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Irritable bowel syndrome: treatment based on pathophysiology and biomarkers
  1. Michael Camilleri1,
  2. Guy Boeckxstaens2
  1. 1 Clinical Enteric Neuroscience Translational and Epidemiological Research (CENTER), Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
  2. 2 Center of Intestinal Neuroimmune Interaction, Division of Gastroenterology, Translational Research Center for GI Disorders (TARGID), Leuven University, Leuven, Belgium
  1. Correspondence to Dr Michael Camilleri, Gastroenterology, Mayo Clinic, Rochester, Minnesota, USA; camilleri.michael{at}mayo.edu

Abstract

Objective To appraise the evidence that pathophysiological mechanisms and individualised treatment directed at those mechanisms provide an alternative approach to the treatment of patients with irritable bowel syndrome (IBS).

Design A PubMED-based literature review of mechanisms and treatment of IBS was conducted independently by the two authors, and any differences of perspective or interpretation of the literature were resolved following discussion.

Results The availability of several noninvasive clinical tests can appraise the mechanisms responsible for symptom generation in IBS, including rectal evacuation disorders, abnormal transit, visceral hypersensitivity or hypervigilance, bile acid diarrhoea, sugar intolerances, barrier dysfunction, the microbiome, immune activation and chemicals released by the latter mechanism. The basic molecular mechanisms contributing to these pathophysiologies are increasingly recognised, offering opportunities to intervene with medications directed specifically to food components, receptors and potentially the microbiome. Although the evidence supporting interventions for each mechanism is not at the same level of proof, the current state-of-the-art provides the opportunity to advance the practice from treatment based on symptoms to individualisation of treatment guided by pathophysiology and clinically identified biomarkers.

Conclusion These advances augur well for the implementation of evidence-based individualised treatment for patients with IBS based on actionable biomarkers or psychological disturbances.

  • irritable bowel syndrome

Data availability statement

All data relevant to the study are included in the article.

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WHAT IS ALREADY KNOWN ON THIS TOPIC

  • The current guidelines suggest algorithms regarding the sequence of choice of medications based on predominant symptoms particularly bowel dysfunction in patients with irritable bowel syndrome (IBS).

WHAT THIS STUDY ADDS

  • This review documents the evidence that pathophysiological mechanisms and individualised treatment directed at those mechanisms provide an alternative approach to the management of patients with IBS.

HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY

  • This review focuses the attention of researchers to the translational and basic molecular mechanisms that deserve further studies to enhance the diagnosis and management of IBS, and it informs policy makers and those involved in developing guidelines for clinical practice regarding the importance of ‘splitting’ IBS, thereby increasing the opportunities to provide specific targeted treatment.

Introduction

The objectives of this review are to review some of the pathophysiological principles involved in irritable bowel syndrome (IBS), the actionable biomarkers that can be used to identify and specifically treat mechanisms resulting in the symptoms of IBS, and treatments based on the pathophysiology or predominant symptoms.

The mechanisms underlying IBS include central nervous system hypervigilance, psychosocial factors, genetic predisposition and mechanisms directly involving the gastrointestinal (GI) tract. Although it is commonly perceived that IBS is a disorder of gut–brain interaction, it is relevant to note that there are gut-specific mechanisms that can be corrected without use of central neuromodulators. There is a role for hypnotherapy, psychotherapy and central neuromodulators in the appropriate patients with IBS. However, it is important to recognise opportunities for addressing the mechanisms or pathophysiology in the gut. Thus, in addition to the irritable bowel, there is accumulated evidence that the gut may also be irritated in IBS by products of digestion, neurotransmitters, prior enteritis, the microbiome, mucosal immune activation and increased mucosal permeability.1 These factors lead to altered gut motor function, altered sensation and rectal evacuation disorders.

Update on pathophysiology of IBS and its diagnosis

The pathophysiological features of significance in IBS are evacuation disorders, abnormal colonic transit, bile acid diarrhoea (BAD), increased colonic and rectal sensation, disaccharidase deficiency, local immune reactions to food and altered microbiota.

Through studies that were designed to demonstrate the pathophysiology, several diagnostic tests have been developed to facilitate recognition of the mechanisms leading to patient symptoms.

