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Irritable Bowel Syndrome (IBS) — Detailed Notes

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1. DEFINITION

• Recurrent abdominal pain in association with altered bowel habits
• Occurring in the absence of a detectable structural or organic abnormality of the gut
• No clear diagnostic (pathognomonic) markers exist; diagnosis is therefore based on clinical presentation

Rome IV Update (2016): The Rome III criteria were updated to Rome IV. The key change is that Rome IV requires abdominal pain to occur at least once a week (more stringent), and eliminates "discomfort" as an acceptable criterion. Painless diarrhoea or constipation alone does NOT fulfil diagnostic criteria for IBS.

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2. EPIDEMIOLOGY

• Estimated worldwide prevalence: ~5% (one source); other sources cite 10–20% of adults and adolescents globally have symptoms consistent with IBS
• In Western populations: up to 1 in 5 people report IBS-consistent symptoms
• IBS accounts for ~40% of all referrals to gastroenterology
• Up to 40% of all patients seen in specialist gastroenterology clinics have IBS
• Young women are affected more often than men (women diagnosed 2–3× more frequently; make up 80% of those with severe IBS)
• Most patients have their first symptoms before age 45
• Significant socioeconomic burden: ~£45.6 million annually to UK healthcare; ~$8 billion in the USA
• ~25% of UK IBS patients take 7–13 days off work per year

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3. AETIOLOGY (ETHOLOGY)

A. Behavioural and Psychosocial Factors

• Early life adversity: Learning difficulties or emotionally challenging interactions during childhood may contribute to IBS in later life
• Psychiatric illness: ~50% of hospital-referred IBS patients have a psychiatric illness (anxiety, depression, somatisation, neurosis, panic attacks). General practice patients are less likely to have psychological problems
• Psychological stress: Acute stress and overt psychiatric disease alter visceral perception and GI motility
• Abuse history: Prior sexual, physical, or verbal abuse is associated with IBS development; linked to greater pain reporting, psychological distress, and poor health outcomes
• Abnormal illness behaviour: Frequent consultations for minor symptoms, reduced coping ability
• Adverse life events: Psychological stress, occupational dissatisfaction, and difficulties in interpersonal relationships precede exacerbations

B. Physiological / Genetic Factors

• Brain–gut axis dysregulation is central to IBS pathogenesis
• Serotonin (5-HT) dysregulation:
  • Relatively excessive 5-HT release in IBS-D (diarrhoea-predominant)
  • Relative 5-HT deficiency in IBS-C (constipation-predominant)
• SERT polymorphisms: Serotonin reuptake transporter gene polymorphisms affect IBS habit subtypes; SERT expression is downregulated in IBS due to gram-negative gut dysbiosis
• TPH1 polymorphism: Tryptophan hydroxylase 1 (rate-limiting enzyme in enterochromaffin serotonin synthesis) polymorphism is associated with IBS habit subtypes
• Twin studies support a genetic component

C. Luminal (Gut Environment) Factors

• Gut dysbiosis (altered flora): Both quantitative and qualitative alterations in intestinal bacterial microbiota
  • ↓ Bifidobacterium and Faecalibacterium (anti-inflammatory, butyrate-producing organisms)
  • ↑ Enterobacteriaceae, Lactobacillaceae, Bacteroides (potentially pro-inflammatory)
  • Increased Firmicutes-to-Bacteroidetes ratio; decreased microbiota diversity
• Small Intestinal Bacterial Overgrowth (SIBO): Present in some patients
• Bile acid malabsorption: Up to 30% of IBS-D patients may have this
• Dietary factors / FODMAPs: Chemical food intolerances (not allergy) to fermentable oligo-, di- and monosaccharides, and polyols (FODMAPs) — e.g., lactose, fructose, sorbitol. These are poorly absorbed, fermented in the colon, leading to gas, bloating, pain, and altered bowel habit — exaggerated by visceral hypersensitivity
• Non-coeliac gluten sensitivity: Gluten exposure causes symptoms in some IBS patients; overlap with non-coeliac gluten sensitivity

D. Triggering Events

• Affective disorders (depression, anxiety)
• Psychological stress and trauma
• Gastrointestinal infection (post-infectious IBS — 7–30% of IBS onset preceded by infectious diarrhoea)
• Antibiotic therapy
• Sexual, physical, or verbal abuse
• Pelvic surgery
• Eating disorders

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4. PATHOPHYSIOLOGY

A. GI Motor Abnormalities

• Under unstimulated conditions, no consistent colonic myoelectrical/motor abnormalities are found
• Under stimulated conditions (eating, stress):
  • IBS patients exhibit increased rectosigmoid motor activity for up to 3 hours after eating
  • Rectal balloon inflation in both IBS-D and IBS-C leads to marked and prolonged distention-evoked contractile activity
  • In diarrhoea-prone IBS: greatly increased motility index and peak amplitude of high-amplitude propagating contractions (HAPCs) in the transverse, descending, and sigmoid colon — associated with rapid colonic transit and abdominal pain
• Small bowel: prolonged ambulant recordings show high incidence of abnormalities in small-bowel motility during waking hours; nocturnal motor patterns are normal

B. Visceral Hypersensitivity

• IBS patients exhibit exaggerated sensory responses to visceral stimulation
• Rectal balloon inflation produces pain and nonpainful sensations at lower volumes in IBS patients than healthy controls — indicating visceral afferent dysfunction
• Lipids lower thresholds for first sensation of gas, discomfort, and pain — explaining postprandial symptoms via a nutrient-dependent exaggerated gastrocolonic response
• The afferent pathway disturbances are selective for visceral innervation — somatic pathways are spared
• Food intolerance perceptions are ≥2× more common in IBS than the general population
• Prolonged fasting is often associated with symptom improvement, while postprandial pain is linked to food bolus entry into the caecum in 74% of patients

C. Central Neural Dysregulation (Brain–Gut Interaction)

• Emotional disorders, stress, and the therapeutic response to centrally acting agents all implicate CNS involvement
• fMRI studies: In response to distal colonic stimulation, IBS patients show:
  • Greater activation of the mid-cingulate cortex (involved in attention and response selection; modulates subjective unpleasantness of pain)
  • Preferential activation of the prefrontal lobe (vigilance network; increases alertness)
• These CNS changes may represent cerebral dysfunction causing increased visceral pain perception
• HPA axis dysregulation and autonomic dysfunction also contribute

D. Abnormal Psychological Features and Their Mechanism

• Abnormal psychiatric features recorded in up to 80% of IBS patients at referral centres
• Patients show exaggerated symptoms in response to visceral distention, which persists even after exclusion of psychological factors — suggesting psychology amplifies an underlying organic sensitisation
• Stress alters sensory thresholds: psychological stress → release of proinflammatory cytokines → altered intestinal permeability → immune activation → symptom generation
• Brain fMRI (abuse history): Greater activation of the posterior and middle dorsal cingulate cortex (affect processing) in IBS patients with past sexual abuse

E. Post-Infectious IBS

• GI infection (Campylobacter, Salmonella, Shigella) predisposes to IBS
• In 544 confirmed bacterial gastroenteritis patients, one-quarter subsequently developed IBS
• ~one-third of IBS patients experienced a "gastroenteritis-like" illness at onset
• Mechanism: Increased rectal mucosal enteroendocrine cells, T lymphocytes, and gut permeability following Campylobacter enteritis — these changes can persist for >1 year
• Risk factors (in order of importance): prolonged duration of initial illness, toxicity of infecting bacterial strain, smoking, mucosal markers of inflammation, female sex, depression, hypochondriasis, adverse life events in preceding 3 months
• Age >60 years appears protective against post-infectious IBS; antibiotic use is associated with increased risk

