Irritable bowel syndrome management: current insights

INTRODUCTION

Irritable bowel syndrome (IBS) is a highly prevalent functional gastrointestinal (GI) disorder (FGID) characterised by recurrent abdominal pain or discomfort and altered bowel habits, and is defined by Rome IV criteria based on predominant symptom presentation: constipation-predominant (IBS-C), diarrhoea-predominant (IBS-D), mixed (IBS-M; based on stool form or frequency) or unclassified.[1] The pathophysiology is complex and multifactorial,[2,3] affecting millions worldwide and significantly impacting quality of life.[4]

Beyond the symptom-based subgrouping of IBS defined by Rome IV criteria, growing evidence has unravelled the complex biological mechanisms in IBS, and this has allowed us to bridge pathophysiological understanding with clinical management. In recent years, new treatment options that target key mechanisms in IBS have been developed, allowing for targeted therapeutic strategies that address the underlying pathophysiology. In a recent case-controlled study, IBS patients demonstrated higher levels of adrenocorticotropic hormone, cortisol, serotonin (5-HT) and proinflammatory markers (IL6, IL8) and lower anti-inflammatory cytokine (IL10) compared to controls. In addition, Bacteroides was more prevalent in IBS patients compared to controls, while Bifidobacteria, Lactobacillus and Clostridium showed opposite trends.[5] Thus, IBS is a complex product of a biopsychosocial mechanism where genetic, epigenetic and environmental factors interact with psychosocial elements and intrinsic physiological dynamics of the gut regulated by neurotransmitters and gut microbiota to produce the clinical phenotype of FGIDs.[2,3,4,6,7] Table S1 (Supplemental Digital Appendix) summarises the different pharmacological approaches in IBS based on the current literature.

First-line therapies target the predominant symptom. For IBS-D, loperamide is recommended, although evidence is limited.[8] For IBS-C, an increase in dietary fibre intake, particularly soluble fibre, improves constipation but has less prominent effects on other IBS symptoms.[9] Polyethylene glycol is an osmotic laxative that is well established for IBS-C.[10] Antispasmodics are often used as first-line for pain-predominant IBS. Peppermint oil exerts its effects through calcium channel antagonism, κ-opioid agonist effects affecting gut sensitivity, anti-inflammatory action, serotonergic antagonism and analgesic properties. Meta-analyses have demonstrated its superiority compared to placebo for global IBS improvement.[11,12,13] New treatment options address various factors relevant to symptom generation in IBS. These include the gut microenvironment (via diet and modulation of gut microbiota), intestinal secretagogues, motility and sensation, gut–brain interactions, the immune system within the GI tract, and agents acting on bile acids.[6,7,8,14,15]

MANAGEMENT OF IRRITABLE BOWEL SYNDROME

Dietary modifications

Patients with IBS often report worsening of symptoms after certain foods.[16,17] Foods rich in fermentable oligosaccharides, disaccharides, monosaccharides and polyols (FODMAPs) are incompletely absorbed in the small intestine and undergo colonic bacteria fermentation, leading to rapid gas accumulation and short-chain fatty acid production, which may overstimulate chemosensing enteroendocrine cells, leading to luminal distension and discomfort.[18,19] Based on network meta-analyses, a low-FODMAP diet outperforms other dietary interventions in overall IBS symptoms, but these studies did not evaluate the effects of FODMAP reintroduction or dietary personalisation on symptom outcomes.[20,21,22] The American College of Gastroenterology (ACG) supports a limited trial of a low FODMAP diet to improve global symptoms whilst acknowledging that evidence is of low quality.[15] Concerns about cost-effectiveness, complexities surrounding food reintroduction impact on quality of life, and the development of avoidant/restrictive food intake disorder are significant limitations. Although a gluten elimination diet may control IBS symptoms even in the absence of coeliac disease,[23] a gluten-free diet is essentially a diet low in FODMAPs.[24] In addition, emerging evidence suggests that wheat induces intestinal immune activation and mucosal damage.[25] Evidence is currently lacking to support a gluten-free diet for IBS.

