Environmental UVR Levels and Skin Pigmentation Gene Variants Associated with Folate and Homocysteine Levels in an Elderly Cohort

Ultraviolet radiation (UVR) is a ubiquitous exposure which may contribute to decreased folate levels. Skin pigmentation mediates the biological effect of UVR exposure, but its relationship to folate levels is unexamined. Interactions may exist between UVR and pigmentation genes in determining folate status, which may, in turn, impact homocysteine levels, a potential risk factor for multiple chronic diseases. Therefore, independent and interactive influences of environmental UVR and genetic variants related to skin pigmentation (MC1R-rs1805007, IRF4-rs12203592 and HERC2-rs12913832) on folate (red blood cell (RBC) and serum) and homocysteine levels were examined in an elderly Australian cohort (n = 599). Genotypes were assessed by RT/RFLP-PCR, and UVR exposures were assessed as the accumulated erythemal dose rate accumulated over 4 months (4M-EDR). Multivariate analysis found significant negative associations between 4M-EDR and RBC folate (p < 0.001, β = -0.19), serum folate (p = 0.045, β = -0.08) and homocysteine levels (p < 0.001, β = -0.28). Significant associations between MC1R-rs1805007 and serum folate levels (p = 0.020), and IRF4-rs12203592 and homocysteine levels (p = 0.026) occurred but did not remain significant following corrections with confounders. No interactions between 4M-EDR and pigmentation variants in predicting folate/homocysteine levels were found. UVR levels and skin pigmentation-related variants are potential determinants of folate and homocysteine status, although, associations are mixed and complex, with further studies warranted

Intense Sweeteners, Taste Receptors and the Gut Microbiome: A Metabolic Health Perspective

Intense sweeteners (IS) are often marketed as a healthier alternative to sugars, with the potential to aid in combating the worldwide rise of diabetes and obesity. However, their use has been counterintuitively associated with impaired glucose homeostasis, weight gain and altered gut microbiota. The nature of these associations, and the mechanisms responsible, are yet to be fully elucidated. Differences in their interaction with taste receptors may be a potential explanatory factor. Like sugars, IS stimulate sweet taste receptors, but due to their diverse structures, some are also able to stimulate bitter taste receptors. These receptors are expressed in the oral cavity and extra-orally, including throughout the gastrointestinal tract. They are involved in the modulation of appetite, glucose homeostasis and gut motility. Therefore, taste genotypes resulting in functional receptor changes and altered receptor expression levels may be associated with metabolic conditions. IS and taste receptors may both interact with the gastrointestinal microbiome, and their interactions may potentially explain the relationship between IS use, obesity and metabolic outcomes. While these elements are often studied in isolation, the potential interactions remain unexplored. Here, the current evidence of the relationship between IS use, obesity and metabolic outcomes is presented, and the potential roles for interactions with taste receptors and the gastrointestinal microbiota in modulating these relationships are explored

Independent and Interactive Influences of Environmental UVR, Vitamin D Levels, and Folate Variant MTHFD1-rs2236225 on Homocysteine Levels

Elevated homocysteine (Hcy) levels are a risk factor for vascular diseases. Recently, increases in ultraviolet radiation (UVR) have been linked to decreased Hcy levels. This relationship may be mediated by the status of UVR-responsive vitamins, vitamin D and folate, and/or genetic variants influencing their levels; however, this has yet to be examined. Therefore, the independent and interactive influences of environmental UVR, vitamin D and folate levels and related genetic variants on Hcy levels were examined in an elderly Australian cohort (n = 619). Red blood cell folate, 25-hydroxyvitamin D (25(OH)D), and plasma Hcy levels were determined, and genotyping for 21 folate and vitamin D-related variants was performed. Erythemal dose rate accumulated over six-weeks (6W-EDR) and four-months (4M-EDR) prior to clinics were calculated as a measure of environmental UVR. Multivariate analyses found interactions between 6W-EDR and 25(OH)D levels (pinteraction = 0.002), and 4M-EDR and MTHFD1-rs2236225 (pinteraction = 0.006) in predicting Hcy levels. The association between 6W-EDR and Hcy levels was found only in subjects within lower 25(OH)D quartiles (<33.26 ng/mL), with the association between 4M-EDR and Hcy occurring only in subjects carrying the MTHFD1-rs2236225 variant. 4M-EDR, 6W-EDR, and MTHFD1-rs2236225 were also independent predictors of Hcy. Findings highlight nutrient–environment and gene–environment interactions that could influence the risk of Hcy-related outcomes

Folate and Inflammation – links between folate and features of inflammatory conditions

Folate serves as a cofactor for one-carbon (1C) transfer reactions. These reactions are involved in the synthesis of DNA nucleotides, the amino acid methionine, and in the regulation of homocysteine (Hcy) levels. Emerging evidence suggests that these reactions have roles in the development and maintenance of inflammatory responses, with optimal folate availability having key importance in preventing endothelial dysfunction and DNA instability. Low folate levels are commonly observed in chronic inflammatory diseases, indicating that inadequate folate may be involved in the pathogenesis of inflammatory conditions or that chronic inflammation increases folate requirements. These findings highlight folate interventions as a potential treatment in inflammatory disorders. However, current understanding of folate and its influence on inflammatory phenotypes is limited. Evidence indicates that the relationship between folate and inflammation is dependent on several factors, including the timing of intervention, dosage, and interaction with environment and genes. These factors require further investigation before recommendations for folate intake can be made for the prevention and treatment of inflammation. This review outlines the emerging role of folate in inflammation and key factors that may influence this relationship