F. Immune Activation and Mucosal Inflammation (Low-Grade)

• Some IBS patients display persistent low-grade mucosal inflammation with:
  • Activated lymphocytes
  • Increased mast cells in colonic mucosa
  • Enhanced expression of proinflammatory cytokines (IL-6, IL-1β, TNF from PBMCs)
• Mast cells:
  • Located at the host–environment interface, in close proximity to sensory nerves
  • Electromicroscopic evidence of mast cell activation commonly observed
  • Proximity of activated mast cells to submucosal nerve fibers correlates with frequency and severity of abdominal pain
  • Mast cells release histamine, proteases, and prostaglandin E₂ → marked excitation of visceral sensory nerves
  • Some patients respond to mast cell stabilisers (e.g., ketotifen), supporting this pathogenic role
• TRPV1 channels (transient receptor potential vanilloid 1):
  • Mucosal inflammation → increased TRPV1 expression in enteric nervous system
  • Enhanced TRPV1 expression in sensory neurons correlates with visceral hypersensitivity and abdominal pain
• Increased intestinal permeability ("leaky gut"):
  • 39% of IBS-D patients have increased intestinal permeability (measured by lactulose/mannitol ratio)
  • These patients also show higher FBDSI scores and increased hypersensitivity to visceral nociceptive stimuli
  • Psychological stress and anxiety → proinflammatory cytokine release → altered intestinal permeability
• Cytokines and chemokines released from mucosal inflammation may generate extra-GI symptoms such as chronic fatigue, muscle pain, and anxiety

G. Gut Dysbiosis and Its Mechanisms (Detailed)

• Gut dysbiosis + genetic susceptibility + environmental insults → altered mucosal permeability → increased antigen presentation to immune cells in lamina propria → mast cell activation
• Mast cell degranulation products → alter enteric neuronal and smooth muscle function → IBS symptoms
• Dysbiosis-driven cytokines/chemokines from mucosal inflammation → extra-GI symptoms (fibromyalgia, chronic fatigue, mood changes)
• Specific organisms:
  • ↑ Enterobacteriaceae (gram-negative): injures epithelium via lipopolysaccharide → mucosal inflammation
  • ↑ Bacteroides fragilis: produces toxin to dissolve glycoproteins → mucosal inflammation
  • ↑ Lactobacillaceae: produces gas and organic acids from glucose/fructose fermentation → bloating and abdominal pain

H. Abnormal Serotonin Pathways

• Enterochromaffin cells (serotonin-containing) are increased in a subset of IBS-D patients
• Postprandial plasma serotonin levels are significantly higher in IBS-D patients vs. healthy controls
• SERT (serotonin reuptake transporter) expression is downregulated in IBS due to gram-negative gut dysbiosis → serotonin accumulates
• Gut microbes promote colonic serotonin production via short-chain fatty acids acting on enterochromaffin cells
• Serotonin plays a critical role in regulating GI motility and visceral perception → excess serotonin contributes to postprandial symptoms (provides rationale for 5-HT₃ antagonists in IBS-D)

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5. CLINICAL APPROACH (APPROACH TO THE PATIENT)

1. Recognition of positive clinical features
2. Elimination of organic disease
3. Use of symptom-based criteria (Manning → Rome I → II → III → IV)

Clinical Features Suggestive of IBS:

• Recurrence of lower abdominal pain with altered bowel habits over time — without progressive deterioration
• Onset during periods of stress or emotional upset
• Absence of systemic symptoms (no fever, no weight loss)
• Small-volume stool without evidence of blood
• Presence of other functional GI disorders (e.g., functional dyspepsia)
• Non-GI symptoms supporting diagnosis: migraine headaches, dyspareunia, interstitial cystitis

Features AGAINST the Diagnosis of IBS:

• First appearance in old age
• Progressive course from onset
• Persistent diarrhoea after a 48-hour fast
• Nocturnal diarrhoea
• Steatorrhoeic stools
• Anaemia, elevated ESR, leucocytes or blood in stool, stool volume >200–300 mL/day

Differential Diagnosis Considerations:

Factors Determining Aggressiveness of Diagnostic Evaluation:

• Duration of symptoms; change in symptoms over time
• Age and sex of patient; referral status
• Prior diagnostic studies
• Family history of colorectal malignancy
• Degree of psychosocial dysfunction
• A younger individual with mild symptoms → minimal evaluation; older or rapidly progressive → thorough exclusion of organic disease

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6. SIGNS AND SYMPTOMS (WITH PATHOPHYSIOLOGY)

A. Abdominal Pain (Prerequisite for diagnosis)

• Character: Highly variable in intensity and location; frequently episodic and crampy, but may be superimposed on a background of constant ache
• Location: Typically lower abdomen; also colicky/cramping in nature
• Relation to defecation: Pain is related to defecation (improved by passage of flatus or stools)
• Aggravating factors: Eating, emotional stress; worse postprandially; in females, worsens during premenstrual and menstrual phases
• Sleep: Abdominal pain is uniformly present only during waking hours — sleep deprivation is unusual
• Malnutrition: Despite pain, malnutrition from inadequate caloric intake is exceedingly rare
• Pathophysiology: Due to visceral hypersensitivity (lower threshold for visceral pain perception via TRPV1-mediated afferent signalling), mast cell-mediated sensitisation of enteric neurons (histamine, tryptase release), and central neural dysregulation (mid-cingulate and prefrontal lobe hyperactivation)

B. Altered Bowel Habits

• Most consistent clinical feature of IBS
• Most common pattern: constipation alternating with diarrhoea, with one predominating
• IBS is subtyped by predominant bowel pattern (Box 22.27):

• Bowel pattern subtypes are highly unstable: 75% of patients change subtypes; 29% switch between IBS-C and IBS-D over 1 year
• IBS-C features: Infrequent, pellet-like or hard stools with narrowed calibre (due to prolonged colonic retention and spasm → excessive dehydration), sense of incomplete evacuation, repeated defecation attempts; constipation initially episodic, eventually continuous and intractable to laxatives
• IBS-D features: Frequent defecation but low-volume stools (<200 mL); no nocturnal diarrhoea; may be aggravated by emotional stress or eating; stool may contain large amounts of mucus; no bleeding (unless haemorrhoids)
• Pathophysiology: Altered motility (increased HAPCs in IBS-D causing rapid transit; increased segmenting contractions in IBS-C causing slow transit); serotonin dysregulation (excess 5-HT → IBS-D; deficiency → IBS-C); visceral hypersensitivity amplifying sensation of urgency and incomplete evacuation

C. Gas and Flatulence / Bloating

• Patients frequently complain of abdominal distension, increased belching, and flatulence
• Most patients generate no more than a normal amount of gas — the symptom reflects impaired transit and tolerance of intestinal gas loads
• IBS patients tend to reflux gas from distal to proximal intestine → explains belching
• Some patients experience visible abdominal distension with increased abdominal girth
• Pathophysiology: Gut dysbiosis (↑ Lactobacillaceae → gas and organic acid production from glucose/fructose fermentation); FODMAP fermentation producing gas and osmotically active carbohydrates; visceral hypersensitivity amplifying perception of normal gas volumes; impaired gas transit

D. Passage of Mucus

• Common in IBS
• Pathophysiology: Altered mucosal secretion from mast cell mediator release (histamine, proteases, prostaglandin E₂) and immune activation affecting epithelial secretory function

