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Sucrase-isomaltase genotype and response to a starch-reduced and sucrose-reduced diet in IBS-D patients
  1. Andreea Zamfir-Taranu1,
  2. Britt-Sabina Löscher2,
  3. Diab M. Husein3,
  4. Abdullah Hoter3,
  5. Koldo Garcia-Etxebarria4,5,
  6. Usune Etxeberria6,7,
  7. Lucía Gayoso6,7,
  8. Gabriele Mayr2,
  9. Clara Nilholm8,
  10. Rita J. Gustafsson9,
  11. Oliver Ozaydin10,
  12. Tenghao Zheng10,
  13. Cristina Esteban-Blanco1,
  14. Isotta Bozzarelli1,
  15. Ferdinando Bonfiglio11,12,
  16. Sandra Rizk13,
  17. Andre Franke2,
  18. Luis Bujanda4,5,14,
  19. Hassan Y. Naim3,
  20. Bodil Ohlsson8,
  21. Mauro D'Amato1,15,16
  1. 1 Gastrointestinal Genetics Lab, CIC bioGUNE - BRTA, Derio, Spain
  2. 2 Institute of Clinical Molecular Biology, Kiel University and University Medical Center Schleswig-Holstein, Kiel, Germany
  3. 3 Department of Biochemistry, University of Veterinary Medicine Hannover, Hannover, Germany
  4. 4 Department of Gastrointestinal and Liver Diseases, Biodonostia HRI, San Sebastián, Spain
  5. 5 Centro Investigación Biomédica Red Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain
  6. 6 BCC Innovation, Technology Center in Gastronomy, Basque Culinary Center, San Sebastián, Spain
  7. 7 Basque Culinary Center, Faculty of Gastronomic Sciences, Mondragon Unibertsitatea, San Sebastián, Spain
  8. 8 Department of Internal Medicine, Lund University, Skåne University Hospital Malmö, Malmö, Sweden
  9. 9 Department of Gastroenterology and Nutrition, Lund University, Skåne University Hospital Malmö, Malmö, Sweden
  10. 10 School of Biological Sciences, Monash University, Clayton, Victoria, Australia
  11. 11 CEINGE Biotecnologie Avanzate, Naples, Italy
  12. 12 Department of Chemical, Materials and Production Engineering, University of Naples Federico II, Naples, Italy
  13. 13 School of Natural Sciences, Lebanese American University - Byblos Campus, Byblos, Lebanon
  14. 14 Universidad del País Vasco (UPV/EHU), San Sebastián, Spain
  15. 15 Ikerbasque, Basque Foundation for Science, Bilbao, Spain
  16. 16 Department of Medicine and Surgery, LUM University, Casamassima, Italy
  1. Correspondence to Professor Mauro D'Amato, Department of Medicine and Surgery, LUM University, Casamassima, Italy; damato{at}

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Recently in Gut, several reviews and reports have highlighted hypomorphic (dysfunctional) variants of the sucrase-isomaltase (SI) gene in relation to increased risk of irritable bowel syndrome (IBS), particularly the diarrhoea-predominant type (IBS-D).1–4 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 IBS-D carriers,4 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 starch-restricted 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 Spain5 6: we assessed the relation between SI genotype and symptom amelioration in a total of 50 IBS-D patients of European ancestry, defined according to consensus gold standard Rome IV Criteria (table 1).7 High-quality 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 non-synonymous (coding) changes was computationally predicted as previously described.4 8–10 Seven SI hypomorphic variants were identified, namely Val15Phe (dbSNP database entry rs9290264), Pro348Leu (rs77546399), Val371Met (rs138434001), Ile799Val (rs150246328), Tyr975His (rs146785675), Gly1073Asp (rs121912616) and Arg1367Gly (rs143388292), most of which already described in previous studies.4 8–10 Based on available genotype and functional data, IBS-D patients were stratified into SI hypomorphic variant double-carrier, single-carrier and non-carrier groups, and cumulative analyses of SI genotype were performed, as previously done,4 8–10 in relation to SSRD response. A valid hypothesis is that SI carriers, especially double-carriers, would benefit more from a diet (SSRD) that restricts dietary intake of carbohydrates that may be inefficiently digested when SI disaccharidase activity is reduced (as in SI carriers). A logistic regression based on sex-adjusted and age-adjusted additive genetic model did not disclose any direct correlation between SI genotype and SSRD response (not shown). However, as shown in figure 1 where SSRD response after 2 and 4 weeks are reported, all SI hypomorphic double-carriers consistently improved with the diet at both timepoints, while the response in other SI genotype groups varied. Despite the small sample size, this gave rise to a significant p value when SSRD results for IBS-D double-carriers were specifically compared with the remainder of the cohort in a Fisher’s exact test (p<0.05). Hence, while other mechanisms are certainly at play (also non-carriers respond to SSRD treatment), our results suggest that SI hypomorphic variants may affect the response to carbohydrate-focused diets.

Figure 1

Response to SSRD in IBS-D patients, stratified according to SI hypomorphic genotype (double-carrier, single-carrier and non-carrier groups), at 2 weeks (top) and 4 weeks (bottom). *p=0.043 for double-carriers versus other groups (one-tailed Fisher’s exact test). IBS-D, irritable bowel syndrome-diarrhoea; SI, sucrase-isomaltase; SSRD, sucrose and starch-restricted diet.

Table 1

Demographics and clinical characteristics of the patients included in this study

Altogether from this and previous studies,3 4 8–10 compelling evidence is accumulating for a role of SI variants in IBS, which holds potential for the management of IBS-D patients based on their genotype. In line with this and previous observations, a strategy may be envisaged to treat SI hypomorphic (double) carriers with SSRD, while non-carriers may actually benefit more from a low-FODMAP diet. Our results provide rationale for testing this hypothesis in future trials.

Ethics statements

Patient consent for publication

Ethics approval

The Swedish study protocol was approved by the Ethical Review Board of Lund University (2017/171, 2017/192), and registered at (NCT03306381). The Spanish study protocol was approved by the Local Ethics Committee (Comité de Ética del Área Sanitaria de Gipuzkoa, code: BUJ-NUT-2019-01). Participants gave informed consent to participate in the study before taking part.



  • LB, HYN, BO and MD are joint senior authors.

  • Twitter @ZamfirTaranu, @damato_mauro

  • B-SL and DMH contributed equally.

  • Contributors MD'A, LB, HN and BO study design and supervision; B-SL, DH, AH, KG-E, UE, LG, GM, CN, RG, OO, TZ, CE-B, IB, FB, SR, AF, LB and BO data acquisition, patients characterisation; AZT, B-SL, KG-E and GM statistical and computational analyses; AZT, B-SL, DH, LB, HN, BO and MD'A data analysis and interpretation; MD'A obtained funding and technical support; AZT and MD'A drafted the manuscript, with input and critical revision from all other authors. All authors approved the final draft of the manuscript.

  • Funding Funded by MCIN/AEI/10.13039/501100011033 (PID2020-113625RB-I00).

  • Competing interests MD'A has received unrestricted research grants and consulting fees from QOL Medical LLC. HN has received unrestricted research grants from QOL Medical.

  • Provenance and peer review Not commissioned; externally peer reviewed.