Functional gastrointestinal disorders (FGIDs) represent a group of chronic unexplained gut syndromes (1,2). The most widely accepted classification approach is the Rome criteria, and the best-known disorders are the irritable bowel syndrome (IBS) and functional dyspepsia (FD), although 24 separate groups fall under the Rome IV classification system in adults (3–5). Neither IBS nor FD impacts on survival (6), but they are common affecting up to 1 in 5 Americans, while chronic constipation and gastroparesis (which symptomatically overlaps with FD) are associated with reduced survival (6,7). Furthermore, quality of life may be greatly impaired, and because of the burden of these disorders, the economic impact (both direct and indirect) is huge running into billions of dollars annually (6,8,9). Although gastroesophageal reflux (GERD) is not traditionally considered a functional gastrointestinal disorder, GERD overlaps with IBS and FD more than expected by chance (1,2,10), suggesting these disorders do share a common underlying etiopathogenesis waiting to be identified.
Traditionally, FGIDs are considered to have no pathology and be of unknown cause, although various alterations have been identified in the brain-gut axis such as motor derangements, visceral hypersensitivity, and abnormal central processing of sensory signals (11–14).
Because the etiopathogenesis remains obscure, treatment is largely a trial and error process aimed at only reducing symptoms, not complete relief, and therefore remains suboptimal despite a number of new drugs being approved by the Federal Drug Administration in recent years (1,11). The focus here will be on IBS and FD because arguably, new etiological explanations are emerging for major subgroups, and if confirmed, the new observations may change diagnosis and treatment in clinical practice (1,2).
Apparently disparate risk factors for FGIDs yield clues to a unified disease model
In clinical research, the search for risk factors is undertaken in the hope this will lead to etiological clues and new approaches to prevent or even reverse disease if the risk factor is addressed. It is well recognized that IBS and FD share a number of similar risk factors. They also share at least in subsets similar disturbances of underlying gut function, namely regional visceral hypersensitivity and motor (transit) disturbances (14,15). Any putative disease model needs to explain all of these phenomena.
Functional gastrointestinal syndromes cluster in families, implicating both environment and genes (16–18). Both FD and IBS are female predominant which has remained largely unexplained despite research into a possible role for sex hormone differences (19). A number of other risk factors have been identified, and the associations replicated recently, including smoking in FD (20,21), atopic diseases (e.g., asthma), and autoimmune disease in IBS and FD (22,23).
Diet plays a role. In both IBS and FD, symptoms commonly occur after food ingestion so much so a nutrient challenge inducing symptoms can discriminate a functional gut syndrome from health (24,25). Fermentable carbohydrates can induce symptoms in IBS or FD, and a low Fermentable Oligo-, Di-, Mono-saccharides and Polyols (FODMAP) diet reduces symptoms in randomized controlled trials of IBS (26–28). High-fat meals, food chemicals, and caffeine may also play a role in symptom induction in subsets (29). Wheat contains FODMAPS but also antigenic proteins including gliadin and alpha amylase inhibitors, and subjects' self-reporting nonceliac gluten sensitivity in about 50% of cases meet criteria for IBS and/or FD (30,31).
IBS and FD arising after an infectious enteritis are well described (32,33). For example, after a Salmonella outbreak, there was an increased incidence of IBS, FD, and overlapping IBS and FD in Spain (34). Increasing evidence suggests there may be underlying genetic factors that may also prime the host to postinfectious complications (33,35,36).
FGIDs are strongly associated with psychological disorders, most notably anxiety and depression as well as somatization and abuse (37,38), and higher levels of psychological distress do discriminate IBS or FD from health (1,2). Health care–seeking behavior has been postulated to explain the apparent links to IBS (because psychological distress may drive some people with chronic gut symptoms to seek more health care, exaggerating any apparent association in case-control studies from patient settings) (39,40). However, recent population-based studies suggest psychological distress is not a comorbidity (or just due to selection bias) in IBS and FD, but like gut symptoms represents an integral component of the disease experience (41,42). Sleep disturbances are also prevalent in patients with FGIDs, but whether cause or effect is unclear (43).
If psychological distress arises before the new onset of unexplained gut symptoms, this would suggest a brain to gut (central nervous system) directed pathway perhaps through the stress response; if, on the other hand, gut symptoms precede the new onset of psychological distress, this would implicate the intestinal tract as the primary origin. Population-based research suggests new-onset IBS or FD may arise in about half of cases from brain-gut and in the other half from gut-brain pathways, although the symptom phenotype is very similar regardless of whether psychological distress or gut dysfunction arises first, and there is lifelong cross-talk between the gut and brain (44). These results have been replicated in 2 large independent population-based studies (45,46).