Rectal evacuation disorders

Evacuation disorders mimic the symptoms of IBS with constipation: reduced emptying of the left colon leads to distension, bloating, abdominal pain and constipation. Evacuation disorders may result in delayed colonic transit, particularly in the left colon.2 In clinical practice, two general types of pelvic floor dysfunction are recognised: spastic evacuation disorders in which the puborectalis is spastic (‘dyssynergia’),3 or the anal sphincter does not relax (‘anismus’); a second category represents a flaccid disorder, especially in descending perineum syndrome,4 which typically affects older patients, particularly women who have had three or four vaginal deliveries,4 or Ehlers-Danlos syndrome, hypermobility or vascular types, with loss of connective tissue support of the perineum.5 6 The anchor of diagnosis of rectal evacuation disorders is anorectal manometry with balloon expulsion, and the most useful parameters are increased resting anal sphincter pressure, markedly negative rectoanal pressure differential and prolonged balloon expulsion time4 relative to normal values based on sex and age.

Motor dysfunction

Motor dysfunction has been demonstrated noninvasively using radiopaque markers studies Or scintigraphy. A Swedish study7 showed that about a third of patients with diarrhoea and a third of those with constipation have transit abnormalities. Transit measurement is not indicated at the first encounter and may be indicated after insufficient response with first-line therapies such as treatment with loperamide for IBS-diarrhoea (IBS-D) or with fibre and osmotic laxative for IBS-constipation (IBS-C). Measurement of transit is particularly relevant in patients with IBS-C. Using scintigraphy to measure transit, there is a significant relationship between the emptying of the proximal colon at 36 hours and the 24-hour stool weight.8 In addition, the distribution of radiolabeled colonic content differed significantly in IBS-D compared with healthy controls, with more isotope appearing in the stool and rectosigmoid and less in the descending colon.8 The transit profile in the colon was abnormal at 24 or 48 hours, respectively, in patients with IBS-D and IBS-C, and patients with mixed or alternating IBS had a transit profile quite similar to that of patients with IBS-D at 48 hours.9 Transit measurements are established as a diagnostic biomarker with the important proviso to exclude rectal evacuation disorders in patients with evidence of slow colonic transit.2 However, transit measurements cannot differentiate IBS-D from functional diarrhoea or IBS-C from functional constipation, and this is understandable given the transition of these symptom complexes.10 In patients with rapid colonic transit associated with IBS-D, the objective measurement may corroborate the patient’s report of severity of diarrhoea or impact the choice of pharmacological treatment such as addition of second-line treatment such as a 5-hydroxytryptamine (5-HT3) antagonist to the first-line treatment with loperamide. In case of slow transit, objective measurement of transit may indicate the need for the addition of a secretagogue to a first-line osmotic laxative for constipation in IBS-C.

IBS is associated with visceral hypersensitivity or hypervigilance to visceral signalling

In a classical study by Ritchie,11 patients with IBS had rectal hypersensitivity to a distended balloon and more patients had evidence of pain sensation at lower volumes of distension in IBS compared with healthy controls. Further studies at University of California-Los Angeles (UCLA)12 showed two types of increased rectal sensation: hypersensitivity or hyperalgesia. Thus, there are patients in whom distension of the balloon in the rectum leads to pain or other sensations at lower thresholds of distension, whereas those who have a normal threshold of distension experience increased discomfort or hyperalgesia, consistent with hypervigilance to or reduced downregulation of normal visceral afferent input. Importantly, the pain scores reported by patients are rather subjective and strongly influenced by the psychological burden of the patient,13 questioning to what extent this test is actually assessing visceral afferent dysfunction. Live calcium recordings from rectal biopsies however demonstrated increased excitability of submucosal neurons in response to agonists of the pro-nociceptive transient receptor potential (TRP) channels (TRP vanilloid (TRPV1, TRPV4) and TRP ankyrin 1 (TRPA1)).14 15 Although submucosal neurons are most likely not involved in pain signalling, these observations indicate that the submucosal microenvironment contains TRP channel sensitising factors that might equally affect visceral afferents. These data favour interventions directed at peripheral mechanisms involved in aberrant pain signalling in addition to opportunities to target central mechanisms associated with visceral hypervigilance.

One in four patients with IBS-D actually has idiopathic BAD

Primary bile acids, chenodeoxycholic acid and cholic acid, are derived from cholesterol, undergo taurine or glycine conjugation (which increases their solubility), and pass into the small intestine after meal ingestion and gall bladder contraction to facilitate fat digestion and absorption. About 90%–95% of the bile acids are reabsorbed in the terminal ileum by the active transporter, apical sodium-coupled bile acid transporter.16 Bile acids undergo enterohepatic cycling, and the remaining 5%–10% pass into the colon where they can increase the permeability because of their detergent effects. Once in the colon, the primary bile acids are deconjugated with removal of glycine and taurine and are converted to secondary bile acids through 7α dehydroxylation or 7β epimerisation by the colonic microbiota. The main secondary bile acids are lithocholic acid, deoxycholic acid and ursodeoxycholic acid. In the colon, bile acids cause increased secretion, increased mucosal permeability and stimulate motility (eg, high amplitude colonic contractions).17 BAD affects both adolescents and adults.17 18

