Circulating Biomarkers of Gut Barrier Function: Correlates and Nonresponse to Calcium Supplementation among Colon Adenoma Patients

Abstract

Background Gut barrier dysfunction contributes to several gastrointestinal disorders, including colorectal cancer, but factors associated with intestinal hyperpermeability have been minimally studied in humans. Methods We tested the effects of two doses of calcium (1.0 or 2.0 g/d) on circulating biomarkers of gut permeability (anti-flagellin and anti-lipopolysaccharide [LPS] immunoglobulins [Igs], measured via ELISA) over a 4-month treatment period among colorectal adenoma patients in a randomized, double-blinded, placebo-controlled clinical trial (n = 193), and evaluated factors associated with baseline levels of these biomarkers. Results Baseline concentrations of anti-flagellin IgA and anti-LPS IgA were, respectively, statistically significantly proportionately higher by 11.8% and 14.1% among men, 31.3% and 39.8% among those with a body mass index (BMI) ≥ 35 kg/m2, and 19.9% and 22.0% among those in the upper relative to the lowest sex-specific tertile of waist circumference. A combined permeability score (the summed optical densities of all four biomarkers) was 24.3% higher among women in the upper tertile of plasma C-reactive protein (ptrend < 0.01). We found no appreciable effects of supplemental calcium on anti-flagellin or anti-LPS Igs. Conclusion Our results suggest that 1) men and those with higher adiposity may have greater gut permeability, 2) gut permeability and systemic inflammation may be directly associated with one another, and 3) supplemental calcium may not modify circulating levels of gut permeability biomarkers within four months. Impact Our findings may improve understanding of the factors that influence gut permeability to inform development of treatable biomarkers of risk for colorectal cancer and other health outcomes.

Influence of Dietary Patterns on Plasma Soluble CD14, a Surrogate Marker of Gut Barrier Dysfunction

“…In other subgroup analyses, we observed stronger associations between the Western dietary pattern and sCD14 concentrations in overweight and obese participants, those with high CRP levels, those not regularly taking aspirin or other NSAIDs, and among men (although the P values for interaction for BMI and sex were not statistically significant, we observed large differences in ORs in the strata of these potential effect modifiers). These results are in line with findings in previous studies of markers of gut bacterial translocation and disease endpoints ( 4 , 5 ). In a nested case-control study, Kong et al ( 4 ) investigated the associations of serum anti-LPS and antiflagellin IgA and IgG with colorectal cancer risk.…”

Obesity-associated cancer risk: the role of intestinal microbiota in the etiology of the host proinflammatory state

“…For example, serum flagellin, LPS, or both were detected in most patients with short bowel syndrome, but not in normal control sera, using an ELISA for immunoglobulins specific for flagellin and LPS (210). In patients with colon adenomas, IgA antibodies to bacterial LPS from Escherichia coli and flagellin from Salmonella typhimurium were both increased by obesity, and antibody concentrations were higher in men than women (211). …”

“…The associations in men between immunoglobulins and cancer risk were stronger in those subjects with either obesity, higher CRP concentrations or higher alcohol intakes (212). In another study using the same biomarkers of bacterial exposures, men were identified to have higher intestinal permeability and concentrations of bacterial immunoglobulin biomarkers than women, and in both sexes higher CRP and higher BMI was associated with higher biomarker concentrations (211). In two population-based case-control studies, higher serum antibodies to flagellin were associated with increased colorectal cancer risk (213).…”

Yogurt consumption and risk of conventional and serrated precursors of colorectal cancer

“…Yogurt may also reduce adenoma risk by exerting anti-inflammatory effects on colon mucosa and ameliorating gut barrier dysfunction 9. As male patients with adenoma present with increased gut permeability,10yogurt may benefit more for men compared with women.…”