Brain-gut or gut-brain disorders
Traditionally, both IBS and FD have been conceptualized as brain-gut disorders, although Rome IV places increased emphasis on the gut potentially driving brain dysfunction too (3). However, the disease model proposed fails to explain a number of the known risk factors, such as the female predominance, the link to smoking, and the atopic or autoimmune associations, and fails to identify many new testable hypotheses.
Furthermore, any disease model must account for the established overlap of IBS with FD and GERD that is not explained by chance (10,47). Data from natural history studies of FD support an intimate connection with IBS and GERD symptoms. Over 10 years of follow-up of FD in a community sample confirmed through a normal esophagogastroduodenoscopy, approximately 1 in 10 with only FD developed incident (new-onset) IBS, 1 in 5 developed incident GERD symptoms, and 1 in 10 developed incident overlapping IBS and GERD symptoms (48). The data imply the 3 disorders all may share a common underling etiopathogenesis (48).
A testable integrated human disease model
A disease model that ties together the disparate evidence, and that identifies hypotheses that can be tested to confirm or refute the model, has been needed. Here, a model is proposed for FD and its inter-relationships with IBS and GERD symptoms.
FD is often misdiagnosed as GERD, IBS, or gastroparesis (2,49). As gastric emptying is delayed in about 20%–30% with FD by Rome IV criteria, and symptoms (aside from vomiting which is not associated with FD) are essentially indistinguishable from gastroparesis, the misdiagnosis (and continuing confusion) is understandable (2). In the United States, a diagnosis in practice of nonulcer dyspepsia or FD has declined (as has Helicobacter pylori–related peptic ulcer) paralleling the availability of proton pump inhibitors (PPIs) for GERD, but notably, the prevalence of FD symptoms in the general population has not reduced (49). Because heartburn is commonly associated, FD may be misdiagnosed as GERD alone, and if PPIs fail, PPI-resistant GERD may be the label applied, confusing optimal management (yet infrequently considered in expert reviews of the topic) (2). Patients with FD report bloating but may often really mean postprandial fullness; a label of IBS may then be applied rather than FD especially if minor bowel symptoms are also present as is common (50). The changes in diagnostic coding for FD in the United States may also reflect the fact there are no Federal Drug Administration-approved medications for FD, unlike IBS and GERD (1,2).
In the general population, FD is common impacting up to 1 in 6 people (2). Endoscopic population-based studies which have excluded organic pathology have confirmed the most prevalent subtype (70%–80%) is postprandial distress syndrome (PDS), characterized by unexplained early satiety (inability to finish a normal-sized meal) or postprandial fullness (51). Epigastric pain syndrome alone (unexplained intermittent pain or burning) is less common in the general population (2,4) but epigastric pain often occurs with PDS in clinical practice consulters (52).
Traditionally, FD has been conceptualized as a primary gastric disorder (4). Although the gastric pump is not paretic, gastric emptying is delayed in a 20%–30% with FD, but symptoms do not correlate with the mild to moderate slowing observed (2,4,53). Gastric hypersensitivity does occur in a subset with FD, as does failure of gastric fundus relaxation postprandially (fundic disaccommodation) (2,4). More recently, duodenal hypersensitivity to acid and distention has also been observed (54). The question is why do these abnormalities occur, and could these findings all be interlinked?
Evidence for gut pathology
FGIDs by definition have no observed microscopic gut pathology, but recent studies suggest this paradigm needs revision. In animal models, intestinal inflammation limited to the mucosa can alter gut motor and sensory function through release of mediators including cytokines and neuropeptides (55).
In FD, immune activation with subtle increases in eosinophils in the duodenum in adults (and increased eosinophil degranulation) has been observed globally (20,56–62) since the original first case-control report by Talley and Walker et al. in 2007 (20,56–62). The increased eosinophils are linked to PDS rather than EPS in most studies and may be present in more than 50% of those affected by PDS (2) (Figure 1). Similar changes with duodenal eosinophilia have been observed in nonceliac gluten sensitivity (63).
Furthermore, duodenal eosinophilia in FD was associated with a 6-fold increased risk of incident GERD symptoms developing; whether this was due to increased pathological acid reflux, reflux hypersensitivity, or functional heartburn in this population-based study is unknown (64), but other data suggest increased pathological acid reflux often co-occurs in heartburn-negative FD cases (65).
Mast cells have also been observed to be increased (Figure 1) and to degranulate in the duodenum in FD (57), although in these studies, many had concurrent IBS symptoms as discussed next. Eosinophils when degranulating release toxic chemicals such as major basic protein (Figure 2) (2). Furthermore, elegant studies from Leuven, Belgium, indicate increased duodenal permeability occurs in FD alongside submucosal duodenal neurons which are structurally and functionally abnormal, and the nerve damage correlates with the degree of duodenal inflammation (57,62).