Patients with BAD have increased fasting serum 7 alpha-hydroxy-4 cholesten-3-one (7αC4), an indirect marker for bile acid synthesis in the liver.19 Ileal absorption of bile acids normally stimulates the enterocyte nuclear receptor, farnesoid X receptor (FXR), leading to synthesis of fibroblast growth factor 19 (FGF-19), a portal circulation hormone that reaches the hepatocyte and inhibits bile acid synthesis. Thus, there is a reciprocal relationship between FGF-19 and serum 7αC4. The rate of synthesis of bile acids (indirectly measured by serum 7αC4) is directly proportional to faecal bile acid excretion over 48 hours. There are three biochemical parameters validated for diagnosis of BAD20: total 48-hour faecal bile acid, increased faecal primary bile acids in the stool and fasting serum C4 (collected before 9:00 hours). An additional method available in some countries is the scintigraphic test measuring 75-selenium homocholic acid taurine (75SeHCAT) retention after 7 days. Recent validation of combined fasting serum 7αC4 and primary bile acids in a single sample of stool21 or faecal bile acid concentration in a single stool sample22 provide opportunities for simplifying the diagnosis and decreasing the costs for diagnosis compared with the 75SeHCAT retention test.

The specificity of the serological tests approximates that of the 75SeHCAT and 48-hour faecal bile acid excretion tests. In addition, the combination of fasting serum 7αC4 and primary bile acids in a single stool21 has 68% sensitivity at 80% specificity receiver operating characteristic curve–area under the curve (0.86) for diagnosing BAD, relative to the gold standard 48-hour faecal bile acid excretion. It is anticipated that this simple combined serum and single stool test will become available in clinical practice in the near future. One could legitimately ask: Why still include the patients who have evidence of bile salt diarrhoea in IBS using Rome IV criteria, and should this group be excluded in future clinical trials of IBS-D? The current approach in IBS is to make a symptom-based diagnosis, and therefore, in the absence of simple and inexpensive screening tests, patients with BAD are included in IBS-D or functional diarrhoea. With the introduction and widespread availability of simple combined serum and single stool test, patients with BAD should be excluded from IBS-D diagnosis or clinical trials, just as patients with coeliac disease (with the same population prevalence of about 1%) are excluded based on screening serological testing for coeliac disease.

Carbohydrate maldigestion or malabsorption

The normal small intestine very avidly absorbs monosaccharides and disaccharides in the presence of normal disaccharidases; usually, these are absorbed within the first 2 m of the small intestine,23 24 and the absorption of monosaccharides is greater in the jejunum than the ileum.25 Monosaccharides and disaccharides are absorbed from the intestinal lumen at equal rates. Monosaccharides are transported by carrier-mediated mechanisms across the enterocyte brush border, and up to 50% of this transport is dependent on a sodium ion (Na+) gradient. There are five functional mammalian facilitated hexose carriers characterised by molecular cloning: 3 high affinity transporters of glucose (GLUT-1, GLUT-3 and GLUT-4) and one low-affinity transporter (GLUT-2), whereas GLUT-5 is primarily a fructose carrier. Because their Michaelis-Menten constant (Km) values (that is, substrate concentration at which the reaction velocity is 50% of the Vmax) are below the normal blood glucose concentration (6 mmol/L), the high-affinity transporters function at rates close to maximal velocity. Transport of glucose across the apical brush border of intestinal (and kidney) epithelial cells is an active process that requires the presence of a sodium (Na+) gradient, maintained by Na+, potassium (K+) and a group of enzymes that catalyse the hydrolysis of a phosphate bond in adenosine triphosphate (ATPases).26 Any maldigested or malabsorbed carbohydrates that reach the colon are metabolised by colonic bacteria with production of gas, carbon dioxide (CO2), and water, and increased osmotic load leading to diarrhoea. In fact, 25%–75% of patients with disaccharidase deficiency meet IBS criteria.27

Lactase deficiency

It is estimated that 65% of the human population has, to some extent, a reduced ability to digest lactose after infancy.28 The highest prevalence is in southeast Asia and South Africa, with lower prevalence in the Mediterranean littoral and far lower prevalence in more northern latitudes. It is relevant that, when lactose intake is limited to the equivalent of 240 mL of milk or less a day, symptoms are likely to be negligible and the use of lactose-digestive aids unnecessary.29