Gut microbiome-directed therapies

Microbial dysbiosis, characterised by a reduction in microbial diversity, overgrowth of pathogenic bacteria and decrease in beneficial species, may lead to altered bile acid metabolism, short-chain fatty acid production and low-grade immune activation. These microbial shifts can induce toll-like receptor (TLR) signalling and upregulate pro-inflammatory cytokines, leading to disruption of tight junction proteins, impaired barrier integrity and microbial translocation.[26] Microbiome-directed strategies restore intestinal microbial balance. Rifaximin is an oral, nonsystemic and broad-spectrum antibiotic. It reduces small intestinal bacterial overgrowth, dampens TLR-mediated inflammation, and positively influences mucosal inflammation, impaired intestinal barrier function and visceral hyperalgesia, leading to relief of bloating, global symptoms and the composite United States Food and Drug Administration (FDA) endpoint.[27,28] Rifaxamin is approved for IBS-D, including retreatment for up to two times.[28]

Probiotics, including those with Lactobacillus and Bifidobacterium strains, alleviate IBS symptoms through their ability to modulate immune response, promote gut barrier function, alter gut microbiota composition and gut–brain communication, and reduce visceral hypersensitivity.[26,29] Published literature supports an overall benefit of probiotics with no clear evidence of the superiority of one probiotic over another.[30,31] Faecal microbiota transplantation restores microbial homeostasis in IBS[32] and improves stool consistency, bloating and quality of life.[33,34] Although promising results have been shown in two controlled trials,[34,35] more studies are awaited.

Intestinal secretagogues: role in IBS-C

Intestinal secretagogues increase luminal water content through activation of chloride (Cl) secretion by Cl-channel type-2 channels (lubiprostone),[36,37] through activation of the guanylate cyclase receptor and cystic fibrosis transmembrane conductance regulator channel (linaclotide[38,39] and plecanatide[40,41]) or through inhibition of sodium reuptake by the sodium-hydrogen exchanger-3 (NHE-3 tenapanor).[42] Both lubiprostone[36,37] and linaclotide[38,39] improve stool frequency and consistency, and ease of evacuation in IBS-C patients, but linaclotide has additional effects on relief of pain and bloating.[43,44] Tenapanor improves IBS-C symptoms for up to 26 weeks,[42] including abdominal pain and bloating.[45] In a systematic review and meta-analysis of Cl secretagogues, linaclotide 290 μχγ once daily ranked highest in achieving the FDA recommended composite endpoints of relief of both constipation and pain.[46]

Gastrointestinal motility: role of serotonin

Serotonin, or 5-hydroxytryptamine (5-HT), is an important modulator of GI motility and sensitivity.[47] Upregulation of 5-HT₃ receptors in IBS-D and downregulation of 5-HT₄ receptors in IBS-C have been observed. Drugs with 5-HT₃ receptor antagonism include alosetron,[48] which is available only in a limited use programme in the USA due to risks of ischaemic colitis and severe constipation,[49] and ramosetron, which is approved in Japan.[50,51] An earlier study of ondansetron, a first-generation 5-HT₃ antagonist, showed improved stool consistency and urgency in IBS-D patients,[52] but larger studies are in the pipeline. Conversely, 5-HT₄ drugs stimulate motility and secretion through enhanced release of acetylcholine. Prucalopride, a 5-HT₄ agonist, has a more selective and safer pharmacological profile[53] compared to tegaserod, which has been withdrawn, although prucalopride’s efficacy has been demonstrated only in trials of chronic constipation.[54]

Gut–brain interactions

The enteric nervous system shares its embryologic development with the brain and spinal cord. This gut–brain axis, with its norepinephric, serotonergic and dopaminergic neurotransmitters, is crucial in gut motor function and visceral sensation.[55] Various low-dose antidepressants, referred to as gut–brain neuromodulators, are used as second-line treatment options, including tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors and mirtazapine.[56] Among these drugs, SSRIs, which act only on 5-HT receptors, have the least analgesic effect and are not strongly recommended by ACG guidelines.[15] Based on network meta-analysis, TCAs, followed by antispasmodics and peppermint oil, were the most efficacious, with non-significant benefit achieved with SSRIs and ispaghula husk.[12]

Opioid receptors are expressed along the GI tract and play a key role in GI secretion, motility and visceral sensation. Eluxadoline is a mixed μ-opioid and κ-opioid receptor agonist and κ-opioid receptor antagonist available in the USA and Europe for IBS-D.[57,58] However, it is associated with risks of acute pancreatitis and sphincter of Oddi spasm and is contraindicated in patients with prior cholecystectomy.[57,59] Various intestinal secretagogues are efficacious in pain control. For IBS-C, linaclotide 290 μχγ once daily and tenapanor 50 mg twice daily ranked first and second, respectively, for reducing abdominal pain.[46] For IBS-D, ramosetron 2.5 μχγ once daily, ramosetron 5 μχγ once daily and alosetron 1 mg twice daily ranked first, second and third, respectively, for reducing pain.[60] The 5-HT₃ receptor antagonists (ondansetron, alosetron and ramosetron) retard colonic transit and reduce visceral pain, placing them as a class with the highest level of efficacy for relief of pain and diarrhoea compared to rifaximin and eluxadoline.[60,61]