E. Upper GI Symptoms

• 25–50% of IBS patients have dyspepsia, heartburn, nausea, and vomiting
• Suggests that GI involvement extends beyond the colon
• Prevalence of IBS higher in dyspepsia patients (31.7%) vs. those without dyspepsia (7.9%); conversely, 55.6% of IBS patients report dyspepsia symptoms
• Patients can flux between predominant dyspepsia and predominant IBS, suggesting possible overlap as one extensive digestive disorder
• Pathophysiology: Small bowel motility abnormalities during waking hours; gastric and oesophageal hypersensitivity (similar mechanisms to visceral hypersensitivity in the colon); involvement of broader brain–gut axis dysfunction

F. Non-GI (Extraintestinal) Symptoms

• Painful periods (dysmenorrhoea)
• Pain following sexual intercourse (dyspareunia)

• Frequency, urgency
• Nocturia (passing urine at night)
• Incomplete emptying of bladder

• Joint hypermobility
• Back pain
• Headaches / migraine headaches
• Bad breath, unpleasant taste in the mouth
• Poor sleeping
• Fatigue

• Pathophysiology: Systemic release of proinflammatory cytokines and chemokines from low-grade mucosal inflammation reaches extra-GI sites; central sensitisation from brain–gut axis dysregulation affecting autonomic and somatic pain processing more broadly; shared autonomic nervous system involvement across pelvic organs (bladder, uterus, colon)

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7. INVESTIGATIONS (WITH EXPECTED OUTCOMES)

Diagnostic Criteria — Rome IV (2016)

• Recurrent abdominal pain at least 1 day per week on average in the last 3 months (symptom onset ≥6 months before diagnosis), associated with ≥2 of the following:
  1. Related to defecation
  2. Onset associated with a change in frequency of stool
  3. Onset associated with a change in form (appearance) of stool

Alarm Features — Mandate Further Investigation (Box 23.75)

Investigations and Expected Outcomes

Key principle: "The diagnosis is clinical in nature and can be made confidently in most patients using the Rome IV criteria, combined with the absence of alarm symptoms and without resorting to complicated tests." — Unnecessary investigations are costly and potentially harmful.

Laboratory features arguing AGAINST IBS: Anaemia, elevated sedimentation rate, leucocytes or blood in stool, stool volume >200–300 mL/day.

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8. MANAGEMENT

Overview of Severity-Stratified Management (Table 327-3)

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A. Patient Education and Reassurance (First-Line for All)

• Most important step: Make a positive diagnosis, educate, and reassure
• Communicate diagnostic certainty to prevent further unwarranted testing
• Explain that symptoms are due to behavioural, psychosocial, physiological, and luminal factors — NOT cancer or serious organic disease
• Break the cycle of anxiety → colonic symptoms → heightened anxiety
• Establish and maintain a good clinician–patient relationship from the outset

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B. Dietary Modifications

• Regular meals
• Adjustment of fibre intake (increase for IBS-C; reduce insoluble fibre in IBS-D)
• Adequate fluid intake
• Reduce caffeine and alcohol
• Decrease fat intake
• Assess spicy meal components triggering symptoms
• Eliminate identified trigger foods (coffee, disaccharides, legumes, cabbage, excessive fructose, artificial sweeteners like sorbitol/mannitol)

• FODMAPs are poorly absorbed by the small intestine → fermented by colonic bacteria → produce gas and osmotically active carbohydrates → bloating, flatulence, diarrhoea
• FODMAPs also serve as nutrients for gram-negative commensal bacteria → may induce epithelial damage and subclinical inflammation
• Evidence: Systemic review of 7 studies → low FODMAP diet associated with reduced global symptoms in 50–80% of IBS patients
• Gaining support as first-line treatment for moderate-to-severe symptoms
• Common FODMAP sources: apples, pears, watermelon, honey, high-fructose corn syrup, wheat, rye, barley, milk products, legumes, pistachios, mushrooms
• Should be implemented under dietitian guidance to prevent nutritional deficiencies

• Gluten-free diet: Up to 30% may benefit from wheat-free diet; overlap with non-coeliac gluten sensitivity
• Lactose exclusion: May benefit those with lactose intolerance overlap
• Excess artificial sweeteners (sorbitol) should be addressed

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C. Stool-Bulking Agents (High-Fibre Diets)

• Mechanism: Water-holding action increases stool bulk (↑ faecal bacterial output); speeds up colonic transit in most people; hydrophilic properties bind water — preventing both excessive hydration and dehydration of stool
• Soluble fibre (psyllium preparations) preferred over insoluble (wheat bran) — produces less bloating and distension; psyllium has been shown to reduce perception of rectal distension (positive effect on visceral afferent function)
• Target: 20–30 g of total dietary and supplementary fibre per day (titrate slowly over weeks)
• Variable results in controlled trials (IBS is heterogeneous); generally beneficial for constipation; some benefit in alternating type; no response in diarrhoea- or pain-predominant IBS
• Caution: Even judicious fibre use can exacerbate bloating, flatulence, constipation, and diarrhoea

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D. End-Organ (Pharmacological) Treatments

1. Antispasmodics / Smooth Muscle Relaxants

• Mechanism: Anticholinergic drugs inhibit the gastrocolic reflex
• Use: For postprandial crampy pain — give 30 minutes before meals so effective blood levels are achieved before anticipated pain onset
• Agents:
  • Natural belladonna alkaloids (side effects: xerostomia, urinary hesitancy/retention, blurred vision, drowsiness — use with caution in elderly)
  • Synthetic anticholinergics: Dicyclomine (dicycloverine) — fewer side effects; Mebeverine hydrochloride
  • Peppermint oil — reduces abdominal cramps by undefined mechanism; meta-analysis of 9 RCTs (n=726) showed significantly superior improvement in IBS symptoms and abdominal pain vs. placebo; most common adverse event = mild transient heartburn

2. Antidiarrhoeal Agents (IBS-D)

• Peripherally acting opiate-based agents are initial therapy of choice for IBS-D
• Mechanism: Increase segmenting colonic contractions, delay faecal transit, increase anal pressures, reduce rectal perception
• Loperamide: 2–4 mg every 4–6 h (max 12 mg/day); less addictive than paregoric or codeine; intestines do not become tolerant of antidiarrhoeal effect; most useful if taken before anticipated stressful events; high doses may cause cramping
• Codeine phosphate; Co-phenotrope — alternatives
• Eluxadoline — μ- and κ-opioid receptor agonist and δ-opioid receptor antagonist
• Cholestyramine resin (bile acid binder): 4 g with meals — indicated because up to 30% of IBS-D may have bile acid malabsorption
• Alosetron (5-HT₃ receptor antagonist): 0.5–1 mg twice daily — available only in the USA; approved for severe IBS in women

3. Osmotic Laxatives (IBS-C)

• Mechanism: Hypertonic agents extract fluid into intestinal lumen by osmosis → soften stool and enhance colonic transit
• Polyethylene glycol (PEG): Iso-osmotic; induces bowel movement by high-volume lavage; Cochrane review of 10 RCTs showed PEG superior to lactulose for stool frequency and abdominal pain
• Lactulose syrup, 70% sorbitol — similar laxative effects; however, bacterial metabolism → gas production → abdominal pain (limits long-term use)
• Magnesium hydroxide/citrate: Effective but chronic use may cause severe hypermagnesaemia in renal impairment
• Sodium phosphate: Avoid frequent use → risk of hyperphosphataemia, hypocalcaemia, hypokalemia

4. Secretagogues (IBS-C)

• Lubiprostone (24 mg twice daily): Bicyclic fatty acid derived from prostaglandin E₁; activates type 3 chloride channels in apical membrane of intestinal epithelial cells → chloride secretion → water follows; FDA-approved for IBS-C; main side effects: nausea and diarrhoea
• Linaclotide (290 μg once daily): Minimally absorbed 14-amino-acid peptide; guanylate cyclase-C (GC-C) agonist; binds and activates GC-C on luminal intestinal epithelium → ↑ cyclic GMP → activates CFTR → fluid secretion; FDA-approved for IBS-C; main side effect: diarrhoea (<5%)
• Plecanatide (3 mg once daily): Also a GC-C agonist; similar efficacy and tolerability to linaclotide; FDA-approved
• Tenapanor (50 mg twice daily): Small-molecule inhibitor of GI sodium–hydrogen exchange-3 (NHE3); more effective than placebo in IBS-C