Sucrase-isomaltase deficiency

Recent literature in adults has identified sucrase isomaltase deficiency in adults with symptoms of IBS-D.30–33 This condition is more clearly recognised in paediatric practice. Four genetic mutations in the sucrase or in the isomaltase domain account for the most common nucleotide changes in children with congenital sucrase-isomaltase deficiency.30 In adults, the same four mutations in the sucrase or isomaltase gene and one other mutation controlling the stalk that anchors the protein in the cell membrane have been identified.31 The latter mutation has been shown to be associated with increased stool frequency.32 Sucrase maltase deficiency is more prevalent in patients with IBS than in controls: in one study,31 2.1% in IBS vs 1.2% in controls, and in another study,32 4% in IBS vs 2.8% in controls. Studies using the UK Biobank showed that patients with an International Classification of Diseases, 10th revision code diagnosis of IBS were more likely to have a significant OR for sucrase-isomaltase deficiency compared with controls, in contrast to patients with self-diagnosis of IBS33 for whom the OR was not significant. With more widespread recognition and availability of screening tests, sucrase-isomaltase deficiency would be separated from IBS-D.

Barrier dysfunction

Several published studies have documented increased intestinal or colonic permeability in patients with IBS34; the increased permeability predisposes to immune activation or inflammation.35 A systematic review identified that permeability was increased compared with healthy controls in IBS-D (9/13 studies) and in postinfectious-IBS (4/4 studies), but only in a minority of IBS-C (2/7 studies).36 In addition, there was a positive association between loss of barrier function and symptoms such as abdominal pain and changes in bowel function.36 The increased permeability was particularly noted in patients with BAD whose permeability was increased relative to IBS-D.37 Alternatively, increased permeability may be secondary to immune or mast cell activation.38 Although the systematic review36 suggested that urine collections of orally-administered probe molecules at 0–8 hours reflect proximal GI permeability, and 0–24 hours reflect lower GI permeability, a combined study of permeability using oral probes and imaging within the GI tract of concomitantly-administered radioisotopic markers show those timings reflect both proximal and distal GI permeability since urine collections at 0–2 hours reflect small bowel, 2–8 hours reflect both small bowel and colon, and 8–24 hours reflect exclusively colonic permeability.

Immune activation

Several lines of evidence document mucosal immune activation in IBS.

Numbers and activation of immunocytes

There is a higher number and activation of mucosal B cells and plasma cells in close proximity to mast cells, consistent with a local adaptive immune activation in IBS, with no increase in serum IgG in contrast to increased luminal IgG.39 In addition, recently acquired mechanistic evidence demonstrates increased release of nociceptive mediators by immune cells and the intestinal epithelium, leading to increased excitability of pro-nociceptive receptors of neurons leading to visceral hypersensitivity.38 Single-centre, proof-of-concept studies have documented the clinical efficacy in relief of pain as well as downregulation of nociceptive functions with non-sedating histamine H1 receptor (H1R) antagonist in IBS.15

Mucosal expression of immune mechanisms

The relationships of mucosal inflammation or immune activation and symptoms or subgroups of IBS have been studied. Evidence of immune activation in the rectum and left colon was documented, though there was no relationship to symptoms or predominant bowel disturbance.40 41 In a study of colonic mucosal biopsies from patients with IBS (30 females with IBS-C, and 31 females and 13 males with IBS-D) there were differential expressions of 181 genes in ascending colon and 199 genes in rectosigmoid colon. The majority were gene upregulations in IBS-D, with functions reflecting activation of inflammation genes, TRPV1 (visceral hypersensitivity) and neurotransmitters/receptors (specifically purinergic, gamma-aminobutyric acid and cannabinoid) (figure 1). Although gene differential expressions in the ascending and rectosigmoid colon mucosa of the IBS-C and IBS-D were different, the diverse upregulated genes involved immune functions, receptors, transmitters, ion channels and transporters in both IBS subgroups. Conversely, there was reduced expressions of peptidase inhibitor (PI) PI15 and PI16 genes that inhibit proteases in IBS-D, suggesting vulnerability of the mucosa to the effects of proteases (eg, pancreatic or bacterial) in IBS-D.42 The differential immune activation in ascending colon mucosal biopsies in 11 patients with BAD and 33 controls with IBS-D showed greater activation in BAD43 which is consistent with the detergency and mucosal irritation by bile acids, particularly the di-α hydroxy bile acids, chenodeoxycholic acid and deoxycholic acid.44 There were minimal differences in mucosal expression between ileal biopsies from patients with IBS-C or IBS-D and healthy controls.44 However, extensive studies conducted using jejunal mucosa obtained from patients with IBS have documented aberrant immunological responses, increased humoral immunity, disturbed molecular and functional intestinal epithelial barrier, impaired bile acid metabolism, proximity of plasma cells to nerves, mast cell activation and protease and neuropeptide signalling and dysbiosis that may be related to the origin of symptoms in IBS patients. These data also suggest the role of the small bowel in the pathophysiology of IBS, particularly IBS-D.39 45–47