Immune modulators

Immune activation has been increasingly recognised in IBS pathophysiology, especially in post-infectious IBS. Proinflammatory mediators released by mast cells and proinflammatory cytokines, such as IL-6 and TNF-α, disrupt tight junction proteins and impair barrier integrity, leading to microbial translocation, sensitisation of afferent neurons and visceral hypersensitivity. However, results have been inconsistent for the anti-inflammatory drug mesalamine,[62] which is not recommended as a standard of care in current guidelines.[63] Beyond mesalamine, other immune-targeted therapies, including neurokinin receptor antagonists,[64] which are also not recommended as a standard of care in current guidelines,[65] have shown symptomatic improvement in early studies, although further studies are required to establish their efficacy.

Bile acid modulation

Increased bile acid loss into the colon may occur in IBS-D.[66,67,68] Bile acids, which are normally reabsorbed in the terminal ileum, can accumulate in the colon and stimulate secretion and motility, causing diarrhoea. Bile acid sequestrants not only bind intraluminal bile acids, but also have additional effects, including modification of colonic mucosal gene expression by downregulating nuclear farnesoid X receptor and membrane Takeda G protein-coupled receptor 5, in turn influencing epithelial and immune signaling pathways.[66,67,68] However, these agents may cause side effects, including bloating and constipation. Conversely, in IBS-C, increasing colonic bile acid concentration through antagonism of the ileal bile acid transporter improves both colonic water content and GI motility.[69]

Gut barrier dysfunction

Increased intestinal permeability contributes to immune activation and systemic inflammation. Gut barrier stabilising therapies include tenapanor, a minimally absorbed inhibitor (NHE-3), which is approved for IBS-C. Besides its effects on intestinal sodium handling, tenapanor increases intestinal barrier integrity and reduces visceral hypersensitivity.[42,70]

CONCLUSION

Novel treatment options target key underlying mechanisms in IBS pathophysiology. Rome IV criteria have laid the groundwork for a revolution, likely to continue with Rome V criteria, where FGIDs are defined as disorders of gut–brain interaction.[4,6] A combination of dietary, pharmacological and microbiome-based therapies reflects a shift from symptom-based management towards a personalised, mechanism-based treatment approach.

Conflicts of interest

There are no conflicts of interest.

Supplemental digital content

Appendix at http://links.lww.com/SGMJ/A328

APPENDIX

Table S1.

