GI-Related Clinical Assessments
GI-Related-Clinical-Assessments

Looking for Clues: Nutrition and GI-Related Clinical Assessments in the Functional Medicine Toolkit

Published On: November 8, 2022Categories: PLMI Blog

The Functional Medicine practitioner must often take the role of sleuth in determining the root cause of a patient’s health issue. Picking the correct tests saves time for the patient and for the practitioner – what cannot be positively identified by tests often must be figured out by the process of elimination, which takes considerable time. Sometimes, finding the root cause of gastrointestinal (GI) issues is complicated by its relationship to nutrition. Nutritional deficiencies or toxicities can feed into GI issues, and GI issues can affect the breakdown and absorption of nutrients.

The skill of the functional medicine practitioner is made evident by picking the right test (or tests) that can positively identify a root cause. Fortunately, many labs are providing the means to perform highly accurate and illuminating nutrition and GI-related clinical assessments. There is not enough space in this forum to cover all related tests, so this article will simply highlight some of the most useful clinical assessment tools FM practitioners might use for sleuthing. Complementary information about clinical assessments can be found in the previous article, “Malnutrition in Obesity.”

GENETIC ASSESSMENTS:

MTHFR! I’m a mutant! – One genetic test, in particular, the Methylenetetrahydrofolate reductase (MTHFR) genetic test, can shed light on a multitude of health issues, including GI issues, anxiety, fatigue, depression, mood swings (bipolar, schizophrenia), attention deficit disorder (ADD/ADHD), chronic pain, and increased homocysteine. The term “MTHFR” can be used to refer to both the relevant genes and the enzymes these genes help create. Various locations on the DNA strand affect the MTHFR enzymes, but the 2 locations that correlate with symptoms are locations 1298 and 677. At each location, one allele is inherited from the mother, and one is inherited from the father. Each location has a genotype that is the most desirable, with single nucleotide polymorphisms (SNPs) causing less desirable outcomes- mutations. Mutations reduce the overall functioning of the MTHFR enzymes, which then sets off a cascade of negative health effects. It is estimated that mutations affect up to 40% of the US population (1).

MTHFR enzymes help convert dietary folate into its activated form that can then be used by the body. The normal genotype for location 677 is two cytosines (CC). A person with tyrosine (T) in the place of one or both cytosines does not convert their folate into activated (methylated) forms very efficiently, with 2 mutations showing a stronger depression of folate conversion (2).

A lack of usable folate affects many processes in the body, including negatively affecting the production of red blood cells (anemia) and the methyl cycle involving homocysteine and methionine. The activated folate is required for the process to convert some portion of homocysteine back into methionine, which serves as a natural cap for homocysteine levels. Less activated folate means less homocysteine is converted to methionine, which leads to high homocysteine levels in the blood. High homocysteine is correlated with increased inflammation and high oxidative stress (3), which in turn are risk factors for heart attack (4) and stroke (5).

In regards to GI issues, DNA hypomethylation due to the MTHFR-impaired folate methylation cycle is associated with a higher risk for colorectal cancer and inflammation in Inflammatory Bowel Disease (IBD) patients. Increasing amounts of folate can address IBD complications and reduce the risk of IBD (6). Anxiety or hyperactivity from MTHFR-related ADHD can also contribute to GI issues, as these emotional or mental states may trigger “fight or flight” autonomic responses that suppress digestive functions.

Hypomethylation from MTHFR mutations affects vitamin B12 (cobalamin) metabolism because B12 gets activated by a donated methyl group from activated folate (7). The complicated relationship between the deficiency of folate and vitamin B12 absorption has not been entirely worked out, but B12 serum levels are low when folate is low, and increase when folate deficiencies are corrected (8, 9). Additionally, folate deficiencies can mask B12 deficiencies, so it is recommended to test for activated vitamin B12 using serum methylmalonic acid (MMA) and supplementing before addressing folate deficiencies (10).

COMT – A hidden driver of GI issues – Catechol-O-methyltransferase (COMT) is the name for the gene and the enzyme created from that genetic blueprint. The enzyme helps break down the whole class of chemicals called catecholamines which include estrogen and some neurotransmitter substances such as dopamine and norepinephrine. Variations in the alleles of this genetic area can reduce enzyme activity, resulting in higher amounts of catecholamines and introducing imbalances. The most common area to look at is the COMT V158M, rs4680.

There are 3 possible genotypes: AA, AG, and GG. The G is the wild-type with the guanosine (G) coding for valine. A single nucleotide polymorphism (SNP) substitution of adenosine (A) for guanosine (G) can result in making methionine instead of valine, causing a 75% decrease in the enzyme activity the wild-type might enjoy. So the AA “worrier” genotype results in lower COMT activity and higher levels of catecholamines, resulting in “enhanced vulnerability to stress” and a lower pain threshold. The GG “warrior” genotype has a higher rate of COMT activity resulting in a very fast breakdown of neurotransmitter substances, lowering dopamine levels, and increasing the pain and stress thresholds (11). The AA genotype of COMT alleles is more correlated with “anticipatory worry (12),” and ADHD (13), which can send patients into doctors’ offices with GI symptoms induced by worry or hyperactivity (14).

Anecdotally, MTHFR mutations plus the COMT A/A genotype in a patient seem to raise the risk for anxiety-induced GI symptoms such as nausea, stomach ache, or lack of appetite caused by an unbalanced autonomic system stuck in “fight or flight.” When the patient presents with GI issues seemingly induced by anxiety, finding underlying genetic predispositions can be helpful for their acceptance and proactive management of symptoms through supplementation or diet changes.