Figure 1

Cellular mechanisms that are similarly or differentially expressed in colonic mucosa of patients with IBS-D compared with mucosa from patients with IBS-C. Mechanisms that appear in green boxes showed increased differential expression; those in orange boxes showed decreased expression; those in blue boxes showed similar expression in mucosa from IBS-D compared with mucosa from IBS-C. Reproduced from Camilleri et al.42 GABA, gamma-aminobutyric acid; IBS-C, irritable bowel syndrome-constipation; IBS-D, IBS-diarrhoea.

Immune activation and inflammation in diagnosis and treatment

To date, the role of mucosal immune activation in IBS has not been extensively explored in clinical diagnosis other than the appreciation of the overlap of symptoms between microscopic colitis and IBS-D48 and the recommendation to exclude microscopic colitis by measuring faecal calprotectin or lactoferrin. Other studies explored the efficacy of the anti-inflammatory 5-aminosalicylcic acid compounds in the treatment of IBS, without evidence of clinical benefit.49 50 Nevertheless, current evidence suggesting that immune activation contributes to the pathology seen in patients with IBS has been summarised elsewhere51 including the role of mast cells.

It is also conceivable that more widespread screening for BAD [in the overlap with IBS-D or microscopic colitis (see above)] may identify patients for more tailored treatments such as with bile acid sequestrants or, in the future, FXR agonists. Similarly, screening in urine for mast cell mediators52 such as histamine, p-hydroxybenzoic acid and azelaic acid, or in faeces might identify patients in whom mast cell activation underlies visceral hypersensitivity, providing support to treat these patients with mast cell stabilisers such as ketotifen53 or histamine H1 receptor antagonists such as ebastine.15

Chemicals released in association with immune activation

Several chemical and molecular factors in the intestine are reported to be altered and to have potentially significant roles in IBS, particularly in IBS-D. These include bile acids, short-chain fatty acids, mucosal barrier proteins, mast cell products such as histamine, proteases and tryptase, enteroendocrine cell products and mucosal messenger RNA, proteins and microRNAs.54

The biochemical mechanisms have been reviewed recently with particular emphasis on how immune mediators, particularly those released by mast cells, can directly activate or sensitise pain-transmitting nerves, leading to increased pain signalling and abdominal pain.51 The putative mechanisms include several mechanisms involved in visceral hypersensitivity such as histamine, serotonin, proteases and nerve growth factor (NGF), all of which have been demonstrated in mucosa of patients with IBS, as reviewed by Aguilera-Lizarraga et al.51 Thus, histamine acts on histamine H1 receptors to sensitise TRPV1, TRPA1 and TRPV4 channels via H1R. Histamine and serotonin increase TRPV4 expression and translocation to the membrane in nociceptors leading to neuron hypersensitivity. Trypsin and other proteases in the mucosa lead to protease-activated receptor 2; a gene-protein-coupled receptor] endocytosis mediating persistent afferent hyperexcitability, likely through sensitisation of the same TRP channels. Increased levels of NGF, produced by mast cells, increase nerve fibre density. Along the same line, increased nerve sprouting was also observed with increased levels of brain-derived neurotrophic factor.51

The origin of mucosal immune activation in IBS is thought to result from altered food-derived or bacterial products following dysbiosis,55 or a disrupted epithelial response. For example, the bacterial metabolite, tryptamine, which stimulates colonic mucosal secretion, was increased in patients with IBS-D and was associated with an enrichment in inflammation-related pathways56; however, the studies were conducted in small numbers of patients with flares in IBS and require replication. Another example is the demonstration that a Klebsiella aerogenes strain, carrying a histidine decarboxylase gene variant, produces high amounts of histamine leading to mastocytosis and to mast cell activation via histamine-H4 receptors leading to the release of histamine and proteases that induce visceral hypersensitivity.57

Alternatively, it is hypothesised that mast cell activation may be directly induced by bacterial or food-derived products, as well as by neurogenic inflammation and psychological stress. The evidence of food antigen induced local inflammation in 12 patients with IBS compared with 8 healthy controls (with allergic diathesis or mast cell problems excluded in all participants) was demonstrated in elegant studies of intramucosal injection of the antigens (soy, wheat, gluten and milk) into rectosigmoid mucosa and observation of mucosal reactions. This study characterised a peripheral mechanism that underlies food-induced abdominal pain on loss of local oral tolerance, mediated by food antigen specific IgE-dependent activation of mast cells in the colon,58 and resulting in sensitisation of TRPV1 mediated by H1R in IBS. These findings explain the observation that treatment with ebastine, a H1R antagonist, reduced visceral hypersensitivity and abdominal pain in patients with IBS.15 Along the same line, confocal laser endomicroscopy studies had previously shown that the duodenal mucosa of patients with IBS undergoes profound structural remodelling on exposure to food antigens.59 Prior study has also documented that gluten intolerance without coeliac disease is more likely in carriers of the HLA DQ2/8 genotype.60

