacteria in the autistic children studied.
These results were totally at odds with an earlier study led by a research group headed by Feingold that found the exact opposite. (2) The conflicting results can be explained by the difference in how gut flora was obtained.
In the Feingold study, the researchers relied on stool samples. Because Bacteroidetes species, a largely benign and normal component of human colonic flora, were being displaced by pathogens, their counts were higher in the stool samples tested leading to the erroneous conclusion that those suffering from autism had higher, not lower levels of Bacteroidetes.
Moreover, this recent study showed that the decrease in Bacteroidetes was accompanied by an increase in various Clostridium strains, namely Clostridium ruminococcaceae and Clostridium lachnospiraceae. Clostridia, by the way, are a class of gram-positive, spore-forming bacteria.
Because they form spores, they are resistant to antibiotics and can lay dormant for extended periods of time before blooming when conditions are favorable. In humans, those favorable conditions are often the depletion of the beneficial gut flora that normally keep them under tight control.
One last point before I wrap this section up. The bacterial species that appear in the colon are partly dependent on the diet a human eats, and on how well that food is digested in the small intestine.
If the small intestine is incapable of properly breaking down and absorbing fats, amino acids/peptides and mono- or diasaccharides, those undigested substrates will reach the colon. Here they will be set upon by bacteria.
Many bacteria specialize in the substrates they ferment. Bacteria that thrive on undigested fat is often not the same bacteria that thrive on undigested protein or carbohydrate and vice versa. The composition of colonic gut flora will therefore reflect the substrates that reach the large intestine as well as the health, or lack thereof, of the beneficial bacteria in this part of the gastrointestinal tract.
So while tracking shifts in colonic bacterial populations is certainly worthy of study, I believe the focus needs to be placed further up the digestive tract. Once small intestinal dysbiosis is corrected, problems in the colon often resolve themselves assuming beneficial colonic bacteria like bifidobacteria reestablish themselves in sufficient enough quantities to control potentially pathogenic bacteria.
Less diverse gut flora
A recent study comparing autistic children to neurotypical children found that those with autism have a less diverse gut flora than normal children. (3) Sadly, this study relied on stool analysis to reach its conclusions. It’s therefore handicapped by the limitations I just mentioned.
Nevertheless, less diverse gut flora is a common finding in those who suffer form various gastrointestinal disorders like irritable bowel syndrome and inflammatory bowel disease. I have no cause to doubt these findings, but confirmation from studies utilizing gut biopsies would prove more convincing.
Gut dysbiosis never exists without leaky gut. The reason is simple. Beneficial gut flora is essential for maintaining the health and barrier function of the gut along its entire length. Disturb these communities for whatever reason, and the chances for pathogens to colonize the gut wall grow.
Once established, these pathogens begin compromising the integrity of this vital barrier. For example, Clostridium difficile and its toxic metabolites, can actually induce changes to the shape of the epithelial cells lining the intestine.
When viewed under a microscope, epithelial cells or enterocytes, are rectangular in shape. They are also in very close proximity to adjacent enterocytes where they are joined together by tight-junction proteins. This physical structure allows what needs to be absorbed for nourishment, but keeps out potentially harmful substances.
Clostridium difficile toxins cause these cells to “round-up”. (4) By doing so, the space between enterocytes (paracellular gaps) increases, allowing these toxic metabolites, and much else that happens to be in the lumen, to spill through provoking downstream inflammatory cascades.
While we are still at the beginning of understanding how various bacterial toxins affect the permeability of the gut wall, it is certainly biologically plausible to assume that these same toxic metabolites increase the permeability of the blood-brain barrier once they reach systemic circulation.
Furthermore, the same mechanisms of action I outlined in my post on Alzerheimer’s disease could be at work in the neurocellular processes affecting children with autism. Recall that kynurenine easily crosses the blood-brain barrier and serves as the precursor for highly oxidative and neurodegenerative 3-hydroxykynurenine and quinolinic acid.
Elevated Cortisol Secretion
In a recently published Indian study, 45 autistic children had their urine samples analyzed for levels of free cortisol. (5) Autistic children were divided into three groups of 15 comprised of high-functioning autism (HFA), medium-functioning autism (MFA) and low-functioning autism (LFA). All were compared to a normal control group.