PPIs are efficacious in FD, but there is no evidence that gastric acid is increased in FD, although daytime duodenal acid exposure may be increased (66,67).
A meta-analysis concluded PDS, not EPS, may be responsive to PPI (66), and PPIs are anti-inflammatory, blocking interleukin-13–induced eotaxin release (68). Other evidence suggests PPIs may reduce duodenal eosinophilia which might explain their efficacy in a subset with FD (PDS subtype), but randomized controlled trials are awaited (69). Histamine is released from mast cells and may also be released by the microbiome (70), and combination H1 and H2 blockade may also be efficacious in FD, although clinical trials are needed to confirm these observations (71).
Mast cells may play a role in IBS, but the prevalence is unclear. In the small intestine, increased mast cells have been observed in those with FD and IBS overlap (72). Small intestinal permeability is also increased in a major subset with IBS-diarrhea (72) as is also observed in FD (57). Experimental evidence in volunteers has implicated a stress-induced pathway acting on mast cells that can be blocked by a mast cell stabilizer (73). Increased mast cell numbers in the colon of patients with IBS-diarrhea have been inconsistently reported. For example, studies from Italy and Spain suggest mast cells are increased in IBS but have not been replicated by studies from Northern Europe and the United States, although a meta-analysis has concluded colonic mast cells are probably increased in a subset with IBS (74–78). Mast cells release serotonin, histamine, and proteases that can directly activate nerves, as well as nerve growth factors that may upregulate transient receptor potential cation channel subfamily v member 1 vanilloid receptors increasing the response to gut distention (79). Mast cell activation has been demonstrated in IBS in studies of referred patients through measurement of mast cell mediators in supernatants (74,75). However, the procedures for handling the biopsies and undertaking the supernatant studies have been inconsistent (80).
There is other evidence implicating increased immune activation and disturbed intestinal homeostasis in FD and IBS. Increases in circulating α4+β7+ gut-homing T cells have been observed in FD and β7+ in IBS, indicating recruitment of immune cells to the small intestine in this subset and indirectly supporting the observations of eosinophil-mast cell axis inflammatory alterations (81,82). Overall, the data identifying changes in the proportions of gut-homing T lymphocytes in IBS and FD suggest there has been a loss of mucosal homeostasis in a major subgroup and indicates a Th2 or a Th17 immune phenotype characterizes a major subset of both these syndromes (83,84).
The duodenum is a master controller of proximal gut function; immune activation and duodenal disease conceivably could result in more proximal gut motor and sensory abnormalities and extraintestinal symptoms (85). For example, the cytokine TNF alpha is significantly increased in both IBS and FD (81–83) and correlates with increased anxiety (82), and further TNF alpha blockade reduces central nervous system dysfunction at least in Crohn's disease in remission (86). Increased circulating homing small intestinal T cells are significantly correlated with delayed gastric emptying in FD (81,83). Duodenal motor dysfunction in FD increases duodenal acid contact time (54), and duodenal acid impairs fundic accommodation (87). Impaired fundic accommodation may in turn induce increased transient lower esophageal sphincter relaxations (88), a key mechanism of GERD, which may account for the increased risk of GERD symptoms with duodenal eosinophilia (64).
After any damage or inflammation, the intestine has a limited symptom response repertoire, so no wonder lumping symptoms together into groupings we recognize as FD and IBS combines many disparate disease entities (and argues further “symptom refinement” will be an exercise in futility). Identifying more homogeneous groups and potential etiologies is critical if to cure disease is the goal. About 50% of those with IBS or FD report their gut symptoms came on first before any psychological distress, suggesting a primary gut disease process (44–46). New etiological clues are emerging based on the observation there is intestinal pathology in subsets with FD and IBS.
Acute gastroenteritis induces an acute inflammatory response that heals, but in those genetically primed, intestinal sensitization may result (32,33). Gastroenteritis preceding symptom onset is only reported by a minority with IBS or FD, but subclinical infection is likely to be more common (89,90). A hypothetical model based on the attack rate of acute bacterial gastroenteritis annually in the United States and the subsequent risk of postinfectious IBS suggested that the population-based prevalence of IBS may nearly all be explained by acute gastroenteritis (90).