The microbiome

The healthy intestinal microbial community can be characterised in terms of diversity, stability and resistance, and resilience.61 Intestinal dysbiosis refers to the compositional and functional alterations of the gut microbiome and may be associated with one or more of the following non-mutually exclusive characteristics: bloom of pathobionts, loss of commensals and loss of diversity. The mechanisms that contribute to the development and maintenance of a dysbiotic state are infection and inflammation, diet and xenobiotics, genetics, familial transmission and other causes, such as circadian disruption, maternal high-fat diet, pregnancy and physical injury.62

A systematic review and meta-analysis of the literature on microbiota in IBS concluded that there is not a true microbial signature associated with IBS, no overt or demonstrable differences between microbiome of patients with IBS-D compared with IBS-C, and the quality of evidence is not ideal.63 Further longitudinal studies of the microbiome conducted in about 30 individuals with IBS-C, IBS-D, and healthy controls also showed significant overlap, though there was evidence of differences in beta-diversity between the groups. Moreover, it is interesting to note that there appeared to be differences in the microbiota in about six patients with IBS-D and six patients with IBS-C who experienced a flare of their symptoms.56 The diagnostic and therapeutic significance of the characterisation of the microbiome in IBS has still not reached clinical significance, and the role of faecal microbiota transplantation (FMT) is discussed below.

Actionable biomarkers

Table 1 summarises the pathophysiological mechanisms discussed above and illustrates the application of the pathophysiology-actionable biomarker approach to managing patients with IBS.64

Table 1

Application of pathophysiology-actionable biomarker approach to managing patients with IBS (derived from Camilleri and Chedid)64

The utility of many of these tests and their sensitivity, specificity and predictive values have been reported, although predominantly from the studies previously reported from Mayo Clinic where this approach has been put into practice.2 4 64–72 It is important to note that the most invasive biomarkers are based on physical examination, noninvasive tests other than the minimally invasive anorectal manometry and balloon expulsion tests.

Treatment strategy

First steps

Recommendations from several gastroenterology societies (European, American, Canadian, Japanese, British societies)73–79 provided general principles regarding education, doctor–patient relationship, diverse diet options and first-line symptomatic treatments including osmotic laxatives for constipation, loperamide for diarrhoea, simple psychotherapy and first-line anti-spasmodics. Some guidelines go on to prioritise the sequence of pharmacological agents and brain–gut behaviour therapy that are recommended for moderate and severe IBS.77 78 Based on the rich evidence of mechanisms and biomarkers identified in IBS and documented in this review, using the algorithmic approach to treatment based on symptoms and response to the three tiers of treatment (figure 2), one might miss opportunities for optimising management of IBS.

Figure 2

Clinical decision support tool developed by the American Gastroenterological Association guideline committee for diarrhoea or constipation in IBS. Reproduced from Lembo et al 77 and Chang et al 78. Note that tegaserod has since been withdrawn and is unavailable for prescription. AGA, American Gastroenterological Association; FODMAP, fermentable oligosaccharides, disaccharides, monosaccharides and polyols; IBS, irritable bowel syndrome; IBS-C, IBS-constipation; IBS-D, IBS-diarrhoea.

Dietary approaches

Dietary approaches include increase in soluble fibre, low fermentable oligosaccharides, disaccharides, monosaccharides and polyols (FODMAP) diet and gluten-free diet. Soluble fibre or psyllium is more efficacious than bran if patients have abdominal pain and discomfort with IBS.80 There are several relatively small low FODMAP diet trials and several systematic reviews and meta-analyses in the literature. In addition to questions that have been posed regarding blinding and trial design, the efficacy over placebo or other diets (eg, National Institute for Health and Care Excellence (NICE) and British Dietetic Association recommended diets) is marginal or quite comparable.81 82

