Gastroenterology 2016;150:1305–1318 The Intestinal Microenvironment and Functional Gastrointestinal Disorders Giovanni Barbara,1 Christine Feinle-Bisset,2 Uday C. Ghoshal,3 Javier Santos,4 Stepen J. Vanner,5 Nathalie Vergnolle,6 Erwin G. Zoetendal,7 and Eamonn M. Quigley8 1Department of Medical and Surgical Sciences, School of Medicine, University of Bologna, Italy; 2University of Adelaide Discipline of Medicine, and National Health and Medical Research Council of Australia Centre of Research Excellence in Translating Nutritional Science to Good Health, University of Adelaide Discipline of Medicine, Adelaide, South Australia; 3Department of Gastroenterology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India; 4Lab Neuro-Immune-Gastroenterology, Digestive System Research Unit, Department of Gastroenterology, Institut de Recerca Vall d’Hebron, Hospital Vall d’Hebron, Barcelona, Spain; 5Gastrointestinal Diseases Research Unit, Queen’s University, Kingston, Ontario, Canada; 6INSERM, U1220, Toulouse, France; Université de Toulouse, UPS, Institut de Recherche en Santé Digestive, Toulouse, France; 7Laboratory of Microbiology, Department of Agrotechnology and Food Sciences, Wageningen University, the Netherlands; and 8Lynda K and David M. Underwood Center for Digestive Disorders, Division of Gastroenterology and Hepatology, Houston Methodist Hospital and Weill Cornell Medical College, Houston, Texas MICROENVIRONMENT For decades, interactions between the enteric neuromus- research had been performed on interactions with diet and/or cular apparatus and the central nervous system have served the products of digestion in the FGID sufferer. As the com- as the primary focus of pathophysiological research in the plexities of the human microbiota are increasingly under- functional gastrointestinal disorders. The accumulation of stood, the possibility that microbe-host interactions, including patient reports, as well as clinical observations, has belat- immune and metabolic responses, might be relevant to the edly led to an interest in the role of various luminal factors FGIDs has emerged. How any one or a combination of these and their interactions with each other and the host in func- luminal factors interact with each other and with the host is a tional gastrointestinal disorders. Most prominent among subject of considerable research interest and putative path- these factors has been the role of food. As a consequence, ophysiological mechanisms have been postulated (Figure 1). although not always evidence-based, dietary interventions These will be explored further in this review. Caveats are enjoying a renaissance in irritable bowel syndrome that might limit the outcomes of the current review must be management. Not surprisingly, given its exploration in many acknowledged. Although we aim to refer to human studies, disease states, the gut microbiota has also been studied in animal data could be mentioned when instrumental to functional gastrointestinal disorders; data remain incon- better understand the role of microenvironmental factors in clusive. Likewise, there is also a considerable body of experimental and some clinical data to link the pathogenesis FGID. As most studies have been conducted in patients of functional gastrointestinal disorders to disturbances in suffering from functional dyspepsia (FD) and irritable bowel epithelial barrier integrity, abnormal enteroendocrine syndrome (IBS), we will address other FGIDs only margin- signaling, and immune activation. These data provide ally. Pharmacological and other interventional approaches growing evidence supporting the existence of micro-organic involving the intestinal microenvironment will not be sys- changes, particularly in subgroups of patients with func- tematically reviewed here. tional dyspepsia and irritable bowel syndrome. However, their exact role in the complex pathophysiology and symp- Food tom generation of functional gastrointestinal disorders There is increasing recognition that dietary factors can needs to be further studied and elucidated, particularly with play a major role in the etiology and the pathogenesis of longitudinal and interventional studies. Abbreviations used in this paper: BA, bile acid; BAM, bile acid malab- Keywords: Microbiota; Bile Acids; Serotonin; Immune System; sorption; CRF, corticotropin-releasing factor; EC, enterochromaffin cell; Food; Irritable Bowel Syndrome; Functional Dyspepsia. FD, functional dyspepsia; FGID, functional gastrointestinal disorder; FODMAP, fermentable oligosaccharides, disaccharides, mono- saccharides, and polyol; GI, gastrointestinal; 5-HT, 5-hydroxytryptamine, serotonin; IBS, irritable bowel syndrome; IBS-C, irritable bowel syndrome with constipation; IBS-D, irritable bowel syndrome with