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Polymorphic Influence on Intestinal Absorption
by Rebecca Snowden, LAc, LMT, MIfHI,
ATH Asst. Editor of Naturopathy
Editor's Note from Rebecca Snowden: Much of this article is a summary of research exploring the process by which celiac disease can develop and repercussions the condition can have. For a more detailed scientific explanation, you can view the full reference that was used as a source for this information, entitled "Celiac Disease and Gluten- Associated Diseases" by Steve Helms, ND.
Systems and organs of the whole body are dependent on the ability of our intestinal tract to absorb the nutrients, minerals and amino acids they need. Other than through breathing, skin absorption, and IV methods, there is no other way to get these things into the body, so to understand and appreciate the valuable yet delicate intestinal mucosa is to understand just what a portal it is to great health. Genetic propensities often discourage us and make us feel we have little control over our health status but this should not be the case, instead an awareness of genetic status should give us an upper hand on what choices to make in efforts to ensure manifestation of undesirable genetically-linked conditions do not occur. How can genetic variation influence the simple function of absorption in the intestine? What are the kinds of impacts that can be made by this variation? This paper serves as an exploration into these types of questions using just one example of the virtually limitless interplay between genetics and digestive function. Let’s take a look now at just a few key players in the everyday biochemical functioning of our bodies and see the extensive impact they make. Then take a look at one polymorphic influence that can prevent absorption of them all.
First let us take a look at tryptophan. Tryptophan is an essential amino acid that is a precursor to two biochemical pathways. One is the kynurenine pathway which leads to the formation of nicotinamide also known as niacinamide, the biologically active form of niacin (Vitamin B3). Niacin becomes NAD which is essential in the breakdown of carbohydrates, proteins and fats, and it becomes NADH which is involved in essential fatty acid and cholesterol synthesis. Among other actions, niacin also has a role in reducing LDL and increasing HDL. Down another pathway, tryptophan becomes serotonin, an important neurotransmitter involved in mood and happiness. As well, it becomes melatonin, a compound that regulates the sleep-wake cycle. Tryptophan is also instrumental in controlling appetite and carbohydrate cravings. When there is a deficiency of tryptophan, depression, insomnia and excessive carbohydrate cravings often develop.
Iron is a mineral that is crucial for cellular respiration to occur smoothly. Oxygen transport to cells is dependent on iron. It is a cofactor for antioxidant enzymes such as peroxidase and catalase which protect cells from destructive hydrogen peroxide. It is a cofactor for myeloperoxidase which leads to the production of a prooxidant that white blood cells use to kill bacteria. Iron is used in the production of energy, collagen, and myoglobin which transports iron in the muscles thus delivering oxygen to muscles. Synthesis of serotonin, dopamine and norepinephrine depend on the availability of iron, with the latter two being important catecholamine neurotransmitters and hormones. A decrease in iron levels lead to decreased oxygen delivery to tissues and muscles, less production of energy and elimination of toxins, and anemia.
Vitamin B12 is another big player in the body. It’s active all throughout the nervous system in the form of methylcobalamin. As adenosylcobalamin, it is used in the processing of amino acids and in the formation of long chain fatty acids. In the form of transcobalamin, it acts as a transport protein, delivering B12 to tissues. B12 is a cofactor in two major pathways, one converting homocysteine to methionine which further becomes SAMe, a methyl group donor on which numerous metabolic reactions are dependent. The other pathway leads to the formation of Succinyl-COA, an intermediate in the TCA cycle which leads to energy production and gluconeogenesis. When there is B12 deficiency, homocysteine can become high, leading to cardiovascular disease. Fatigue, depression and weakness tend to present. Megaloblastic anemia can develop as well as “glove and stocking” neuropathy that occurs from demyelination. Dementia and balance may also manifest as the whole nervous system can become affected.
The last big player we will look at is calcium. Calcium is of course crucial for bone and teeth health, but it is also involved in blood pressure, neuronal impulses and neurotransmitter release. It operates in cell membrane as a transport ion. In muscles, it is used in the production of glycogen which delivers the energy used by muscles to effect muscle contractions. Various hormonal secretions depend on calcium as does the immune system for its maintenance. This is in short, a breakdown of the vast dependence multiple systems have on calcium, so we can see when it is in low supply in the body, such conditions can develop as muscle cramps, hypertension, osteoporosis, anxiety, depression and insomnia.