Interactions between taste receptors and the gastrointestinal microbiome in inflammatory bowel disease

Incidence rates of inflammatory bowel disease (IBD) are increasing worldwide. This correlates with increased consumption of red meats, alcohol, refined sugars, oils and animal fats, typical of a “Western” diet. Poor dietary habits are the most ubiquitous environmental factor implicated in IBD, along with gastrointestinal dysbiosis. Taste genetics and oral receptor expression levels determine dietary preferences and therefore, nutritional intake. Taste receptors (TRs) are also expressed throughout the gastrointestinal tract, where they are involved in modulating metabolic processes and gastrointestinal function. Importantly, these receptors are known to be involved in the modulation of inflammatory processes in the respiratory tract. In this system, TRs detect and respond to bacteria and bacterial signalling molecules and initiate protective responses. We propose that TRs play a similar role in the gastrointestinal tract, thereby modulating risk for IBD. TRs may indirectly affect risk for IBD by altering dietary intake, and therefore microbial composition and function. Alternatively, TRs may directly detect and respond to gastrointestinal bacterial components. Overall, there is evidence to suggest an emerging role for TRs in the aetiology of IBD. Furthermore, targeting these receptors via dietary modulation may have therapeutic potential

Population based study: atopy and autoimmune diseases are associated with functional dyspepsia and irritable bowel syndrome, independent of psychological distress

Background: The pathogenesis of functional GI disorders (FGIDs) is uncertain. However, underlying immune activation and psychological distress has been documented in irritable bowel syndrome (IBS) and functional dyspepsia (FD). Epidemiological data from the UK suggest that FGIDs are linked to atopy and certain autoimmune diseases but this has not been confirmed. Aim: To test if allergic or autoimmune diseases are independently associated with FGIDs, irrespective of psychological distress in a large population based study. Methods: A total of 3542 people (mean age 57.9\ua0years and 52.7% females) randomly selected from the Australian population, returned a mail survey (response rate\ua0=\ua043%). The survey asked about a physician diagnosis of autoimmune disease (scleroderma, psoriasis, rheumatoid arthritis and diabetes mellitus) or allergic conditions (asthma, food, pollen and/or animal allergy). The questionnaire assessed psychological distress and Rome III criteria for FD and IBS. Results: Asthma, food, pollen and animal allergies, psoriasis and rheumatoid arthritis were univariately significantly associated with IBS and FD. Food allergy (OR\ua0=\ua01.66; 95% CI\ua0=\ua01.15-2.40, P\ua0=\ua00.007), psoriasis (OR\ua0=\ua01.81; 95% CI\ua0=\ua01.19-2.74, P\ua0=\ua00.006) and rheumatoid arthritis (OR\ua0=\ua01.68; 95% CI\ua0=\ua01.15-2.4, P\ua0=\ua00.007) were independent risk factors for IBS, controlling for age, gender and psychological distress. In FD, asthma (OR\ua0=\ua01.32; 95% CI\ua0=\ua01.04-1.68, P\ua0=\ua00.025) and food allergy (OR\ua0=\ua01.78; 95% CI\ua0=\ua01.28-2.49, P\ua0=\ua00.001) were independent predictors, controlling for age, sex and psychological distress. Conclusions: There is evidence that both atopic and autoimmune diseases are risk factors for FGIDs, independent of psychological distress, differing in IBS and FD. This provides evidence that different peripheral pathways may be involved in the pathogenesis of certain FGIDs

Role of Intestinal Transit in the Pathogenesis of Gallbladder Stones

Increasing evidence implicates prolonged intestinal transit (slow transit constipation) in the pathogenesis of conventional gallbladder stones (GBS), and that of gallstones induced by long term octreotide (OT) treatment. Both groups of GBS patients have multiple abnormalities in the lipid composition and physical chemistry of their gallbladder bile - associated with, and possibly due to, an increased proportion of deoxycholic acid (DCA) (percentage of total bile acids). In turn, this increase in the percentage of DCA seems to be a consequence of prolonged colonic transit. Thus, in acromegalic patients OT treatment significantly prolongs large bowel transit time (LBTT) and leads to an associated increase of the percentage of DCA in fasting serum (and, by implication, in gallbladder bile). LBTT is linearly related to the percentage of DCA in fasting serum and correlates significantly with DCA input (into the enterohepatic circulation) and DCA pool size. However, these adverse effects of OT can be overcome by the concomitant use of the prokinetic drug cisapride, which normalizes LBTT and prevents the rise in the percentage of serum DCA. Therefore, in OT-treated patients and other groups at high risk of developing stones, it may be possible to prevent GBS formation with the use of intestinal prokinetic drugs