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AAPI’S NUTRITION GUIDE TO OPTIMAL HEALTH: USING PRINCIPLES OF FUNCTIONAL MEDICINE AND NUTRITIONAL GENOMICS function, which leads to increased gut permeability (49,50). Six variants of DLG5 have been associated with IBD: p.R30Q (DLG5 113G>A), p.P1371Q, p.G1066G, rs2289308, DLG_e26, and p.D1507D (35,37). Stoll et al. found that the DLG5 113G>A SNP resulted in an altered scaffolding protein that is involved in the maintenance of epithelial integrity (40). (Scaffolding proteins bring together various other proteins in a signaling pathway and allow for their interaction (51)). They concluded that the presence of the DLG5 gene variant alters intestinal permeability which increases risk for IBD. Stoll also looked at potential epistatic (gene-gene) interactions. They stratified the study sample according to the presence of risk-associated CARD15 variants. (A gene is said to be epistatic when its presence suppresses the effect of a gene at another locus.) They reported ‚a significant difference in the association of the 113A DLG5 variant with Crohns disease in affected individuals carrying the riskassociated CARD15 alleles versus those carrying nonrisk-associated CARD15 alleles‛, which suggests that there are epistatic interactions between CARD15 and DLG5 (40). This is an important point as it is not always the presence of just one gene variant or another that can lead to increased risk for a condition as much the epistatic interactions influence on disease susceptibility. Considering that the DLG5 has been shown to be a susceptibility gene in many studies, it was interesting that DLG5 was not a relevant disease susceptibility gene for IBD in German or Hungarian subjects (42). This suggests that DLG5 may be more important as a CD susceptibility gene in some populations than in others. Also, Buning et al. did not find genetic interactions between DLG5 and CARD5 variants. Buning could not even demonstrate that DLG5 variants were associated with intestinal permeability (42). However, Buning states that his results should be interpreted cautiously as the sample size in his study was small (42). SLC22A4/SLC22A5 (OCTN1/OCTN2) 92 2012 The SLC22A4/A5 genes are located on chromosome 5q31 (39). They function mainly in the transport of sodium-dependent L-carnitine and encode the sodiumindependent organic cation transporters OCTN1 and OCTN2 (52) thereby resulting in the elimination of cationic drugs (ie. verapamil, cimetidine, lidocaine, quinidine) in the intestine (25). Several SNPs have been identified, but two variants are SLC22A4 1672 C>T and SLC22A5 -207G>C. (The two are sometimes referred to as the ‚TC haplotype‛(25)). The two-allele risk haplotype was observed with significant frequency in CD patients, however not all studies confirm this (53). The impact of the SLC22A5 -207G>C SNP appears to be to disrupt a heat shock transcription factor binding element (39) resulting in significantly decreased transporter activity compared with the wild-type form and increasing risk for Crohn’s disease (41). The presence of the variants associated with the A4/A5 genes seems to reduce carnitine transport in a cell-type and diseasespecific manner, thus leading to OCTN expression impairment and ultimately disease. Defects in impaired fatty acid beta oxidation in intestinal epithelium is initiated and is exacerbated by bacterial metabolites, thereby causing colitis (54,55). Alternatively, the effects of the SLC22A5 -207G>C variant on OCTN1 transporter specificity may also diminish uptake of physiologic compounds while increasing uptake of potential toxins, such as putrescine, derived from bacterial catabolism. In either scenario, a role for OCTNs in handling enteric bacteria or their byproducts is consistent with the effects of CARD15 mutations on cellular responses to bacterial products and provides a basis for the genetic interaction between these loci (39). There is strong interaction among SLC22A4, SLC22A5 and CARD15 in Crohn’s disease and a suggested interaction between SLC22A4 and RUNX1 in rheumatoid arthritis (56). These findings suggest that OCTNs participate in multiple pathways underlying chronic inflammation. Summary of Gene Variants and Their Potential Impact On IBD Pathogenesis CARD 15/NOD2 – Alterations in this gene have been associated with a defective bacterial signal that leads to NF-κB overexpression and subsequent excessive
