I recently discussed at length the potential relationship of high ammonia levels in autism, in addition to the fact it may be implicated as a causal factor in a number of environmental illnesses including multiple chemical sensitivity and irritable bowel syndrome. Chemical sensitivity in autism has been noted for many years and I find it curious that a writer from 2003 notes several things about autism including autism therapies (Deth, Cully) that are similar to therapies for treatment of MCS in Pall's book "Unexplained Illness" and the NO/ONOO cycle. While the true cause of autism is still unknown, for the last several years, a number of health experts have proposed that symptoms of autism may be associated with small bacterial overgrowth (SIBO) and excess ammonia in the intestinal tract. Recent reports also suggest a role of bacteria and high ammonia in the inflammatory and pain and anxiety conditions, inflammatory bowel disease and irritable bowel syndrome, respectively. Enterochromaffin cells are secretory cells in the digestive tract and regulates intestinal responses depending on the immunological profile of the inflammatory response (TH1/Th2). In post-infectious IBS (PI-IBS) the enterocromaffin cells which are associated with serotonin secretion are implicated in some of the "mood" issues including anxiety and depression as well as, responding to the chemical composition of gut contents and pathophysiological contractions. (Nozawa) Of MCS significance, Tack has recently identified that "odorants present in the luminal environment of the gut may stimulate serotonin release via olfactory receptors present in human enterochromaffin cells" that may influence gut motility, nausea, vomiting and IBS. (Braun) Also, TRPV1 nociception which has been implicated in MCS also may alter motility through EC cells. (Nozawa, Pall) Kim explains that the normal mucosal layers of the intestinal tract may play a role in the chronic inflammatory process in inflammatory bowel disease. Further he says, "the enteric microbiota may drive the development of the gut immune system and can induce immune homeostasis as well as contribute to the development of IBD although the precise etiology is still unknown. However, the interactions with microbiota with T cells, intestinal epithelial cells, dendritic cells have all been implicated as contributors to the condition. (Kim) It might be wise to consider that environmental triggers might influence the constituents of the microbiota to act differently that lead to more pathogenic behavior. In colitis, a recent report suggests that a higher level of serotonin is the result of an increase in enterochromaffin cells (EC), and/or more serotonin in them and a decrease in the serotonin exporter RNA. (Bertrand) Other reports show the involvement of GSK-3b protein which interacts with something called the Wnt/Catenin pathway and may increase ammonia levels as well as, shut of the astrocyte protective and antioxidant system Nrf2 which increases the likelihood of tissue injury and potential nerve damage from intestinal inflammation. Inhibitors of GSK-3b have been protective of endotoxic shock and also show significant benefits in treating mood disorders, prevent weight loss and activations of the inflammatory cascade by a protein called NF-kappaB. (Whittle) These mechanisms also support a recent discovery of a significant communication pathway of regulation between the gut and the brain, and even more strongly supports why inflammation in the gut may lead to changes in neurotransmission and upregulate or downregulate a number different genes and therefore, play a part in sickness syndrome.
Two decades ago, a study determined that H pylori, a bacteria in the gut, causes elevations of gastric juice ammonia (which can also bind transition metals) and subsequent findings include alterations in other gastric juices and enterochromaffin cells, changes in stomach mucosa and general injury and inflammation. (Lichtenberger) As far as the role of bacterial overgrowth goes as an important factor in IBS, this is still somewhat controversial, however, the idea is gaining in popularity. Spiller explains that recovery from post infectious-IBS can take 5 years or more and that time-table does not include potential for reinfection. The most recent studies on some strains of probiotics show promise for treatment and these findings are interesting because they support ammonia involvement in intestinal issues. Hyperammonemia is a common complication of acute and chronic liver disease and therapy may consist of antibiotics and lactulose that slows down the production and absorption of ammonia. In treating, hepatic encephalopathy lactulose works by reducing absorption from the gut to prevent the toxin from getting to the brain. Under pathological conditions, ammonia can pass through the blood brain barrier and may impair brain function, cause confusion and in the most severe cases, coma. (NetDoctor) Elevated levels can be consistent with chronic conditions and as we noted before, have been implicated in causing symptomatic issues in autism. Nicaise et al demonstrates that in his study probiotics decrease blood and fecal levels of ammonia and were better at it than lactulose. He found the study probiotics strains were able to convert ammonia to alanine to reduce ammonia levels. Astrocyte swelling is reduced with probiotic use and expression of Nrf2 has been shown to protect astrocytes from damage in hyperammonemia. Also, the probiotics decreased hyperammonemia by acting on the ammonia transporter and genetically-altered-probiotic-consuming NH3 strains reduced ammonia levels even farther. Recently, other studies show probiotics may be used effectively in IBS, colitis and Crohns and are able to modulate IL-10 an anti-inflammatory cytokine. This same cytokine is implicated in modulating sickness syndrome and is regulated by HO-1 which is modulated by Nrf2.