We just took a look at four of the most basic and fundamental nutrients upon which much of the body depends, all the way from the cardiovascular system, to the brain, bones, and muscles. Adequate absorption of nutrients such as these is essential to ensure delivery to where they are needed. Clearly when there is a disruption in the ability of the intestinal wall to absorb, this can potentially wreak havoc through the whole body. There can be many causes of intestinal malabsorption. Among them are surgery, trauma, cholestasis, biliary atresia, AIDS/HIV, certain cancers, damage from radiation, liver disease, medications, and more. Food allergies, such as to soy and lactose, can also be a significant contributor to malabsorption, but it is actually gluten that we will be examining a bit closer now.
Gluten, from several types of grains, consists of two types of proteins which are what cause problems in gluten intolerance. These proteins are gliadin and glutenin, with the former being the biggest contributor. Normally, when gluten is ingested, an enzyme called tissue transglutamase (TG2) breaks it down. TG2 is an enzyme found in the enterocytes, the cells of the intestinal lumen, through which absorption also occurs. When there is a disruption in this enzyme or the capability of it to work properly, we lose the ability to break down gluten as we should, as other enzymes from the pancreas, stomach or elsewhere in the intestine are not able to do so.
There are a few genetic polymorphisms that are found to be culprits in gluten intolerance, or Celiac disease. One of the major ones is a Human leukocyte antigens (HLA) polymorphism. HLA are proteins of the Major Histocompatibility Complex which is a system that allows our immune systems to recognize self from non-self. MHC class I and class II cells differ in the way that class I cells have HLA proteins on the surface of nucleated cells of the self and class II cells have HLA proteins on the surface of specialized cells of the self such as macrophages and B cells or other cells that are involved in antigen-presenting. The purpose of HLA is to let the body know that these cells and tissues are supposed to be there and not to attack them. MHC class II cells will find antigens floating around that are outside a cell, as opposed to inside a cell which is often a virus invasion scenario, and these antigens will then be bound to their antigen receptor protein and presented to T-lymphocyte cells which then, assuming the cell has presented an non-self antigen, stimulate the production and mobilization of T-helper cells. T-helper cells then trigger B-cells to form antibodies to the non-self antigens that have been presented and it is these antibodies that then bind to those antigens. An antigen-antibody complex is then formed that leads to full-force immune attack on those complexes.
HLA-DQ is a type of MHC class II cell surface antigen receptor protein that is found in a variety of isoforms ranging from HLA-DQ1 to HLA-DQ9. In the case of Celiac disease, we often find that HLA-DQ2 and HLA-DQ8 are polymorphic genotypes that present. What is known to happen is that these particular variations have an affinity for binding to TG2. As enzymes are usually stimulated when there is a need for them, TG2 production will be increased at the ingestion of gluten and decreased in the absence. In Celiac disease, when gluten in ingested and TG2 is stimulated and begins to breakdown gliadins, the HLA-DQ2 and HLA-DQ8 proteins bind the TG2-gliadin complex. When this antigen is presented to the T-lymphocytes to determine whether or not it is of the self, the entire complex is misread and determined not to be of the self, leading to the formation of TG2 antibodies and subsequent autoimmune attack at that site. Since the site of the TG2 enzyme is in enterocytes, destruction of the enzyme results in casualties of innocent bystanders, the luminal wall cells themselves in which the attack occurs.
Through repeated ingested of gluten, there seems to be both a local inflammatory response from these attacks which results in cell wall damage, as well as a systemic response that contributes. Activated immune cells release enzymes and induce cytokines to aid in the destruction. This results in local damage, including to the tight junctions which are highly regulated gaps between cells walls. When the tight junctions become compromised, larger molecules are then able to pass through the intestinal barrier, which lead to the influx of foreign proteins too large for recognition by the body. A systemic response is then triggered to defend against this influx.