Treatment class	Drug Name	Dosage	Mechanism of action	Evidence/Reference
Pain
Anti-spasmodics	Hyoscine	10-20mg tds	Inhibition of muscarinic Ach receptors	OR 0.68 (0.57-0.71) NNT :3.5 Quartero et al.,2005 [1]; Ford et al., 2008 [2]
	Cimetropium otilonium/ pinaverium	50mg bd tds (cimetropium) 40mg bd/tds (otilonium) 50mg-100mg tds (pinaverium)	Block Ca2+ channels in smooth muscles	NNT cimetropium, 3; otilonium, 4.5; pinaverium, 3 Quartero et al.,2005 [1]; Ford et al., 2008 [2]
	Peppermint oil	Colpermin (1 tab to 2 tab tds)	Anticholinergic + calcium channel blocker, activates TRPM8 receptors on nociceptive afferents	OR: 0.43 (0.32-0.59); global RR 2.23 (1.78-2.81); NNT 2.5 Ford et al., 2008 [2] ; Black et al., 2020 [3]; Khanna et al 2014 [4]
Anti-depressants	TCAs, SSRIs, SNRIs	Amitriptyline (10-50mg/day) Desipramine 25-100mg/day) Paroxetine (10-40mg/day) Sertaline (25-100mg/day)	Psychological, antinociceptive effects	OR global symptoms 0.67 (0.58-0.77); OR abdominal pain 0.62 (0.43-0.88); NNT 4 Black et al., 2020 [3]; Ford et al., 2014 [5]
CONSTIPATION
Osmotic	PEG	Macrogol/Forlax	Osmotic secretion	Improvement in SBMs and CSBMs; no effect on pain/bloating/incomplete evacuation Chapman et al., 2013 [6]
Secretory	Lubiprostone	8-24 ug bd	Cl channel activator and CFTR stimulate Cl secretion	Pooled analysis from 2RCTs: response rate 17.9% vs 10.1% (placebo) for moderate relief of global symptoms for 2 of 3 months Drossman et al 2009 [7]; Chey 2012 [8]
	Linaclotide	290 ug om	Guanylate cyclase-C activator, stimulates Cl and water secretion via CFTR; visceral analgesic	Adequate relief of IBS: RR 1.95 (1.3-2.9); Abdominal pain RR 1.58 (1.02-2.46) for 290 μg Videlock et al 2013 [9] Luthra et al 2019 [10]
	Plecanatide	3mg-6mg om		FDA composite endpoint for 6 mg: RR 0.87 (0.81-0.94); 3mg RR 0.88 (0.82-0.94) Brenner et al 2018 [11] ; Barish et al 2018 [12]
Anti-absorptive	Tenapanor	50mg bd	NHE3 inhibitor stimulates Na+ and water secretion	35.5%(Tenapanor) vs 24.3% (Placebo) achieved abdominal pain response and CSBM response for 13 of 26 weeks. Chey et al 2021 [13]
5HT4 receptor agonists	Prucalopride	1-2mg om	Stimulates colonic motility and transit	RR for 2mg: 0.82 (0.78-0.86) for failure to achieve ≥ 3 CSBM/week Luthra et al 2019 [10]
IBAT inhibitor	Elobixibat	5-15mg om	Increases colonic bile acid levels to induce motility and secretion	Effective for chronic constipation 5mg: RR 0.90 (0.83-0.98); 10mg: RR 0.96 (0.89-1.04) Nakajima et al 2018 [14]
DIARRHOEA
Opioid agents	Loperamide	2-16mg/day	μ-opioid agonist inhibits secretion/transit	Effective for diarrhoea; not evaluated in IBS
	Eluxadoline	75-100mg bd	k- and μ-opioid receptor agonist; 𝛿 -opioid receptor antagonist	Effective for FDA-composite endpoint (pain+diarrhoea) 100mg: OR 0.87 (0.83-0.91) Effective for composite diarrhoa+pain; diarrhoea alone but not pain alone Black et al., 2020 [15]
5HT3 receptor antagonists	Ondansetron Alosetron Ramosetron	Ondansetron 4-8mg tds Alosetron 1mg bd Ramestron 5-10mcg/day	Slows colonic transit, pain relief	Global RR 1.60 (1.49-1.72); Pain RR 1.30(1.22-1.39); FDA composite: OR 0.69 (0.60-0.80) Ondansetron: Effective for diarrhoea/urgency/bloating, not for pain Alosetron/Ramosetron: Effective for composite diarrhoea + pain; diarrhoea alone; pain alone Black et al., 2020 [15]; Andresen et al., 2008 [16]
Bile acid sequestrants	Cholestyramine Colestipol Colesevelam	Cholestyramine 4-12g/day Colestipol 5-30g/day Colesevelam 2.5-3.75g/day	Binds intraluminal bile acids	Efficacy in open-label studies; ineffective in one RCT Vijayvargiya et al 2020 [17] ; Camilleri et al 2015 [18] ; Bajor et al., 2015 [19]
Antibiotic	Rifaxamin	550mg bd-tds for 14 days	Non-absorbable antibiotic	FDA composite: OR 0.92 (0.87-0.98) Global OR 0.91(0.77-1.07) Black et al, 2020 [15]; Menees et al 2013 [20]

Adapted from

1. Camilleri M, Boeckxstaens G. Irritable bowel syndrome: Treatment based on pathophysiology and biomarkers. Gut 2023; March72(3):590-99.

2. Camilleri M. Diagnosis and treatment of irritable bowel syndrome. A review. JAMA 2021;325: 865-877.

Abbreviations: Ach: acetylcholine; OR: odds ratio; RR: relative risk; NNT: number needed to treat; TRPM 8: transient receptor potential cation channel subfamily melastatin member 8; TCA: tricyclic antidepressant; SSRI: selective serotonin reuptake inhibitor; SNRI : selective serotonin norepinephrine reuptake inhibitor; PEG: polyethylene glycol; SBM: spontaneous bowel movement; CSBM: complete spontaneous bowel movement; Cl: chloride; CFTR: cystic fibrosis transmembrane conductance regulator; Ca: calcium; NHE₃ : sodium-hydrogen exchanger-3; Na⁺ : sodium; 5HT₄ :serotonin type 4; FDA: US Food and Drug Administration; RCT: randomized controlled trial.

Funding Statement

Nil.