It is nevertheless intriguing that basic science studies show that low FODMAP diet may reduce the transfer of endotoxin (lipopolysaccharide) across the mucosa in an animal model, and this is associated with less contraction of the abdominal musculature measured by electromyography in response to exposure of the rectal mucosa of the animal to the supernatant of stool of patients with IBS, which presumably has the high level of faecal endotoxin.83 84 A recent study indicated that FODMAPs favour the production of faecal histamine by Klebsiella aerogenes in a subgroup of IBS patients, leading to mast cell accumulation and visceral hypersensitivity in mice.57 These patients had high urinary histamine, indicating that urinary histamine might be a biomarker to identify patients that may benefit from low FODMAP diet or treatment with H1R antagonists.57 Moreover, a reanalysis of data from a trial of low FODMAP diet in IBS,52 revealed a moderate correlation (r=0.44, p=0.009) between visceral pain severity and the concentration of urinary histamine.57 It has recently been proposed that not all FODMAPs are created equal and that fructans are significant detrimental molecules.85 86 This observation was consistent with physiology of saccharide absorption in the human small intestine (as discussed above).

The American College of Gastroenterology guideline supports a limited trial of a low FODMAP diet to improve global symptoms while acknowledging that this is a conditional recommendation based on very low-quality evidence and a high risk of bias.73 A recent American Gastroenterological Association clinical practice update guideline87 recommended following a three-phase sequence: (1) restriction (lasting no more than 4–6 weeks), (2) reintroduction of FODMAP foods and (3) personalisation based on results from reintroduction. However, managing the reintroduction and personalisation of the diet has not been adequately studied and there are several potential deficiencies including complexity, cost, greatest effectiveness when administered by a specialised GI dietician and possible negative or unknown impacts on quality of life, the gut microbiota, potential for development of avoidant/restrictive food intake disorder, cibophobia and nutritional deficiencies. Thus, in addition to strategies for lactose intolerance, a case can be made for individualising food restriction such as avoiding fructans, galactans and sugar alcohols that are poorly metabolised in the human small intestine, reach the colon and are fermented by bacteria to increase osmolality and gas production.

The evidence of efficacy of gluten withdrawal in patients with IBS is unproven based on two randomised controlled trials involving 111 participants who responded to a gluten-free diet and then randomised to continue the diet or diet ‘spiked’ with gluten (RR 0.42; 95% CI 0.11 to 1.55).88 However, a prospective study of 50 patients with IBS documented that the presence of antigliadin IgG was associated with overall reductions in symptoms (adjusted OR compared with patients without this antibody, 128.9; 95% CI, 1.16 to 1427.8; p=0.04).These data suggest that antigliadin IgG can be used as a biomarker to identify patients with IBS who might have reductions in symptoms, particularly diarrhoea, on a gluten-free diet.89 However, it has been demonstrated that the presence of IgG antibodies is also a sign of exposure to a food antigen.90

A novel approach to correcting sucrase-isomaltase deficiency has been reported, and it is analogous to supplementation of lactase enzyme in patients with hypolactasia. This approach uses a commercially available enzyme called sacrosidase, which was shown to reduce symptoms and breath hydrogen in a sucrose challenge test in a 23-year-old patient with postprandial diarrhoea since infancy associated with bloating, abdominal pain and nausea.91

Pharmacological agents

Table 2 summarises the evidence of the efficacy of treatments with diverse pharmacological approaches in IBS based on summary analyses such as systematic reviews and meta-analyses.92–94

Table 2

Summary of current medications approved (in at least some countries) for treatment of IBS symptoms (updated from references92–94)

In clinical practice, pharmacological agents are often prescribed in patients with IBS.

For relief of pain associated with IBS, there are limited data on efficacy of antispasmodics, with the greatest efficacy reported for agents acting on calcium channels (most unavailable in many countries such as USA) or peppermint oil. A single-centre study documented improvement of pain in IBS patients treated with the H1 receptor blocker, ebastine.15 Although widely used and recommended, the evidence in support of central neuromodulators (mostly antidepressants) is relatively weak as it is based on only three high-quality trials, possible publication bias and overestimated efficacy by inclusion of smaller trials with unprecedented response rates (eg, 10% responders in placebo arm).95 96 Analysis of publications with network meta-analysis reported that, among medications for the relief of pain in IBS, the order for relative efficacy was tricyclic agents, followed by antispasmodics and peppermint oil, with non-significant benefit for selective serotonin reuptake inhibitors and ispaghula husks.95

The first-line approach of treatment of constipation (PEG 3350) has not been formally evaluated in IBS-C. On the other hand, there are extensive studies of diverse chloride secretagogues (lubiprostone, linaclotide and plecanatide), and the sodium hydrogen exchanger inhibitor 3 (NHE3), tenapanor. A systematic review and meta-analysis documented the efficacy of all these medications in achieving the USA Food and Drug Administration (FDA) recommended composite endpoint for IBS-C, that is the relief of constipation and pain components.93 Although the 5-HT4 receptor agonist, tegaserod, was approved for patients with IBS-C under the age of 65 years without cardiovascular disease, it was recently withdrawn from some markets (eg, USA) for commercial reasons.