The chemical and inflammatory damage imposed on the enterocytes leads to the inability of them to properly absorb much needed nutrients. In thinking of the four nutrients previously described, we can see the domino-effect that a single genetic polymorphism such as this can have, leading to extensive repercussions throughout the body. But the mere malabsorption that presents in the case of Celiac disease is only one consequence of this condition. Not only do we see Celiac disease leading to nearly all of the conditions associated with the major nutrient deficiencies described earlier, but we also see systemic and often inexplicable repercussions likely via the overactive immune response that occurs. Celiac disease is often a trigger for the development of many other autoimmune conditions which could include autoimmune thyroiditis, dermatitis herpetiformis, Sjogren’s, rheumatoid arthritis, Type I Diabetes Mellitus, and even a sort of autoimmune “Parkinson’s” presentation. Additionally, we see Celiac disease leading to other neurological conditions such as headache, epilepsy, and peripheral neuropathies. Schizophrenia has been shown to have a great association with gluten intolerance.
It is interesting to think that a seemingly minor genetic variation could lead to so many widespread and complex complications. It is even more interesting to think about how simple of a dietary adjustment needs to be made in order to prevent these complications. I certainly do not mean to downplay the challenge on the patient’s end in leading a gluten-free lifestyle for some period of time or indefinitely depending on individual protocol, but in terms of what is involved for the clinician, it is a simple recommendation to be made which results in optimal treatment and management of this condition.
Celiac disease usually goes undiagnosed and a laundry list of complications develop that are never attributed to a root cause of underlying immune attack on enterocytes resulting in malabsorption and systemic immune hyperactivity, which can be traced back to a genetic HLA polymorphism that we may not be able to remove, but that we can work with and not against. Though still so much is still not understood about the underlying mechanisms of Celiac pathogenesis and so much is still not understood about these and other genetic polymorphic influences that may be involved in the progression, still we can use what we do know and work with individual genetic quirks in efforts to work with biochemical weaknesses and not against them. Just because a person has the HLA-DQ2 or HLA-DQ4 polymorphism does not necessarily mean that they will end up having this type of cascade of events occur at any attempt to breakdown the gliadin peptide; however, most of the population of Celiac sufferers do have this polymorphism and it can be useful in determining if a person might have susceptibility to this condition. Still, this polymorphism is present in a significant percentage of the population that consumes gluten but does not have the same type of autoimmune response. This contributes to the, as of yet, many unanswered questions regarding genetic predisposition and disease manifestation. So, for the Celiac sufferer, preservation of the delicate structure of the intestinal wall and its ability to absorb nutrients in the right size, shape, form and manner is key. For the clinician, an ability to detect when they have a potential Celiac sufferer in their office is key and an appreciation and understanding of polymorphic influences that can potentially make or break one’s health is important to this type of early disease detection, or better yet prevention, and treatment.
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About the Author
Rebecca Snowden, LAc, LMT, ATH Asst. Editor of Naturopathy, is a student member of the American Association of Naturopathic Physicians and is a 2nd year ND Candidate at the Southwest College of Naturopathic Medicine (SCNM) in Tempe, AZ. She began paving a path in the healthcare field when she received training at the Swedish Institute for Massage Therapy in New York City. Once licensed in New York for Massage, she continued her studies in a Master's Degree program at the Tri-State College of Acupuncture (NYC), where she graduated with honors. Currently, she is an Arizona State licensed Acupuncturist and Massage Therapist in part-time private practice while she works on her Doctorate at SCNM. It is at this medical school that she enjoys the opportunity to build on her previous training and experience of the body by furthering her studies to incorporate Homeopathy, western Herbal medicine, and other natural modalities while also integrating western medical training.
As part of her medical school trek, she is also honored to hold positions in the American Medical Student Association (AMSA) as the Naturopathic Medicine Interest Group Facilitator and as the AMSA Director for the Naturopathic Medical Student Association. She enjoys being active in the advancement of her school and Naturopathic Medicine through involvement in SCNM's Student Government Association, Naturopathic and Community Awareness Team, and Naturopaths Without Borders. She is also a Student Representative for Wise Woman Herbals, a manufacturer of high quality whole herb supplements.
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