APOE4 – Inherited predisposition to form plaques – The ApoE gene is the blueprint for making the “apolipoprotein E” protein. This protein, combined with lipids in the body, forms lipoproteins. Lipoproteins package fats (such as cholesterol) and transport them through the bloodstream, as well as playing a role in glucose metabolism and inflammation in the brain (15). Again, one allele in the genotype is inherited from the mother, and one allele is inherited from the father. There are 3 possible alleles – E2, E3, or E4. In the past, 6 genotypes were divided into groups as “Apo E2,” “Apo E3,” and “Apo E4” responses because the way they responded to types and amounts of dietary fats were similar.

More than half the population is of the genotype 3/3 (16). However, it’s estimated that 25% of the general population has one E4 allele (17). The Apo E3 allele is considered the “normal” type, and E4 is the problematic one. Apo E4 types have a higher risk for cardiovascular disease, various types of atherosclerotic conditions, and Alzheimer’s disease (18). Unfortunately for E4 types, moderate amounts of alcohol will lower HDL (the so-called “good” cholesterol) and raise LDL. Not only that, even moderate amounts of fat will quickly raise small, dense LDL (the small, sticky type) that is more associated with an elevated risk of coronary artery disease (CAD) (19). Having the 4/4 genotype raises the risk for Alzheimer’s up to 12 times over genotypes lacking the E4 variant (20). Reportedly almost half of Alzheimer’s patients have at least one E4 (21), which increases the tendency to form the amyloid-B plaque associated with Alzheimer’s (15).

STOOL TESTS:

When it comes to clinical assessments concerning GI issues, the modern stool test is outstanding for the sheer amount of information it can provide. Reports from these tests show measures of dysbiosis, inflammation, and/or immune involvement of the intestines, a variety of GI functions, and an in-depth analysis of the microbiota. Stool tests use a vast array of methods to show helpful measurements: the host of commensal and potentially pathogenic bacteria, measurements of inflammation (fecal SigA, calprotectin), detection of the overgrowth of yeast, and the presence of a variety of parasites.

When looking for diagnostic clues, these stool tests may be particularly interesting to FM doctors:

Pancreatic elastase (PE-1) – With about 11% of the US population having diabetes (22), anything to detect degradation of the pancreas at early stages is welcome. Some symptoms of a compromised pancreas do not show until almost 90% of the pancreatic function has been lost (23), so this early indicator of a compromised pancreas is worth being acquainted with. In this test, the PE 1 digestive enzyme that is produced by the pancreas is measured, producing a good picture of pancreatic sufficiency (or insufficiency) and possibly saving the patient from endoscopy. PE-1 is measured by Shebo ELISA, utilizing a monoclonal antibody that specifically reacts with human PE-1.

Products of protein breakdown – Undigested or unabsorbed protein that makes it into the large intestine gets fermented by bacteria, creating byproducts called “products of protein breakdown.” This scenario is increasingly common due to the rising population of those who naturally have weak or insufficient stomach acid. However, the biggest contributor to undigested matter making it to the large intestine is likely to be the use of acid-blockers and proton pump inhibitors (PPIs) which reduce the strength and volume of stomach acid. PPIs are one of the most widely prescribed medications in the world (24), are over-prescribed, and are widely abused (used very long-term instead of short-term) (25). To confound the issue, the symptoms of an overly acidic stomach are the same as a stomach with very weak acidity (25). Weak stomach acid can be addressed through supplementation with digestive enzymes, but also by not ingesting acid-blockers or acid-reducers.

Fecal lactoferrin – Another ELISA-based test is used to detect lactoferrin in the stool. Secreted by mucosal membranes and fusing with neutrophils, lactoferrin is a glycoprotein that can bind iron. The lactoferrin is released by the neutrophil when inflammation occurs. The usefulness of lactoferrin is that it can help a practitioner differentiate between Inflammatory Bowel Disease (IBD) and irritable bowel syndrome (IBS). A high score of lactoferrin may be due to IBD and is a signal to explore the possibility of IBD through colonoscopy or looking for signs of infection in the stool results. Low results can discount further exploration and possibly save the patient some time and expense (26).

Genomic typing of the microorganisms – DNA testing by PCR on the microbes in the stool sample yield a lengthy list of genera and species of bacteria. These are typically compared to a reference population and can be scrutinized for obvious imbalances to be corrected. The newest method of analysis uses shotgun whole genome sequencing (WGS) to produce a stunning in-depth report of the patient’s microbiota. One testing company can detect 28,000 species of microorganisms, including ones that produce methane or could become pathogenic (due to overgrowth, for example). Shotgun WGS, combined with the comparison to a vast database, also has the potential to identify new species. Some testing can even estimate the likelihood of the microbiota to produce various metabolites such as hexa-LPS, vitamins, and histamine.

In Conclusion: 

If a Functional Medicine practitioner is looking for tests that will produce results that can be acted upon, stool and gene testing can be quite an ally. Suites of tests are designed to find drivers (sometimes hidden drivers) of health conditions that appear in wide swaths of the population. With bigger databases and more advanced genomic analyses, nutritional and digestive issues are getting easier to identify, allowing practitioners to diagnose and treat patients more quickly and efficiently.

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