5. Serotonin Receptor Modulators

• Prucalopride (2 mg once daily): Selective 5-HT₄ agonist; dihydrobenzo-furancarboxamide derivative; prokinetic; approved by EMA and FDA for chronic constipation; most common side effects: headache, nausea, diarrhoea (mostly transient); no significant cardiovascular side effects (unlike older 5-HT₄ agonist tegaserod)
• Tegaserod: 5-HT₄ agonist; also prokinetic; previously used for IBS-C; withdrawn in 2007 (↑ cardiovascular complications); re-approved in 2019 by FDA for women <65 years with no history of ischaemic cardiovascular disease and ≤1 cardiovascular risk factor

6. Antidepressants

• Tricyclic antidepressants (TCAs):
  • Mechanism: Slow jejunal migrating motor complex propagation; delay orocecal and whole-gut transit (motor inhibitory effect); alter visceral afferent neural function; reduce visceral sensation; alter GI motility
  • Beneficial effects are independent of effects on depression (occur faster and at lower doses)
  • Primarily for IBS-D: Improvements observed in IBS-D; no improvement in IBS-C
  • Agents: Amitriptyline, imipramine, clomipramine (start 25–50 mg at night, adjust)
  • Side effects: Dry mouth, drowsiness (usually mild); patients with somatisation tolerate poorly — use lower doses
  • Caution: Use with care; patients with major psychological disorders may require specific treatment
• Selective Serotonin Reuptake Inhibitors (SSRIs):
  • Paroxetine (SSRI): Accelerates orocecal transit → potentially useful in IBS-C
  • Citalopram (SSRI): Blunts perception of rectal distension; reduces gastrocolonic response magnitude; small placebo-controlled study showed pain reduction (not confirmed in subsequent RCT)
  • SSRIs: Evidence for IBS needs further confirmation; may be combined with prokinetic (domperidone) or smooth muscle relaxant (mebeverine) for IBS-C

7. Antiflatulence Therapy

• Dietary advice: Eat slowly; do not chew gum or drink carbonated beverages; avoid flatogenic foods; exercise; lose excess weight
• Low FODMAP diet: Most effective to reduce gas and bloating
• Antibiotics (rifaximin): May help in a subgroup with predominant bloating
• Beano (oral β-glycosidase): May reduce rectal passage of gas (not bloating/pain)
• Pancreatic enzymes: Reduce bloating, gas, fullness during and after high-calorie, high-fat meals
• Simethicone (surfactant): Conflicting data

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E. Modulation of Gut Flora

1. Antibiotics

• Rifaximin (550 mg twice daily × 2 weeks):
  • Non-absorbed oral antibiotic acting strictly on gut lumen
  • Most thoroughly studied antibiotic for IBS
  • Systemic review and meta-analysis of 5 studies: more effective than placebo for global symptoms and bloating (OR 1.57; NNT = 10.2)
  • The only antibiotic with demonstrated sustained benefit beyond therapy cessation in IBS patients
  • Favourable safety/tolerability profile vs. systemic antibiotics
  • Mechanism: uncertain (may restore gut flora balance)
  • Caution: Currently insufficient data to recommend routine use

2. Probiotics

• Defined as live microorganisms that confer health benefit when administered in adequate amounts
• Meta-analysis of 10 studies: significant relief of pain and bloating with Bifidobacterium breve, Bifidobacterium longum, and Lactobacillus acidophilus vs. placebo
• No change in stool frequency or consistency in meta-analysis
• Large-scale studies in well-phenotyped IBS patients are needed to establish efficacy
• Future work will focus on subgroups (especially IBS-D) and correcting the microbiome on an individual basis

3. Prebiotics

• Nondigestible food ingredients stimulating gut bacterial growth/activity
• 3 of 4 randomised trials found prebiotics worsened or did not improve IBS symptoms (consistent with adverse effects of high-carbohydrate diet on IBS)

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F. Psychological Interventions (Reserved for Most Difficult Cases)

• Cognitive Behavioural Therapy (CBT): Most widely studied psychotherapy for IBS; may improve bowel symptoms, quality of life, and psychological distress
• Relaxation therapy
• Gut-directed hypnotherapy
• Formal psychotherapy (Ch. 31)
• Anxiety and affective disorders require specific treatment

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G. Summary of Drug Therapy by Dominant Symptom (Table 327-4)

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9. COMPLICATIONS (WITH PATHOPHYSIOLOGY)

A. Impaired Quality of Life

• Pathophysiology: Chronic, unpredictable pain and bowel dysfunction from persistent visceral hypersensitivity and brain–gut dysregulation create functional impairment; anxiety and depression (present in up to 80%) further diminish coping capacity
• Significant impairment of daily activities and social functioning
• ~25% of UK IBS patients take 7–13 days off work annually

B. Psychiatric Comorbidity and Psychological Deterioration

• Up to 80% of referred IBS patients have abnormal psychiatric features
• Anxiety, depression, somatisation, panic attacks
• Pathophysiology: Bidirectional brain–gut axis dysregulation — psychological distress amplifies visceral hypersensitivity and GI symptoms, which in turn worsen psychological state; altered HPA axis function; proinflammatory cytokines from gut inflammation reach the brain and modulate mood (contributing to anxiety/mood disorders)
• Cycle: Anxiety → ↑ proinflammatory cytokines → ↑ intestinal permeability → immune activation → ↑ visceral sensation → worsened symptoms → ↑ anxiety

C. Extra-GI Complications (Systemic)

• Fibromyalgia: IBS coexists with fibromyalgia; shared central sensitisation mechanisms; cytokine-mediated diffuse musculoskeletal pain
• Chronic Fatigue Syndrome: Coexists with IBS; cytokine and chemokine release from mucosal inflammation contributes to fatigue; altered immune activation
• Temporomandibular joint dysfunction: Shared central sensitisation / nociplastic pain mechanism
• Pathophysiology shared by all three: Systemic cytokines/chemokines from mucosal inflammation → extra-GI symptom generation; diffuse central sensitisation extending beyond the visceral afferent pathway

D. Nutritional Consequences of Restrictive Diets

• Low FODMAP and other exclusion diets — if not supervised — risk nutritional deficiencies
• Dietary advice should always be implemented under dietitian guidance to prevent this complication

E. Narcotic Bowel Syndrome / Opioid Dependency Risk

• Patients with severe, refractory symptoms are at risk of escalating opioid use
• Document states: "Narcotics should always be avoided" in pain/gas/bloat syndrome variants
• Pathophysiology: Opioid-induced bowel dysfunction (altered motility, constipation, paradoxical hyperalgesia) worsens the underlying condition; opioid tolerance requiring increasing doses; narcotic bowel syndrome characterised by paradoxical opioid-induced abdominal pain worsening

F. Medication Side Effects as Complications

• TCAs: Anticholinergic side effects (urinary retention, constipation)
• Alosetron: Ischaemic colitis — a rare but serious complication (reason for restricted availability in the USA)
• Chronic magnesium hydroxide use: Severe hypermagnesaemia in renal impairment
• Frequent sodium phosphate laxatives: Hyperphosphataemia, hypocalcaemia, hypokalaemia
• Tegaserod (historical): Cardiovascular complications — reason for 2007 market withdrawal