Alterations in cortico-releasing factors (CRF), a key regulator of cortisol in the brain have been associated with IBS, depression and anxiety. I recently wrote how hyperammonemia is associated with negative effects of cortico-releasing hormone(CRF) on mood and how high ammonia levels cause a number physiological effects in trout that are comparable to symptoms in sickness syndrome. These changes may include changes in dopamine and serotonin and the latter, may influence ammonia-mediated appetite suppression. While I hesitate to compare health conditions in humans to those in animals such as fish, these finding are interesting never-the-less. (Ortega) In mice, CRF effects similar behaviors including feeding, anxiety and activation of the sympathetic nervous system. Hyperammonemia alters the circadian rhythym of corticosteroids and motor activity in rats while not producing anxiety (Ahabrach) while flavanoids such as quercetin, can reduce CRF's activation of the HPA axis. (Kawabata)
Therer are any number of genes and polymorphisms that can effect metabolism that may lead to diseases of the intestinal tract or any organ for that matter and ammonia is just one of many. At present, scientists have only just begun to discover with the use of genetic studies to discover how these polymorphisms may differently effect the health of individuals and populations. There are many yet to be discovered. Genetic counselors can be a tremendous help in this respect, sometimes just by noting and being familiar with "patterns". Dr. Yasko supplies a pretty good break-down of genetic conditions that may alter and contribute to high ammonia levels in one posted article but it is not all inclusive. A genetic counselor I am not going to discuss each of the genes SNPs because the article is long and detailed but quite informative. She does note that ammonia regimines need to be monitored and sometimes changed and therefore, any therapeutic program that addresses genetic influences needs to be done in consultation with a physician. I have explained how different genetic conditions can impair proper ammonia excretion and much of that is explained in this paper. I am not a doctor and therefore will not comment on her treatments but have read about her practice in the literature. She points out a few things I found interesting including hazards associated with some "alternative" therapeutics including epsom salts, MSM and the consequence they can be metabolically be converted to ammonia and may effect the function of another enzyme. I have researched this enzyme and indeed, there may be some concerns with this enzyme in some people with environmental illnesses. This article in this respect and as a whole provides an interesting read and more importantly possibly warrants a discussion with your doctor. (Yasko) Because ammonia levels may influence autism and other conditions as mentioned above, I believe this discussion may be an important priority.
It is difficult to predict how endogenous and exogenous chemicals are going to react to produce health effects including increasing the tendency for chronic conditions like IBS and autoimmune-type inflammatory disease. A recent study demonstrated different mouse strains have different before and after levels of antioxidant genes including glutathione, Nrf2 and HO-1 and also have higher levels of oxidative stress upon exposure to cigarette smoke. It also demonstrates variations exist between individual organisms (mice) which may be comparable to differences in the immune response that might occur in individuals in different populations. From a population health standpoint, different populations may be more or less susceptible to exposures and consequently certain diseases. This potentially becomes more of a concern when there is a poor quality of health care system and disparities already exist in those populations. To support this idea, a study was released in 2007 that identified population differences exist in the Nrf2 gene and concluded they may make them more or less resistent to oxidative stress and lead to an increased prevalence of disease and lower quality of life. (Marzec) Conditions of mixed and chronic environmental stress where there is a reduction in the ability to activate and control the adaptive response has important and broad implications for the health status and adaptive ability of a population as a whole. Several years ago, one researcher found hydrazine, an agricultural product, had a negative effect on the B12-dependant methionine synthase pathway and as a consequence from homocysteine elevations impaired the urea cycle and sulphur amino acid detoxification. (Kenyon) Exposure to nitrous oxide (laughing gas) can deactivate B12 and potentiate impairments in the cyles that eliminate ammonia and in recent weeks, it was reported that exposure to the greenhouse gas nitrous oxide from home maintainance of lawns can be as significant as the amount produced by agriculture and therefore ubiquitous in the environment. With this in mind and in a mixed environment, the study on cigarette smoke mentioned earlier becomes more significant because in the past cigarettes have added ammonia to make themmaking them more addictive. In addition to the hundreds of contaminants in cigarette smoke, it also contains bacteria that may have the potential to cause infectious disease and contains endotoxin that elicits inflammatory responses. Interestingly, the absence of GSK-3b, the on and off switch for Nrf2, eliminates Tnf-a and NF-kappaB signaling from both endotoxin and cigarette smoke. (Takada) This suggests ammonia in cigarette smoke has the potential to down-regulate the Nrf2 system and may help explain the variety of health effects from these exposures and increased sensitivity to them in some individuals. In support the research by Hubner reported that Nrf2 plays "important roles in cellular defenses against smoking in the epithelium and there is variability within populations of oxidant burden. (Hubner) All of this, can lead one to assume that variants in the exposures to agricultural products, alterations in nutritional status and genetic variants may increase the likelihood of any number of diseases including irritable bowel syndrome and inflammatory bowel disease.
Finally, it is important to review some important general health consequences of high ammonia levels. As we have noted, hyperammonemia can be caused by enzyme deficiencies or liver disease and because liver damage and impairment of antioxidant systems are concerns upon exposures, high ammonia levels should be considered as a factor in patients with environmental illnesses. "Hyperammonemia does cause astrocyte swelling (acute hyperammonemia) to astrocytosis (chronic hyperammonemia) and when the urea cycle is impaired, changes to allow for the excretion of ammonia occur in the brain. Some of these changes include changes in glutamate regulation and drug receptors (benzodiazipine) in the mitochondria. Acute changes include activation of NMDA receptors (although some may argue this) and chronic hyperammonemia may cause increases in tryptophan metabolites including serotonin. As one author stresses, current therapies for hyperammonemia are mediated through reduction of ammonia levels through the gastrointestinal tract and increased ammomia in the muscle." (Butterworth) Further studies show that IDO, an enzyme involved in the catabolism of tryptophan, has protective qualities against certain immune reactions and this is achieved through T cell suppression. These findings may lead to more supportive evidence of a loss of T cell suppression and an increase in autoimmune responses in MCS reactions. Other studies show oxidative stress plays a role in the neuropathology of ammonia toxicity and cause derangements in the cerebellum and cerebral cortex that lead to both increasing or decreasing antioxidant levels in both of these areas in acute and chronic ammonia toxicity.(Singh)
For further emphasis:
- Iron Leads to Memory Impairment that is Associated with a Decrease in Acetylcholinesterase Pathways.
For Clinical Professionals:
Citations located here.
