Gastrointestinal Transcriptomic Response of Metabolic Vitamin B12 Pathways in Roux-en-Y Gastric Bypass

Abstract

Objectives:Vitamin B12 (B12) deficiency after Roux-en-Y gastric bypass (RYGB) is highly prevalent and may contribute to postoperative complications. Decreased production of intrinsic factor owing to gastric fundus removal is thought to have a major role, but other components of B12 metabolism may also be affected. We evaluated changes in the expression levels of multiple B12 pathway-encoding genes in gastrointestinal (GI) tissues to evaluate the potential roles in contributing to post-RYGB B12 deficiency.Methods:During double-balloon enteroscopy, serial GI biopsies were collected from 20 obese women (age, 46.9±6.2 years; body mass index, 46.5±5.3 kg/m2) with adult-onset type 2 diabetes (fasting plasma glucose ≥126 mg/dl; hemoglobin A1c≥6.5%) before and, at the same site, 3 months after RYGB. Gene expression levels were assessed by the Affymetrix Human GeneChip 1.0 ST microarray. Findings were validated by real-time quantitative PCR (RT–qPCR).Results:Gene expression levels with significant changes (P≤0.05) included: transcobalamin I (TCN1) in remnant (−1.914-fold) and excluded (−1.985-fold) gastric regions; gastric intrinsic factor (GIF) in duodenum (−0.725-fold); and cubilin (CUBN) in duodenum (+0.982-fold), jejunum (+1.311-fold), and ileum (+0.685-fold). Validation by RT–qPCR confirmed (P≤0.05) observed changes for TCN1 in the remnant gastric region (−0.132-fold) and CUBN in jejunum (+2.833-fold).Conclusions:RYGB affects multiple pathway-encoding genes that may be associated with postoperative B12 deficiency. Decreased TCN1 levels seem to be the main contributing factor. Increased CUBN levels suggest an adaptive genetic reprogramming of intestinal tissue aiming to compensate for impaired intestinal B12 delivery.

Bariatric Surgery in Obesity: Effects on Gut Microbiota and Micronutrient Status

“…Changes in the architecture of the GIT secondary to gastric fundus resection result in decreased secretion of both HCl and pepsin by the functional remnant segment. This prevents capture of vitamin B 12 from dietary sources and determines loss of food contact with intrinsic factor (IF)-producing cells, leading to cobalamin malabsorption and deficiency [120,121]. Disrupted IF secretion is currently considered the main driver of the post-surgical B 12 deficiency [121,122].…”

“…This prevents capture of vitamin B 12 from dietary sources and determines loss of food contact with intrinsic factor (IF)-producing cells, leading to cobalamin malabsorption and deficiency [120,121]. Disrupted IF secretion is currently considered the main driver of the post-surgical B 12 deficiency [121,122]. A 2017 small-scale study, involving 20 patients submitted to RYGB, proposed that, besides IF, other molecules involved in the vitamin B 12 metabolism may be involved in the pathogenesis of its postoperative deficiency.…”

“…Cobalamin preferentially binds to TCN 1 in the low acidic gastric environment and attaches to IF only in the small upper bowel. Using transcriptomic analysis, increased B 12 -receptor encoding genes' expression (CUBN) was detected at all levels of the GIT, suggesting a potential genetic reprogramming of the intestinal tissue in order to compensate for insufficient B 12 delivery [121]. In spite of indirect improvement of cobalamin absorption following mixed bariatric procedures, studies show a greater incidence of vitamin B 12 deficit after RYGB compared to VSG [123].…”

“…Vitamin B 12 deficiency is reported in 37-50% of gastric bypass patients [122] and, respectively, in 10-20% of patients that underwent VSG [104]. The authors argue that after restrictive BS, although TCN 1 synthesis may be inhibited, exposure of food at the entire intestinal surface area results in local IF production, with B 12 gut transport by IF being less disrupted [121]. B 12 deficiency is associated with a triad of symptoms known as Biermer's disease: megaloblastic anemia, gastrointestinal, and neurologic symptoms [124].…”

Reduced intestinal FADS1 gene expression and plasma omega-3 fatty acids following Roux-en-Y gastric bypass

“…[10] Aside from limiting food intake and compromising nutrient digestion and absorption, we have shown that the anatomical changes that occur following RYGB may alter the expression of intestinal genes. [11][12][13] The effect of RYGB on the metabolism of PUFAs by intestinal cells or on n-3 PUFA status remains unclear. We here consider that the restrictive and malabsorptive procedure of RYGB can decrease significantly the systemic availability of n-3 PUFAs not only by limiting their ingestion and the intestinal surface for their absorption, but also by impacting on the intestinal expression of genes involved in their endogenous synthesis.…”