Functional variants in the sucrase–isomaltase gene associate with increased risk of irritable bowel syndrome

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Abstract

Objective

IBS is a common gut disorder of uncertain pathogenesis. Among other factors, genetics and certain foods are proposed to contribute. Congenital sucrase–isomaltase deficiency (CSID) is a rare genetic form of disaccharide malabsorption characterised by diarrhoea, abdominal pain and bloating, which are features common to IBS. We tested sucrase–isomaltase ( SI) gene variants for their potential relevance in IBS.

Design

We sequenced SI exons in seven familial cases, and screened four CSID mutations (p.Val557Gly, p.Gly1073Asp, p.Arg1124Ter and p.Phe1745Cys) and a common SI coding polymorphism (p.Val15Phe) in a multicentre cohort of 1887 cases and controls. We studied the effect of the 15Val to 15Phe substitution on SI function in vitro. We analysed p.Val15Phe genotype in relation to IBS status, stool frequency and faecal microbiota composition in 250 individuals from the general population.

Results

CSID mutations were more common in patients than asymptomatic controls (p=0.074; OR=1.84) and Exome Aggregation Consortium reference sequenced individuals (p=0.020; OR=1.57). 15Phe was detected in 6/7 sequenced familial cases, and increased IBS risk in case–control and population-based cohorts, with best evidence for diarrhoea phenotypes (combined p=0.00012; OR=1.36). In the population-based sample, 15Phe allele dosage correlated with stool frequency (p=0.026) and Parabacteroides faecal microbiota abundance (p=0.0024). The SI protein with 15Phe exhibited 35% reduced enzymatic activity in vitro compared with 15Val (p<0.05).

Conclusions

SI gene variants coding for disaccharidases with defective or reduced enzymatic activity predispose to IBS. This may help the identification of individuals at risk, and contribute to personalising treatment options in a subset of patients.

Related collections

Most cited references 29

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Self-reported food-related gastrointestinal symptoms in IBS are common and associated with more severe symptoms and reduced quality of life.

Lena Böhn, Stine Störsrud, Hans Törnblom … (2013)

Despite the fact that food and diet are central issues, that concern patients with irritable bowel syndrome (IBS), the current understanding about the association between the intake of certain foods/food groups and the gastrointestinal (GI) symptom pattern, psychological symptoms, and quality of life is poor. The aim of this study was to determine which food groups and specific food items IBS patients report causing GI symptoms, and to investigate the association with GI and psychological symptoms and quality of life. We included 197 IBS patients (mean age 35 (18-72) years; 142 female subjects) who completed a food questionnaire in which they specified symptoms from 56 different food items or food groups relevant to food intolerance/allergy. The patients also completed questionnaires to assess depression and general anxiety (Hospital Anxiety and Depression), GI-specific anxiety (Visceral Sensitivity Index), IBS symptoms (IBS-Severity Scoring System), somatic symptoms (Patient Health Questionnaire-15), and quality of life (Irritable Bowel Syndrome Quality of Life Questionnaire). In all, 84% of the studied population reported symptoms related to at least one of the food items surveyed. Symptoms related to intake of food items with incompletely absorbed carbohydrates were noted in 138 (70%) patients; the most common were dairy products (49%), beans/lentils (36%), apple (28%), flour (24%), and plum (23%). Of these, 58% experienced GI symptoms from foods rich in biogenic amines, such as wine/beer (31%), salami (22%), and cheese (20%). Histamine-releasing foods, such as milk (43%), wine/beer (31%), and pork (21%), were also considered causes of symptoms in IBS patients. GI symptoms were also frequently reported after intake of fried and fatty foods (52%). With increasing IBS symptom severity, patients reported more food items responsible for their GI symptoms (P=0.004), and this was also found in patients with more severe somatic symptoms (P<0.0001). Women tended to report more food items causing symptoms than men (P=0.06). A high number of food items causing GI symptoms was also associated with reduced quality of life and this was significant for the following domains: sleep (r=-0.25; P=0.001), energy (r=-0.21; P=0.005), food (r=-0.29; P<0.001), social functioning (r=-0.23; P=0.001), and physical status (r=-0.16; P<0.05). However, the number of food items reported to provoke GI symptoms was unrelated to body mass index, age, IBS subtype, anxiety, depression, or GI-specific anxiety. The majority of IBS patients believe that certain food items are important triggers of their GI symptoms. This is especially true for foods containing carbohydrates and fat, and also may be relevant for histamine-releasing food items and foods rich in biogenic amines. Self-reported food intolerance is associated with high symptom burden and reduced quality of life.

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Peripheral mechanisms in irritable bowel syndrome.

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Christophe Chassard, Christophe Lacroix (2013)

Due to its scale and its important role in maintaining health, the gut microbiota can be considered as a 'new organ' inside the human body. Many complex carbohydrates are degraded and fermented by the human gut microbiota in the large intestine to both yield basic energy salvage and impact gut health through produced metabolites. This review will focus on the gut microbes and microbial mechanisms responsible for polysaccharides degradation and fermentation in the large intestine. Gut microbes and bacterial metabolites impact the host at many levels, including modulation of inflammation, and glucose and lipid metabolisms. A complex relationship occurs in the intestine between the human gut microbiota, diet and the host. Research on carbohydrates and gut microbiota composition and functionality is fast developing and will open opportunities for prevention and treatment of obesity, diabetes and other related metabolic disorders through manipulation of the gut ecosystem.