For IBS-D, loperamide is usually the first-line therapy, although it has not been tested in large studies in IBS. Eluxadoline has effects on multiple opioid mechanisms, and its greatest benefit is in relief of diarrhoea with limited efficacy on pain. It must be used with great caution as it can cause sphincter of Oddi spasm and pancreatitis and is contraindicated in patients with cholecystectomy. As a class, 5-HT3 receptor antagonists are very efficacious for treatment of IBS-D, and network meta-analyses place them at the highest level for efficacy in the relief of abdominal pain and stool consistency, as well as global IBS symptoms, compared with rifaximin and eluxadoline.97 It is worth noting that rifaximin’s efficacy in patients with IBS-D, as demonstrated in single and repeat treatment trials was greater for global symptoms, bloating and the composite FDA endpoint, but not for diarrhoea or stool consistency.98 99 These observations are not surprising given the fact that rifaximin actually accelerates colonic transit100 and that it has only modest and transient effects on gut microbial taxa.101

Only open-label studies are available to support bile acid sequestrants efficacy in BAD.

Faecal microbial transplantation

Based on systematic reviews and meta-analyses, there is equivocal data regarding the efficacy of FMT for IBS. A recent report of 3-year outcomes of treatment of IBS with FMT provided by a single super donor102 or from treatment of IBS in primary care centres in Belgium103 support the use of FMT for IBS. However, pitfalls identified in study design and questions regarding clinical relevance of 50-point response on the 500-point IBS-Symptom Severity Scale104 105 suggest that evidence of significant clinical efficacy or effectiveness is still required. Therefore, further research is needed to identify the beneficial microbiota and the mechanism involved to ideally transfer a selection of well-characterised ‘therapeutic’ microbiota and to avoid the risk of introducing potential pathogens.

Treatment: from choice based on symptoms to strategy based on pathophysiological mechanisms

Figure 2 documents the clinical decision support tool developed by the AGA guideline committee for diarrhoea or constipation in IBS.77 78 It essentially provides four tiers of management: first, general measures including diet; second, first-line treatments based on mild symptom severity and bowel dysfunction; third, second-line approaches for moderate severity symptoms based on bowel dysfunction; and fourth, based on third-line treatments or centrally directed pharmacological or behavioural treatments.

There are several controversial choices in the proposed tiers. Should bile acid sequestrants be applied as first-line empiric treatment in the absence of a diagnosis, given the availability of serum or single faecal sample diagnostic tests? Where they are available, should rifaximin and eluxadoline be applied ahead of alosetron, given the level of evidence of efficacy of alosetron and the cumulated evidence of safety of that medication, the limited efficacy of rifaximin (which accelerated colonic transit) for diarrhoea, and the relative risks associated with eluxadoline and contraindication in patients with prior cholecystectomy?

All these insights and the opportunity to individualise treatment based on identified pathophysiological mechanisms as shown in tables 1 and 2 led to the recommendations in figure 3 where therapeutic choices are guided by pathophysiology and biomarkers.

Figure 3

Therapeutic choices guided by pathophysiology and biomarkers. 5-HT3, 5-hydroxytryptamine; CBT, cognitive behavioral therapy; FMT, faecal microbiota transplantation; SNRI, serotonin and norepinephrine reuptake inhibitor; SSRI, selective serotonin reuptake inhibitor.

Conclusion

The widespread availability of noninvasive clinical tests that can appraise the mechanisms responsible for symptom generation in IBS provides the opportunity to advance the practice from treatment based on symptoms to individualisation of treatment guided by pathophysiology and clinically identified biomarkers.

Data availability statement

All data relevant to the study are included in the article.

Ethics statements

Patient consent for publication

Acknowledgments

The authors thank Mrs. Cindy Stanislav for excellent secretarial assistance.

References

Footnotes

  • Correction notice This article has been corrected since it published Online First. The article type has been changed to

    Recent Advances in Clinical Practice.

  • Contributors MC: guarantor of the article; initial conceptualisation, first and subsequent drafts; GB: conceptual feedback, scientific verification, editing of all drafts of manuscript.

  • Funding MC: grant R01-DK115950 from National Institutes of Health; GB: Leuven University internal funding grant C1 (C14/18/086).

  • Competing interests MC: consulting regarding irritable bowel syndrome for Ironwood; Protagonist Therapeutics; Zealand Biopharma; Aditum Bio; Invea Therapeutics and InveniAI.

  • Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

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