diarrhea; IBS-M, lthough the focus of studies on the pathophysiology irritable bowel syndrome with mixed bowel habits; IFN, interferon; IL, of functional gastrointestinal disorders (FGIDs) has interleukin; JAM, junctional adhesion molecules; MC, mast cell; NCGS, A nonceliac gluten sensitivity; NGF, nerve growth factor; PI, post-infectious; largely been on the enteric neuromuscular apparatus and its SCFA, short-chain fatty acids; SERT, serotonin reuptake transporter; central connections through the gutÀbrain axis, the potential SIBO, small intestinal bacterial overgrowth; TJ, tight junction; TLR, toll-like receptor; TNF, tumor necrosis factor; TpH, tryptophan hydroxylase; ZO, importance of the luminal environment was noted many de- zonula occludens. cades ago in the first descriptions of FGID-type symptoms Most current article developing de novo in the aftermath of an enteric infection.1 © 2016 by the AGA Institute Clinical experience informed us of the importance of food as 0016-5085/$36.00 a symptom precipitant yet, up until very recently, little http://dx.doi.org/10.1053/j.gastro.2016.02.028 1306 Barbara et al Gastroenterology Vol. 150, No. 6 MICROENVIRONMENT Figure 1. Schematic representation of the putative interplay between luminal and mucosal factors in FGIDs. Microenviron- mental factors (eg, food, microbiota, bile acids) may permeate in excess through a leaky epithelial barrier, allowing amplifi- cation of signaling from the lumen to deeper mucosal and muscle layers, including overstimulation of the mucosal immune system. These factors may determine abnormal signaling to neural circuits (intrinsic primary afferent nerves and extrinsic primary afferent nerves), which in turn may affect intestinal physiology and sensory perception. symptoms in both FD and IBS. Their impact could be are also reported to induce symptoms.3 Data on dietary mediated through direct interactions between dietary nutrient composition in FD are limited and inconsistent, components and mucosal receptors that may have been possibly because some patients modify their diets in an sensitized to these stimuli, or via down-stream events trig- attempt to alleviate symptoms. The only available pro- gered by dietary components, such as the release of gut spective study in FD patients noted trends toward lower fat hormones, changes in epithelial morphology, generation of and energy intakes and direct relationships between, on immune responses, or altered signaling between the gut and the one hand, postprandial fullness and fat and energy the brain. intake and, on the other hand, bloating and fat intake.2 Dietary factors that reportedly trigger symptoms include Wheat- and carbohydrate-containing foods have been eating patterns as well as specific foods and/or food com- identified as triggers for symptoms, and FD patients ponents. Only a few small studies have evaluated the direct frequently report symptoms on exposure to milk and dairy effects of administering specific foods or nutrients on products, although their role remains unclear. Data on fiber symptom provocation. No intervention studies have evalu- intake in FD are inconsistent. ated the impact of targeted dietary changes on symptom The majority of IBS patients associate ingestion of a wide improvement in FD. range of foods with symptoms, particularly abdominal Although patients with IBS have long associated their bloating and pain.4 Patients frequently report making di- symptoms with food ingestion, a focused scientific and etary adjustments, including reduced consumption of milk clinical interest in the potential role of food in IBS has products, wheat products, alcohol, and certain fruits or emerged only recently. vegetables that are high in poorly absorbed short-chain carbohydrates and sugar alcohols (eg, onions) and an increased intake of other fruits high in fermentable oligo- Role of Diet saccharides, disaccharides, monosaccharides, and polyols No major differences have been found in eating patterns (FODMAPs; eg, grapes and pears).5 Data on such dietary between FD patients and controls, although limited evi- adjustments in IBS are not consistent. Many IBS patients dence suggests that patients eat fewer meals per week, and report symptoms in response to wheat-containing products, tend to eat more smaller meals/snacks, than controls.2 reminiscent of the sensitivity to gluten that characterizes While up to 80% of patients report that fatty foods/ celiac disease, despite negative celiac serology and normal meals induce their symptoms, and approximately 30% small intestinal morphology, a phenomenon that has exclude fried foods to avoid symptoms, many other foods been termed nonceliac gluten sensitivity (NCGS). Subsets of May 2016 Microenvironment and FGID 1307 patients also report symptoms