G. Missed Organic Disease (Over-Reliance on IBS Diagnosis)

• Premature or over-confident labelling of IBS may delay diagnosis of:
  • Colorectal carcinoma
  • Inflammatory bowel disease (Crohn's disease, ulcerative colitis)
  • Coeliac disease (particularly in IBS-D — serology testing recommended when coeliac sprue prevalence >1%; dominant strategy when prevalence >8%)
  • Microscopic colitis
  • Bile acid diarrhoea
• Pathophysiology of missed diagnosis: Overlapping symptom profiles; absence of alarm features does not exclude organic disease in all cases; IBS patients with concurrent coeliac disease may suffer years of morbidity without appropriate dietary treatment

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KEY SUMMARY TABLE

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1. Definition — Functional bowel disorder, no organic lesion, Rome IV update
2. Epidemiology — Prevalence figures, sex ratios, socioeconomic burden
3. Aetiology — The full biopsychosocial model: psychosocial triggers, physiological/genetic factors (serotonin, SERT/TPH1 polymorphisms, twin studies), luminal factors (dysbiosis, SIBO, bile acid malabsorption, FODMAPs, gluten sensitivity), and specific onset triggers
4. Pathophysiology — Eight detailed mechanisms: motor abnormalities, visceral hypersensitivity, CNS dysregulation (fMRI evidence), psychological features, post-infectious IBS (with risk factors), immune activation/mast cells/TRPV1/leaky gut, gut dysbiosis mechanisms (organism-specific), and serotonin pathway abnormalities
5. Clinical Approach — Features supporting and against IBS, differential diagnosis by pain location, factors determining investigation aggressiveness
6. Signs & Symptoms with pathophysiology — Abdominal pain, altered bowel habits (with subtype table), gas/bloating, mucus, upper GI symptoms, and the full list of extraintestinal symptoms
7. Investigations with expected outcomes — Full table of every test, its purpose, and what to expect in IBS vs. organic disease
8. Management — Severity-stratified; all dietary, pharmacological (with mechanisms and doses from the drug table), gut flora modulation, and psychological interventions
9. Complications with pathophysiology — QoL impairment, psychiatric comorbidity (with the anxiety cycle), extra-GI complications (fibromyalgia, CFS, TMJ — with shared pathophysiology), nutritional risks, narcotic danger, drug-specific complications, and missed diagnosis risk

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Irritable Bowel Syndrome (IBS) — Comprehensive Detailed Notes

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1. DEFINITION

• A functional bowel disorder characterised by recurrent abdominal pain in association with altered bowel habits (abnormal defecation), occurring in the absence of a detectable structural or organic abnormality of the gut
• No clear pathognomonic (diagnostic) markers exist; therefore, the diagnosis is based entirely on clinical presentation

• GI motility
• Visceral hypersensitivity
• Gut microbiota
• Immune and mucosal function
• Central nervous system processing

Rome IV (2016 update): The Rome III criteria were updated to Rome IV. Key changes: abdominal pain must occur at least once per week (stricter frequency requirement), and "discomfort" was eliminated as an acceptable criterion. Painless diarrhoea or painless constipation alone does NOT qualify as IBS.

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2. AETIOLOGY (ETHOLOGY)

A. Behavioural and Psychosocial Factors

• Early life adversity: Learning difficulties or emotionally challenging interactions during childhood may contribute to IBS in adult life
• Psychiatric illness:
  • Most patients seen in general practice do NOT have significant psychological problems
  • However, ~50% of patients referred to hospital have a formal psychiatric diagnosis — anxiety, depression, somatisation, neurosis, or panic attacks
  • No single psychiatric diagnosis predominates
• Acute psychological stress and overt psychiatric disease are known to alter visceral perception and GI motility
• Abnormal illness behaviour: Increased prevalence of frequent consultations for minor symptoms, reduced coping ability
• Abuse history: Prior sexual, physical, or verbal abuse is associated with IBS development; associated with greater pain reporting, psychological distress, and poor health outcome
• These psychosocial factors contribute to but do not cause IBS on their own

B. Physiological / Genetic Factors

• IBS is a disorder of the brain–gut axis with alterations in visceral hypersensitivity
• Serotonin (5-HT) dysregulation:
  • Relatively excessive 5-HT release → IBS-D (diarrhoea-predominant)
  • Relative 5-HT deficiency → IBS-C (constipation-predominant)
  • 5-HT₃ receptor antagonists are effective in IBS-D; 5-HT₄ agonists improve bowel function in IBS-C
• Genetic factors:
  • Twin studies support a heritable component
  • SERT (serotonin reuptake transporter) polymorphisms affect IBS habit subtypes; SERT expression is downregulated in IBS due to gram-negative gut dysbiosis
  • TPH1 (tryptophan hydroxylase 1) polymorphism — TPH1 is the rate-limiting enzyme in enterochromaffin cell serotonin biosynthesis; functional TPH1 polymorphism is associated with IBS habit subtypes
• Low-grade gut inflammation / immune activation (not detectable by standard tests), with raised numbers of mucosal mast cells sensitising enteric neurons by releasing histamine and tryptase

C. Luminal Factors

• Gut dysbiosis (altered microbiota): Both quantitative and qualitative alterations in intestinal bacterial microbiota
  • ↓ Bifidobacterium and Faecalibacterium (anti-inflammatory, butyrate-producing)
  • ↑ Enterobacteriaceae, Lactobacillaceae, Bacteroides (pro-inflammatory potential)
  • Increased Firmicutes:Bacteroidetes ratio; decreased microbiota diversity; increased instability of flora
• Small Intestinal Bacterial Overgrowth (SIBO): May be present in some patients and lead to symptoms; explains response to rifaximin and probiotics ("gut dysbiosis")
• Bile acid malabsorption: Up to 30% of IBS-D patients may have bile acid malabsorption
• Dietary factors — FODMAPs: Chemical food intolerances (NOT allergy) to poorly absorbed, short-chain carbohydrates — lactose, fructose, sorbitol, and others — collectively termed FODMAPs (fermentable oligo-, di- and monosaccharides, and polyols)
  • Fermentation in the colon is normal physiology, but in IBS patients (with visceral hypersensitivity), this leads to bloating, pain, wind, and altered bowel habit
• Gluten/wheat sensitivity: Gluten exposure causes symptoms in some IBS patients; overlap with non-coeliac gluten sensitivity (negative coeliac serology, normal duodenal biopsies)

D. Triggering Factors (Onset Triggers)

• Affective disorders (depression, anxiety)
• Psychological stress and trauma
• Gastrointestinal infection (post-infectious IBS — infectious diarrhoea precedes IBS onset in 7–30% of patients)
• Antibiotic therapy
• Sexual, physical, or verbal abuse
• Pelvic surgery
• Eating disorders
• Adverse life events, occupational dissatisfaction, difficulties in interpersonal relationships

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3. PATHOPHYSIOLOGY

A. GI Motor Abnormalities

• Under unstimulated conditions: No consistent colonic myoelectrical or motor abnormalities are found
• Under stimulated conditions (eating, stress, balloon distension):
  • IBS patients exhibit increased rectosigmoid motor activity for up to 3 hours after eating
  • Rectal balloon inflation in both IBS-D and IBS-C leads to marked and prolonged distension-evoked contractile activity
  • In IBS-D: greatly increased motility index and peak amplitude of High-Amplitude Propagating Contractions (HAPCs) in the transverse, descending, and sigmoid colon → rapid colonic transit → abdominal pain
• Small bowel: Prolonged ambulant recordings show high incidence of small-bowel motility abnormalities during waking (diurnal) hours; nocturnal motor patterns are normal — explaining why IBS symptoms are absent during sleep