Cytotoxic lethal-binding toxin (CdtB) is common to several bacteria causing acute gastroenteritis. CdtB antibodies were reported to be increased in most cases with IBS-diarrhea (91), although this has yet to be convincingly confirmed; 2 Australian studies (1 population-based and 1 clinic-based) failed to confirm the diagnostic utility of the CdtB test in IBS, although there was a signal in FD (92). In a subset, an autoimmune process may play a role through vinculin (89), but this is also uncertain (92). In inflammatory bowel disease in remission, both IBS and dyspepsia symptoms often are experienced, suggesting inflammation can sensitize the intestine resulting in functional type symptoms probably through visceral hypersensitivity in the region of previous inflammation (93,94).
If intestinal inflammation after enteritis plays a pathogenic role in sensitizing the immune system, then it is conceivable the extent of initial inflammation explains the phenotype that develops (2). Those with proximal small intestinal immune activation may develop FD, not IBS. On the other hand, those with distal small intestinal or colonic immune activation may develop IBS, while those with more extensive intestinal involvement may be unlucky enough to develop both IBS and FD. This hypothesis is not established but is eminently testable in animal models and in human studies.
Chronic infection may explain some cases. Helicobacter pylori eradication cures a small subset with FD long term, most notably EPS, although chronic gastritis is not associated with FD symptoms (95). This suggests H. pylori-related FD is distinct from the syndrome of PDS with immune activation. It is also possible antibiotics aimed at eradicating H. pylori actually alter another relevant component of the gastroduodenal microbiome long term in a minority resulting in symptom relief, a hypothesis that needs further testing. Colonic spirochetosis may be uncommon but is strongly associated with IBS-diarrhea and has been recognized to be associated with a characteristic form of colonic inflammation in 2 independent studies (marked by increased colonic eosinophils and subepithelial eosinophil clusters) implying it is a pathogen (96,97). The duodenal microbiome is disturbed in FD compared with controls (98), while in IBS, the colonic and small intestinal microbiome may be altered, although there is no characteristic signature (99). The only risk factor identified in a case-control study of FD was herbivore pets, known to be carriers of parasites; the role of unrecognized parasitosis in FD (and IBS) warrants further research (100).
Small intestinal bacterial overgrowth based on hydrogen breath tests or culture of aspirates is increased in IBS (101). Similarly, small intestinal bacterial overgrowth is increased in Crohn's disease, as might be expected because of small intestinal stasis, but also in ulcerative colitis where the small intestine is not involved (102). Breath tests are confounded by intestinal transit while routine aspirates only culture a limited portion of the small intestinal microbiome. Nevertheless, the evidence supports a role for small intestinal bacteria in disease pathogenesis. Indirect evidence the microbiome may be important in IBS with diarrhea and FD is the symptom response to rifaximin, a nonabsorbable antibiotic, in a subset, although rifaximin may also be anti-inflammatory (103,104). On the other hand, fecal microbial transfer is of unclear efficacy in IBS to date (105) and has not been tested in FD.
Symptoms are often precipitated by food in both FD and IBS (1,2). In IBS, diets low in fermentable carbohydrates (a low-FODMAP diet) improve symptoms. Fermentable sugars are poorly absorbed and are osmotic agents (26,27). The carbohydrates also feed intestinal bacteria which produce gas and may distend a sensitized intestine inducing symptoms; a low-FODMAP diet changes the microbiome but probably does not alter intestinal sensitization or cure disease (26,27). Wheat has a FODMAP component that may induce symptoms, but wheat proteins such a gluten or alpha-1 amylase inhibitors are antigens that may also themselves induce IBS or FD symptoms (30). We have postulated incomplete digestion of wheat by small intestinal bacteria may release antigen epitopes that induce immune activation with a TH17 response that in turn can lead to eosinophil recruitment and mast cell activation, followed by a systemic immune response (30). Other controlled experimental evidence implicates specific food antigens in IBS. In 108 patients with IBS but no evidence of food allergy, 70% had a duodenal reaction to 1 of 4 foods by confocal laser endomicroscopy, and in this group, permeability increased, and acute eosinophil degranulation was observed; wheat was the commonest food implicated, and those with food-sensitive IBS had a higher background prevalence of atopic disorders (106).
Smoking was a risk factor for postinfectious FD (107) and FD in a population-based endoscopic study (21). We have also shown that smokers have higher duodenal eosinophil count than nonsmokers and speculate this explains the findings (20), a hypothesis requiring formal testing.
Alternate etiologic pathways.
Other pathways are likely to lead to similar clinical phenotypes yet will require different treatment paradigms. Examples may include alterations of bile salt absorption in IBS with diarrhea (108), stress-induced alterations of small intestinal inflammasomes (109), and in relatively uncommon cases, genetic mutations (110).
