Sucrase-isomaltase Genotype and Response to a Starch-Reduced and Sucrose-Reduced Diet in IBS-D Patients

Recently in Gut, several reviews and reports have highlighted hypomorphic (dysfunctional) variants of the sucraseisomaltase (SI) gene in relation to increased risk of irritable bowel syndrome (IBS), particularly the diarrhoeapredominant type (IBSD). Similar to congenital (rare recessive) and acquired forms of SI deficiency, impaired SI enzymatic activity is expected to lead to colonic accumulation of undigested disaccharides, thus triggering IBS manifestations via gut microbiota fermentation, gas production and osmotic diarrhoea. Reduced efficacy of a diet low in FODMAPs (fermentable oligosaccharides, disaccharides, monosaccharides and polyols) is also observed for SI hypomorphic IBSD carriers, as this intervention may be suboptimal for individuals with possible defects in the digestion of carbohydrates other than FODMAPs (the lowFODMAP diet does not specifically restrict sucrose and starch, the substrates of SI disaccharidase activity). These results hold strong potential for personalising therapeutic (dietary) interventions in subgroups of IBS patients, though the eventual relevance of SI genotype has not been tested in the optimal dietary context, that is when patients are challenged with reducing the amount of SI substrates, like in a sucrose and starchrestricted diet (SSRD). Aiming to generate specific hypothesis that may be tested in future trials, we conducted a pilot investigation and retrospectively evaluated data from two previous SSRD studies from Sweden and Spain : we assessed the relation between SI genotype and symptom amelioration in a total of 50 IBSD patients of European ancestry, defined according to consensus gold standard Rome IV Criteria (table 1). Highquality SI targeted sequencing data were obtained for all subjects using an Illlumina AmpliSeq DNA assay with optimal coverage of the region of interest (>99% 30 × coverage of 48 SI exons). To identify hypomorphic variants, the functional relevance of SI nonsynonymous (coding) changes was computationally predicted as previously described. 8–10 Seven SI hypomorphic variants were identified, namely Val15Phe (dbSNP database https://www. ncbi.nlm.nih.gov/snp entry rs9290264), Pro348Leu (rs77546399), Val371Met (rs138434001), Ile799Val (rs150246328), Tyr975His (rs146785675), Gly1073Asp (rs121912616) and Arg1367Gly (rs143388292), most of which already described in previous studies. 8–10 Based on available genotype and functional data, IBSD patients were stratified into SI hypomorphic variant doublecarrier, singlecarrier and noncarrier groups, and cumulative analyses of SI genotype were performed, as previously done, 8–10 in relation to SSRD response. A valid hypothesis is that SI carriers, especially Letter