B. Visceral Hypersensitivity

• IBS patients exhibit exaggerated sensory responses to visceral stimulation
• Rectal balloon inflation produces pain and non-painful sensations at lower volumes in IBS patients than in healthy controls — without altering rectal wall tension → indicates visceral afferent dysfunction
• Lipids lower the threshold for first sensation of gas, discomfort, and pain → explains postprandial symptoms via a nutrient-dependent, exaggerated gastrocolonic response
• Postprandial pain is temporally related to food bolus entry into the caecum in 74% of patients
• Prolonged fasting → significant symptom improvement
• The afferent pathway disturbances are selective for visceral innervation — somatic (body) pathways are spared
• Frequency of food intolerance perceptions is ≥ 2× more common in IBS than in the general population
• Similar gastric and oesophageal hypersensitivity is seen in functional dyspepsia and non-cardiac chest pain — suggesting a shared pathophysiological basis

C. Central Neural Dysregulation (Brain–Gut Interaction)

• Evidence: clinical association of emotional disorders and stress with symptom exacerbation; therapeutic response to agents acting on cerebral cortical sites
• fMRI studies — in response to distal colonic stimulation, IBS patients show:
  • Greater activation of the mid-cingulate cortex (involved in attention and response selection; modulates subjective unpleasantness of pain)
  • Preferential activation of the prefrontal lobe (contains a vigilance network that increases alertness)
• These represent cerebral dysfunction → increased visceral pain perception
• HPA axis dysregulation and autonomic nervous system dysfunction also contribute
• Genetic and epigenetic factors early in life modulate brain networks related to emotional arousal, central autonomic control, salience, and somatosensory integration

D. Abnormal Psychological Features and Their Neurobiological Mechanism

• Abnormal psychiatric features recorded in up to 80% of IBS patients at referral centres; no single diagnosis predominates
• These patients show exaggerated symptoms in response to visceral distension, an abnormality that persists even after exclusion of psychological factors — demonstrating an underlying organic sensitisation that psychology amplifies
• Stress alters sensory thresholds: Psychological stress → proinflammatory cytokine release → altered intestinal permeability → immune activation → symptom generation (functional link between psychology, immune activation, and symptoms)
• Abuse and brain changes: fMRI shows greater activation of the posterior and middle dorsal cingulate cortex (affect processing region) in IBS patients with a past history of sexual abuse

E. Post-Infectious IBS

• A prior GI infection predisposes to IBS
• In 544 confirmed bacterial gastroenteritis patients → one-quarter subsequently developed IBS
• ~One-third of IBS patients describe a "gastroenteritis-like" illness at the onset of their chronic IBS symptomatology
• More common in females and younger patients
• Causative organisms: Campylobacter, Salmonella, Shigella
• Mechanism: Following Campylobacter enteritis → increased rectal mucosal enteroendocrine cells, T lymphocytes, and gut permeability — changes that can persist for >1 year and contribute to post-infectious IBS
• Risk factors in order of importance:
  1. Prolonged duration of initial illness
  2. Toxicity of infecting bacterial strain
  3. Smoking
  4. Mucosal markers of inflammation
  5. Female sex
  6. Depression
  7. Hypochondriasis
  8. Adverse life events in preceding 3 months
• Protective factor: Age >60 years protects against post-infectious IBS
• Risk factor for post-infectious IBS: Antibiotic treatment of the initial infection is associated with increased risk of developing IBS subsequently

F. Immune Activation and Mucosal Inflammation (Low-Grade)

• Some IBS patients display persistent low-grade mucosal inflammation with:
  • Activated lymphocytes
  • Increased mast cells
  • Enhanced expression of proinflammatory cytokines
• Peripheral blood mononuclear cells (PBMCs) from IBS patients show abnormal release of IL-6, IL-1β, and TNF
• These abnormalities contribute to abnormal epithelial secretion and visceral hypersensitivity
• Mast cells:
  • Located at the host–environment interface, in close proximity to sensory nerves
  • Electromicroscopic evidence of mast cell activation is commonly seen in colonic mucosa of IBS patients
  • Proximity of activated mast cells to submucosal nerve fibres correlates directly with the frequency and severity of abdominal pain
  • Mast cells release histamine, proteases, and prostaglandin E₂ → marked excitation of visceral sensory nerves innervating the colon
  • Some patients respond to mast cell stabilisers (e.g., ketotifen), supporting a pathogenic role
• TRPV1 channels (transient receptor potential vanilloid 1):
  • Mucosal inflammation → increased TRPV1 expression in the enteric nervous system
  • Enhanced TRPV1 channel expression in sensory neurons of the gut has been observed in IBS
  • This expression correlates with visceral hypersensitivity and abdominal pain
• Increased intestinal permeability ("leaky gut"):
  • 39% of IBS-D patients have increased intestinal permeability (measured by lactulose/mannitol ratio)
  • These patients also have higher FBDSI (Functional Bowel Disorder Severity Index) scores and increased hypersensitivity to visceral nociceptive stimuli
  • Psychological stress and anxiety → proinflammatory cytokine release → altered intestinal permeability → provides a functional link between psychological stress, immune activation, and symptom generation
• Systemic cytokine/chemokine release from mucosal inflammation → generates extra-GI symptoms (chronic fatigue, muscle pain, anxiety)

G. Altered Gut Flora (Dysbiosis) — Detailed Mechanisms

• ↑ Enterobacteriaceae family (gram-negative): injures epithelium via lipopolysaccharide (LPS)-dependent pathway → mucosal inflammation
• ↑ Bacteroides (e.g., B. fragilis): produces toxin that dissolves glycoproteins → mucosal inflammation
• ↑ Lactobacillaceae: produces gas and organic acids from glucose and fructose fermentation → bloating and abdominal pain
• ↓ Faecalibacterium: butyrate-producing, anti-inflammatory; reduces IBS symptoms via IL-17 expression mediation
• ↓ Bifidobacterium: anti-inflammatory; reduces mucosal inflammation in clinical trials

H. Abnormal Serotonin Pathways

• Enterochromaffin (EC) cells (serotonin-containing) in the colon are increased in a subset of IBS-D patients vs. healthy controls or ulcerative colitis patients
• Postprandial plasma serotonin levels are significantly higher in IBS-D patients
• TPH1 (tryptophan hydroxylase 1) is the rate-limiting enzyme in EC cell serotonin biosynthesis; functional TPH1 polymorphism is associated with IBS habit subtypes
• Gut microbes promote colonic serotonin production via short-chain fatty acids acting on EC cells
• SERT (serotonin reuptake transporter) expression is downregulated in IBS due to gram-negative gut dysbiosis → serotonin accumulates in the synapse → not adequately cleared
• Because serotonin regulates GI motility and visceral perception, increased serotonin release contributes to postprandial symptoms → rationale for 5-HT₃ antagonists (e.g., alosetron) in IBS-D treatment

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4. CLINICAL APPROACH (APPROACH TO THE PATIENT)

1. Recognition of positive clinical features
2. Elimination of organic disease
3. Applying symptom-based criteria (Manning → Rome I → Rome II → Rome III → Rome IV)

History (Key Elements)

• Dietary history (food triggers, FODMAP intake, caffeine, alcohol, fat content)
• Medical and surgical history
• Psychological history
• Drug history (anticholinergics, antihypertensives, antidepressants → can cause constipation)
• Family history (colorectal cancer, IBD)
• History of prior gastroenteritis (post-infectious IBS)
• Other functional GI disorders (supports diagnosis)
• Non-GI symptoms: migraine, dyspareunia, interstitial cystitis

Clinical Features SUPPORTING IBS:

• Recurrence of lower abdominal pain with altered bowel habits without progressive deterioration over time
• Onset during periods of stress or emotional upset
• Absence of systemic symptoms (no fever, no weight loss)
• Small-volume stool without evidence of blood
• Presence of other functional GI disorders
• Non-GI features (migraines, dyspareunia, interstitial cystitis)

Clinical Features AGAINST IBS (Red Flags):

• Appearance of disorder for the first time in old age
• Progressive course from time of onset
• Persistent diarrhoea after a 48-hour fast (suggests secretory or osmotic organic cause)
• Nocturnal diarrhoea
• Steatorrhoeic stools (suggests malabsorption)
• Anaemia, elevated ESR/CRP, leucocytes or blood in stool, stool volume >200–300 mL/day

Physical Examination

• Generally unremarkable
• Exception: variable tenderness to palpation of the abdomen
• No palpable masses; no organomegaly

Differential Diagnosis (by predominant feature)

Factors Determining Aggressiveness of Evaluation:

• Duration and progression of symptoms
• Age and sex of patient
• Referral status
• Prior diagnostic studies
• Family history of colorectal malignancy
• Degree of psychosocial dysfunction

A younger individual with mild symptoms → minimal evaluation; an older person or individual with rapidly progressive symptoms → thorough exclusion of organic disease

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5. SIGNS AND SYMPTOMS (WITH PATHOPHYSIOLOGY)

A. Abdominal Pain (prerequisite for diagnosis)

• Character: Highly variable in intensity and location; frequently episodic and crampy, may be superimposed on a background of constant ache
• Location: Typically lower abdomen; colicky or cramping in nature
• Relationship to defecation: Improved by passage of flatus or stools
• Aggravating factors: Eating, emotional stress; worsens postprandially; in females, worsens during premenstrual and menstrual phases
• Timing: Almost uniformly present only during waking hours — sleep deprivation is unusual; nocturnal pain argues against IBS
• Weight: Despite pain, malnutrition from inadequate caloric intake is exceedingly rare
• Pathophysiology:
  • Visceral hypersensitivity (lower pain threshold via TRPV1-mediated afferent signalling)
  • Mast cell sensitisation of enteric neurons (histamine, tryptase, prostaglandin E₂ release)
  • Central neural dysregulation (mid-cingulate cortex and prefrontal lobe hyperactivation on fMRI)
  • Increased HAPCs in IBS-D causing rapid, painful colonic transit
  • Postprandial pain triggered by food bolus entry into the caecum (74%)

B. Altered Bowel Habits (most consistent feature)

• Most common pattern: constipation alternating with diarrhoea, with one predominating
• Bowel pattern subtypes are highly unstable: 75% of patients change subtypes; 29% switch between IBS-C and IBS-D over 1 year

• Infrequent, pellet-like / pellety stools with narrowed calibre (due to prolonged colonic retention and spasm → excessive dehydration of stool)
• Sense of incomplete evacuation → repeated defecation attempts in short span
• Usually in association with abdominal pain or proctalgia
• Initially episodic; eventually continuous and increasingly intractable to laxatives
• May have weeks or months of constipation interrupted by brief periods of diarrhoea
• Pathophysiology: Relative 5-HT deficiency → reduced prokinetic signalling; increased segmenting colonic contractions slow transit; prolonged retention → water absorption → hard, narrow stool

• Frequent defecation but low-volume stools (<200 mL)
• No nocturnal diarrhoea (distinguishes from organic causes)
• Aggravated by emotional stress or eating
• Stool may contain large amounts of mucus
• No rectal bleeding (unless haemorrhoids are coincidentally present)
• No malabsorption or weight loss
• Pathophysiology: Excessive 5-HT release → enhanced prokinetic signalling → rapid colonic transit; increased HAPCs; visceral hypersensitivity amplifies urgency; SERT downregulation prevents clearance of serotonin

C. Gas and Flatulence / Bloating / Abdominal Distension

• Frequent complaints of abdominal distension, increased belching, and flatulence
• Most patients generate no more than a normal amount of intestinal gas — the issue is impaired transit and tolerance of intestinal gas loads
• IBS patients reflux gas from distal to proximal intestine → explains belching
• Some patients experience visible abdominal distension with increased abdominal girth
• Pathophysiology:
  • Gut dysbiosis: ↑ Lactobacillaceae → gas and organic acid production from glucose/fructose fermentation
  • FODMAP fermentation → gas and osmotically active carbohydrates in the colon
  • Visceral hypersensitivity amplifies perception of normal gas volumes (perceived as painful)
  • Impaired gas transit through the intestine

D. Passage of Mucus

• Common in IBS; does not indicate organic pathology
• Pathophysiology: Altered mucosal secretion driven by mast cell mediator release (histamine, proteases, prostaglandin E₂) and immune activation affecting goblet cell and epithelial secretory function

E. Upper GI Symptoms

• 25–50% of IBS patients also complain of dyspepsia, heartburn, nausea, and vomiting
• IBS is more prevalent in patients with dyspepsia (31.7%) vs. those without (7.9%); conversely, 55.6% of IBS patients report dyspepsia
• Patients can flux between predominant dyspepsia and predominant IBS — suggesting they may be two manifestations of one broader digestive disorder
• IBS symptoms are also prevalent in non-cardiac chest pain patients
• Pathophysiology:
  • Small bowel motility abnormalities during waking hours (not nocturnal)
  • Gastric and oesophageal hypersensitivity via the same visceral afferent dysfunction mechanism as colonic hypersensitivity
  • Broad brain–gut axis dysfunction extending beyond the colon

F. Non-GI (Extraintestinal) Symptoms

• Painful periods (dysmenorrhoea)
• Pain following sexual intercourse (dyspareunia)

• Frequency and urgency
• Nocturia (passing urine at night)
• Incomplete emptying of bladder

• Joint hypermobility
• Back pain
• Headaches / migraines
• Bad breath, unpleasant taste in the mouth
• Poor sleeping
• Fatigue

• Chronic fatigue syndrome
• Fibromyalgia
• Temporomandibular joint (TMJ) dysfunction
• Pathophysiology:
  • Systemic release of proinflammatory cytokines and chemokines from low-grade mucosal inflammation → reaches extra-GI target organs
  • Central sensitisation from brain–gut axis dysregulation → diffuse somatic and visceral pain amplification
  • Shared autonomic nervous system involvement across pelvic organs (bladder, uterus, colon) — accounts for urinary and gynaecological symptoms
  • Nociplastic pain mechanisms shared with fibromyalgia and TMJ dysfunction

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6. INVESTIGATIONS (WITH EXPECTED OUTCOMES)

Diagnostic Criteria (Rome IV — Primary Diagnostic Tool)

Recurrent abdominal pain, on average, at least 1 day per week in the last 3 months (with symptom onset at least 6 months prior to diagnosis), associated with ≥2 of the following:

1. Related to defecation
2. Associated with a change in frequency of stool
3. Associated with a change in form (appearance) of stool

Alarm Features Requiring Further Investigation (Box 23.75)

Key principle: "The diagnosis is clinical in nature and can be made confidently in most patients using the Rome IV criteria, combined with the absence of alarm symptoms and without resorting to complicated tests." Unnecessary investigations are costly and potentially harmful.