Urine samples were collected at three different times of the day: 9:00 PM to 7:00 AM (phase I), 7:00 AM to 2:00 PM (phase II) and 2:00 PM to 9:00 PM (phase III):
As you can see, those children with high-functioning autism resembled their normal cohorts. In contrast, those with low-functioning autism displayed the greatest elevation in cortisol. These results are entirely consistent with what we know about endotoxemia’s effect on the hypothalamic-pituitary-adrenal (HPA) axis:
As illustrated here, and discussed at length in this post, pathogens that have breached the gut wall are quite capable of stimulating the HPA axis, and by doing so increase cortisol secretion. Cortisol secretion would be further elevated by immune cytokine signaling acting directly on the adrenal cortex.
Elevated cortisol, in and of itself, always increases intestinal permeability and endotoxemia, which is why chronic stress is so harmful to health. Therefore, the elevated cortisol levels seen in these children are not only the result of leaky gut, but also react back on the intestinal tract perpetuating the condition.
Sulfur metabolism deficiencies
Studies in children with autism have discovered disturbances with the metabolism of important sulfur-containing amino acids. (6) (7) I say important because one of the major end products for this pathway is glutathione, the body’s endogenous master antioxidant.
Increased oxidative stress, as would result from endotoxins and their metabolites flooding into systemic circulation, would deplete glutathione levels in these children. Increased oxidation would have far-reaching effects, including in the brain. Brain cells are especially rich in polyunsaturated fatty acids and are therefore prone to the toxic effects of lipid peroxidation caused by runaway free radical production.
Individuals with autism have also been shown to have difficulty detoxifying many xenobiotic compounds. (8) (9) A xenobiotic is a chemical, drug, metal, pesticide, pollutant, etc. which is found in an organism, but which is not normally produced or expected to be present in it.
The ability to neutralize these compounds relies on both beneficial gut flora and proper liver functioning, in particular stage two detoxification pathways. Detox reactions in turn are heavily reliant on the glutathione status of the liver. Unfortunately, it is this organ that suffers the full and sustained brunt of increased intestinal permeability.
Decreased glutathione levels would make the excretion of heavy metals like mercury very difficult. The buildup of heavy metals in tissue would add to oxidative stress, cellular damage and further depletion of already low levels of glutathione in a feed-forward manner.
I mentioned at the start of this post that males are at greater risk for developing ASDs than females. Part of the reason for this may be due to testosterone’s ability to interfere with sulfur metabolism. (10)
The malfunctioning of this pathway results in the shuttling of S-Adenosyl-L-homocysteine (SAH) away from homocysteine synthesis (a necessary precursor to both cysteine and glutathione), to the production of adenosine instead. As I’ve written in previous posts, adenosine is a normal byproduct of gluten digestion and part of the reason why eating gluten grains can predispose to both gastroesophageal reflux disease (GERD) and constipation. It is an inhibitory neurotransmitter believed to play a role in promoting sleep, suppressing arousal, delaying stomach emptying and slowing intestinal movement.
The neuroinhibitory effect of adenosine could easily impact behavior in those with autism. Its noted effect of slowing gastrointestinal movement would make resolving gut dysbiosis problematic in this population.
A major question that remains to be answered is whether sulfur metabolism deficiencies in those with autism causes gut dysbiosis or whether these deficiencies are the result of increased intestinal permeability. My view is that the dysbiosis comes first, but that the later derangement in sulfur metabolism feeds the dysbiosis.
First by producing elevated levels of adenosine that further impacts already sluggish intestinal motility, thus perpetuating small and large intestinal dysbiosis. Secondly by failing to produce adequate levels of glutathione to neutralize free radicals and support proper phase two liver detox.
I believe it is therapeutically beneficial to increase glutathione levels in those with autism by ensuring adequate intake of vital nutrients like vitamins B-6 and B-12 as well as cysteine, all necessary components of the sulfur metabolic pathway. I would consider cysteine supplementation in the form of N-acetyl cysteine an essential nutrient for anyone suffering from gut dysbiosis, including those with autism. However, this will provide only passing relief if healthy intestinal barrier function is not restored. And the only way to do that is to normalize gut flora populations.
I expect many more studies confirming this gut-autism connection to be published in the coming years.