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Author and article information

Journal

Journal ID (nlm-ta): Gut

Journal ID (iso-abbrev): Gut

Journal ID (hwp): gutjnl

Journal ID (publisher-id): gut

Title: Gut

Publisher: BMJ Publishing Group (BMA House, Tavistock Square, London, WC1H 9JR )

ISSN (Print): 0017-5749

ISSN (Electronic): 1468-3288

Publication date (Print): February 2018

Publication date (Electronic): 21 November 2016

Volume: 67

Issue: 2

Pages: 263-270

Affiliations

[1 ] Department of Biosciences and Nutrition, Karolinska Institutet , Stockholm, Sweden

[2 ] Department of Physiological Chemistry, University of Veterinary Medicine Hannover , Hannover, Germany

[3 ] Institute of Clinical Molecular Biology , Christian-Albrechts-University of Kiel , Kiel, Germany

[4 ] Department of Animal Breeding and Genetics, University of Veterinary Medicine Hannover , Hannover, Germany

[5 ] Internal Medicine Department, University of Maryland School of Medicine , Baltimore, Maryland, USA

[6 ] Meritus Medical Center , Hagerstown, Maryland, USA

[7 ] Max Planck Institute for Evolutionary Biology , Plön, Germany

[8 ] Institute for Experimental Medicine, Christian-Albrechts-University of Kiel , Kiel, Germany

[9 ] Gastroenterology Unit, Department of Clinical Medicine and Surgery, Federico II University Hospital , Naples, Italy

[10 ] Diagnosis and Therapy of Digestive Motility Diseases, Department of Clinical Medicine and Surgery, Federico II University Hospital , Naples, Italy

[11 ] S.C. Gastroenterologia, Azienda Ospedaliera G. Brotzu , Cagliari, Italy

[12 ] Gastroenterology Unit, Padova University-Hospital , Padova, Italy

[13 ] Department of Medicine and Aging Sciences and CeSi, G. D'Annunzio University , Chieti, Italy

[14 ] Division of Neuro and Inflammation Science, Department of Clinical and Experimental Medicine, Linköping University , Linköping, Sweden

[15 ] Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg , Gothenburg, Sweden

[16 ] Center for Functional GI and Motility Disorders, University of North Carolina , Chapel Hill, North Carolina, USA

[17 ] Division of Medicine, Department of Public Health and Clinical Medicine, Umeå University , Umeå, Sweden

[18 ] Division of Internal Medicine, Department of Clinical Sciences, Skåne University Hospital , Malmö, Sweden

[19 ] Division of Internal Medicine, Department of Clinical Sciences, Lund University , Lund, Sweden

[20 ] Department of Medicine, Karolinska Institutet, Center for Digestive Diseases, Karolinska University Hospital , Stockholm, Sweden

[21 ] Division for Family Medicine, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet , Huddinge, Stockholm, Sweden

[22 ] Stress Research Institute, Stockholm University , Stockholm, Sweden

[23 ] Division of Digestive Diseases, Oppenheimer Center for the Neurobiology of Stress, David Geffen School of Medicine, University of California , Los Angeles, USA

[24 ] Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet , Stockholm, Sweden

[25 ] Department of Biomedical Sciences and Human Oncology, University of Bari ‘Aldo Moro’ , Bari, Italy

[26 ] Gastrointestinal Unit, Department of Gastroenterology, University of Pisa , Pisa, Italy

[27 ] Department of Medical and Surgical Sciences, University of Bologna, St. Orsola-Malpighi Hospital , Bologna, Italy

[28 ] Clinical Enteric Neuroscience Translational and Epidemiological Research, Mayo Clinic , Rochester, Minnesota, USA

[29 ] BioDonostia Health Research Institute, San Sebastian and IKERBASQUE, Basque Science Foundation , Bilbao, Spain

[30 ] Unit of Clinical Epidemiology, Department of Medicine Solna, Karolinska Institutet , Stockholm, Sweden

Author notes

[Correspondence to ] Dr Mauro D'Amato, Unit of Clinical Epidemiology, Department of Medicine Solna, Karolinska Institutet, Eugeniahemmet T2, Karolinska University Hospital, Solna 17176, Stockholm, Sweden; mauro.damato@ 123456ki.se

MH and LD, shared first authors; FB, FHa, E-MK, shared second authors; HYN and MD'A shared last authors.

Author information

Mauro D'Amato http://orcid.org/0000-0003-2743-5197

Article

Publisher ID: gutjnl-2016-312456

DOI: 10.1136/gutjnl-2016-312456

PMC ID: 5563477

PubMed ID: 27872184

SO-VID: e618aa99-91ad-45db-8935-c6052c04e9df

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