An overarching hypothesis—diseases of altered immune homeostasis
A major subset with FD (PDS) and with IBS-diarrhea may represent a spectrum of diseases of altered immune homeostasis (Figure 3) (2,111). It is speculated that antigen presentation to the mucosa (e.g., microbial antigens or food proteins after acute gastroenteritis) induces, in a genetically primed host, immune activation of the mucosa with low-grade small intestinal inflammation of variable extent. This in turn induces increased intestinal permeability and a vicious cycle of a systemic immune response. The inflammatory process in FD has been documented to be significantly associated with structural and functional abnormalities of duodenal submucosal nerves, which could account for intestinal sensory and motor alterations (62).
The close relationship of FD and IBS to food ingestion is consistent with this disease model as is the established association with atopic diseases, analogous to non–IgE-mediated food intolerance. Immune activation may account for the female predominance and fluctuations in immune activity for symptom variability over time. Duodenal feedback to the stomach may induce functional changes including delayed gastric emptying and fundic disaccommodation, and fundic alterations may induce increased transient lower esophageal sphincter relaxations and pathological acid reflux (GERD) (88). More distal intestinal inflammation inducing visceral hypersensitivity could result in coexistent IBS. Cytokine release may account for extraintestinal symptoms from anxiety to fatigue.
The current management paradigms rely on gut symptom clustering (Rome criteria) to identify disease, creating uncertainty in the minds of patients and physicians who despite guidelines often undertake endoscopy and other tests to exclude uncommon organic pathology, including malignancy and gastrointestinal ulceration or inflammation (1,2). Next, follow sequential symptom-based therapeutic approaches with at best partial or temporary relief and at worst no benefit (Figure 4). Furthermore, in the absence of head-to-head comparisons of approved therapies for IBS, the choice is based on expert opinion or is often random, far from ideal (1,2).
In the future, the paradigm may be able to shift to pathology-based subtyping based on serological, microbiological, and clinical assessments to identify when targeted therapies should be deployed in subsets (Figure 4). These include therapies to dampen down immune activation or block release of mediators such as histamine, microbial-targeted treatments that may reverse disease, and specific dietary advice to eliminate relevant food antigens after objective in vivo testing. A personalized medicine approach is what patients want and need and our goal should be to retire the rigid conceptualization of the Rome criteria (112). Only by identifying causation can we eventually anticipate cure, and as the true pathology unravels in subsets, this may become a reality.
CONFLICTS OF INTEREST
Guarantor of the article: Nicholas J. Talley, AC, MD, PhD.
Specific author contributions: N.J.T.: drafted and reviewed the manuscript.
Financial support: None to report.
Potential competing interests: N.J. T. reports personal fees from Takeda, Adelphi values, Allergens PLC, GI therapies, IM Health Sciences, Napo Pharmaceutical, Outpost Medicine, Samsung Bioepis, Synergy, Theravance, Sanofi-aventis, Censa, Anatara Life Sciences, Progenity Inc, Viscera Labs, and Avant Foundation, grants from Commonwealth Diagnostics (International) (IBS) (ceased 2017) and NHMRC, nonfinancial support from HVN National Science Challenge NZ, is on committees: Australian Medical Council (AMC) (Council Member) and MBS Review Taskforce, NHMRC Principal Committee—(Research Committee), Asia Pacific Association of Medical Journal Editors (APAME), is a GESA Board Member—Gastroenterology Society of Australia; apart of Medical Journal of Australia (Editor-in-Chief), Up to Date (Section Editor), Precision and Future Medicine—Sungkyunkwan University School of Medicine, on Advisory Board—IFFGD, outside the submitted work. In addition, N.J. T. has patents of Biomarkers of irritable bowel syndrome, a patent Licensing Questionnaires (Mayo Clinic) Talley Bowel Disease Questionnaire, Mayo Dysphagia Questionnaire, and a patent Singapore “Provisional” Patent NTU Ref: TD/129/17 “Microbiota Modulation of BDNF Tissue Repair Pathway” issued, and a patent Nepean Dyspepsia Index licensed to Talley copyright and Committees: Australian Medical Council (AMC) [Council Member]; Australian Telehealth Integration Programme; MBS Review Taskforce; NHMRC Principal Committee (Research Committee) Asia Pacific Association of Medical Journal Editors. Boards: GESA Board Member, Sax Institute, Committees of the Presidents of Medical Colleges. Community group: Advisory Board, IFFGD (International Foundation for Functional GI Disorders). Miscellaneous: Avant Foundation (judging of research grants). Editorial: Medical Journal of Australia (Editor-in-Chief), Up to Date (Section Editor), Precision and Future Medicine, Sungkyunkwan University School of Medicine, South Korea.
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