AAPI’S NUTRITION GUIDE TO OPTIMAL HEALTH: USING PRINCIPLES OF FUNCTIONAL MEDICINE AND NUTRITIONAL GENOMICS immune response, which can lead to chronic gut inflammation in susceptible individuals. DLG5 – Variations in this gene seem to predispose individuals to what has been coined ‚leaky gut syndrome‛, thus allowing for intestinal permeability and integrity dysfunction. SLC22A4/SCL22A5 (OCTN1/OCTN2) – Functional polymorphisms decreasing OCTN activity and/or expression have been associated with chronic inflammation and contribute to CD/IBD pathogenesis. Specifically, this may be due to reduced carnitine transport function resulting in impaired fatty acid metabolism in the gut and toxic bacterial metabolites generated due to reduced ability for proper clearance of bacterial byproducts. Current Medical Management Conventional pharmacological treatment has been directed towards suppressing inflammation. Typical drugs used to treat Crohn’s include aminosalicylates (such as sulfasalazine and mesalamine), corticosteroids (such as prednisone and budesonide), immunosuppressive agents (such as azathioprine, 6mercaptopurine, methotrexate), and antibiotics (57). More recently, anti-TNF-alpha monoclonal antibodies, such as infliximab and related drugs(Remicade®, Enbrel®, Humira®) are being prescribed since tumor necrosis factor appears to play a significant role in the pathogenesis of CD (58,59). Anti-depressants are typically offered for assisting with stress management as stress can also aggravate CD symptoms (60). Unfortunately, medications used in the therapy of IBD often contribute to the development of many nutrient deficiencies. For example, sulfasalazine produces folate malabsorption by competitive inhibition of the jejunal folate conjugate enzyme (61). Corticosteroids suppress small intestinal calcium absorption and increase urinary calcium excretion. Cholestyramine, (which is sometimes used in patients who have undergone post ileal resection in Crohn's disease to prevent diarrhea), produces fat, calcium, and fatsoluble vitamin deficiencies. Sulfasalazine, 5aminosalicylic acid, or metronidazole may cause 93 2012 nausea, vomiting, and dyspepsia, which frequently lead to decreased nutrient intake (62,63). Nutritional Management Elemental diets, elimination diets, omega-3 fish oils, high fiber, low fiber, high protein, low residue diets and bland diets have all been used in one form or another as part of the nutritional management of IBD (25,64-67). However, nutritional protocols have been inconsistent from one health care facility to another despite growing research on IBD. Until recently, theories on nutritional management of IBD have been somewhat disunified. a. Functional Clinical Tests A combination of functional clinical testing (i.e. an intestinal permeability assessment, a gut mucosal assessment or even a comprehensive stool analysis) combined with genetic testing (ie. Screening for CARD15/NOD2, DLG5, etc.) could prove to be a prudent way to identify those at risk of IBD. These types of intestinal function tests are often single tests that determine intestinal permeability, imbalances of intestinal microflora, candidiasis, food allergies and immunodeficiencies (68). They can include a sensitive detection of serum IgA, IgG and IgM antibodies using the ELISA method. (The ELISA (e(nzyme)-l(inked) i(mmunoad)s(orbent) a(ssay)]method is a sensitive immunoassay that uses an enzyme linked to an antibody or antigen as a marker for the detection of a specific protein, especially an environmental or food antigen or antibody.) They are recommended for patients who are suspected of suffering from increased intestinal permeability and malabsorption as seen in Crohn’s disease, candidiasis, food allergy, chemical hypersensitivity, fatigue, abnormal immune cell count and function and who are at a post-operative stage or at risk for sepsis (68). These tests provide an excellent tool for detection of the most common causes of altered intestinal permeability and poor assimilation of essential nutrients. Various CLIA (clinical laboratory improvement amendments) certified labs offer these types of functional tests, including Metametrix Clinical Laboratory, Genova Diagnostics (formerly known as Great Smokies Diagnostic Laboratory), and Doctors Data, Inc.
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