Investigations and Expected Outcomes

• Anaemia
• Elevated erythrocyte sedimentation rate (ESR)
• Leucocytes or blood in stool
• Stool volume >200–300 mL/day

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7. MANAGEMENT

Spectrum of Severity (Table 327-3)

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A. Patient Education and Reassurance (First and Most Important Step — All Patients)

• Make a positive diagnosis and communicate it with certainty — prevents further unwarranted testing
• Explain that symptoms are not due to cancer or serious organic disease but are the result of behavioural, psychosocial, physiological, and luminal factors
• Break the anxiety–symptom cycle: Anxiety → colonic symptoms → heightened anxiety → broken by confident reassurance
• Many patients are worried about cancer — this must be addressed directly
• Establish and maintain a good clinician–patient relationship from the beginning
• Lifestyle and dietary modifications should be the mainstay of management for mild–moderate symptoms

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B. Dietary Modifications

• Regular meals (avoid skipping)
• Adjustment of fibre intake (↑ for IBS-C; adjust for IBS-D)
• Adequate fluid intake
• Reduce caffeine and alcohol
• Decrease fat intake
• Assess spicy meal components
• Eliminate identified trigger foods (coffee, disaccharides, legumes, cabbage, excessive fructose, artificial sweeteners — sorbitol, mannitol)
• Should be implemented under dietitian guidance to prevent nutritional deficiencies

• FODMAPs (fermentable oligo-, di- and monosaccharides, and polyols):
  • Poorly absorbed by the small intestine
  • Fermented by colonic bacteria → gas + osmotically active carbohydrates → bloating, flatulence, diarrhoea
  • Also serve as nutrients for gram-negative commensal bacteria → may induce epithelial damage and subclinical inflammation
  • Fructose and fructans induce IBS symptoms in a dose-dependent manner
• Evidence: Systemic review and meta-analysis of 7 studies → low FODMAP diet associated with reduced global symptoms in 50–80% of IBS patients
• Increasing support for recommending as first-line treatment for moderate–severe IBS
• Common FODMAP foods: apples, pears, watermelon, honey, high-fructose corn syrup, wheat, rye, barley, milk/yogurt/soft cheeses, legumes/lentils/chickpeas, pistachios, mushrooms, garlic, onions

• Gluten-free / wheat-free diet: Up to 30% may benefit; overlap with non-coeliac gluten sensitivity
• Lactose exclusion: May benefit those with concurrent lactose intolerance
• Probiotics (capsule form): May be effective if taken for several months (B. breve, B. longum, L. acidophilus); optimum strains and dose not yet clarified

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C. Stool-Bulking Agents / High-Fibre Diets

• Mechanism:
  • Water-holding action → increases stool bulk (↑ faecal bacterial output)
  • Speeds up colonic transit
  • Hydrophilic properties → bind water → prevent both excessive hydration AND dehydration of stool
  • Psyllium reduces perception of rectal distension → positive effect on visceral afferent function
• Soluble fibre (psyllium preparations) preferred over insoluble (wheat bran) — less bloating and distension
• Target dose: 20–30 g of total dietary and supplementary fibre per day (titrate slowly over weeks)
• Evidence: increases stool weight, decreases colonic transit time, improves constipation
• Most effective in IBS-C and alternating IBS; generally no response in diarrhoea- or pain-predominant IBS
• Caution: Even judicious fibre use can exacerbate bloating, flatulence, constipation, and diarrhoea

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D. End-Organ Pharmacological Treatments

1. Antispasmodics / Smooth Muscle Relaxants

• Indication: Painful cramps related to intestinal spasm
• Mechanism: Anticholinergic drugs inhibit the gastrocolic reflex
• Timing: Give 30 minutes before meals — achieves effective blood levels before anticipated postprandial pain onset
• Agents:
  • Mebeverine hydrochloride — smooth muscle relaxant; fewer anticholinergic side effects
  • Dicycloverine (dicyclomine) hydrochloride — synthetic anticholinergic; less effect on mucous membrane secretion; fewer side effects than natural belladonna alkaloids
  • Natural belladonna alkaloids — side effects: xerostomia (dry mouth), urinary hesitancy/retention, blurred vision, drowsiness; use with caution in the elderly
  • Peppermint oil — reduces abdominal cramps by undefined mechanism; meta-analysis of 9 RCTs (n=726) showed significantly superior to placebo for global IBS improvement and pain reduction; most common adverse event = mild transient heartburn

2. Antidiarrhoeal Agents (IBS-D)

• Peripherally acting opiate-based agents are the initial therapy of choice for IBS-D
• Mechanism: Increase segmenting colonic contractions; delay faecal transit; increase anal pressures; reduce rectal perception
• Loperamide: 2–4 mg every 4–6 hours (max 12 mg/day); most useful if taken before anticipated stressful events; less addictive than paregoric or codeine; intestines do not become tolerant of the antidiarrhoeal effect; high doses may cause cramping
• Codeine phosphate; Co-phenotrope — alternatives
• Eluxadoline — μ- and κ-opioid receptor agonist and δ-opioid receptor antagonist
• Cholestyramine resin (bile acid binder): 4 g with meals — indicated in the up to 30% of IBS-D patients with bile acid malabsorption
• Alosetron (5-HT₃ receptor antagonist): 0.5–1 mg twice daily — available in USA only; approved for severe IBS in women

3. Osmotic Laxatives (IBS-C)

• Mechanism: Hypertonic agents extract fluid into the intestinal lumen by osmosis → soften stool and enhance colonic transit
• Polyethylene glycol (PEG) 3350 (17 g in 250 mL water daily): Iso-osmotic; induces bowel movement by high-volume lavage; Cochrane review of 10 RCTs → PEG superior to lactulose for stool frequency and abdominal pain; PEG consistently induces more bowel movements than placebo in 19 trials
• Lactulose syrup (10–20 g twice daily) and 70% Sorbitol (15 mL twice daily): Similar laxative effects; bacterial metabolism of unabsorbed carbohydrates → gas production and abdominal pain (limits long-term use)
• Magnesium hydroxide (30–60 mL daily): Effective but chronic use may cause severe hypermagnesaemia in renal impairment
• Sodium phosphate-based agents: Avoid frequent use → risk of hyperphosphataemia, hypocalcaemia, hypokalaemia

4. Secretagogues (IBS-C)

• Lubiprostone (24 mg twice daily):
  • Bicyclic fatty acid derived from prostaglandin E₁
  • Activates type 3 chloride channels in apical membrane of intestinal epithelial cells → chloride secretion → electroneutrality maintained → sodium and water follow into lumen
  • FDA-approved for IBS-C; effective in large phase 3 RCTs
  • Side effects: nausea and diarrhoea
• Linaclotide (290 μg once daily) and Plecanatide (3 mg once daily):
  • Minimally absorbed 14-amino-acid peptide guanylate cyclase-C (GC-C) agonists
  • Bind and activate GC-C on the luminal surface of intestinal epithelium
  • → ↑ cyclic GMP → activates cystic fibrosis transmembrane regulator (CFTR) → fluid secretion into GI tract
  • Similar to endogenous peptides uroguanylin (small intestine) and guanylin (colon)
  • Two 12-week RCTs: linaclotide (290 or 145 μg once daily) reduced both constipation and pain; FDA-approved for IBS-C
  • Plecanatide approved at 3 mg once daily; similar efficacy and tolerability to linaclotide
  • Main side effect for both: diarrhoea (occurred in <5%)
• Tenapanor (50 mg twice daily):
  • Small-molecule inhibitor of GI sodium–hydrogen exchanger-3 (NHE3)
  • More effective than placebo in IBS-C

5. Serotonin Receptor Modulators

• Prucalopride (2 mg once daily):
  • Dihydrobenzo-furancarboxamide derivative; selective 5-HT₄ agonist
  • Prokinetic — stimulates peristalsis
  • Effective in 6 of 7 multicentre RCTs for chronic constipation
  • Approved by EMA and FDA for chronic constipation
  • Side effects: headache, nausea, diarrhoea (mostly transient)
  • No cardiovascular side effects (unlike older 5-HT₄ agonist tegaserod)
• Tegaserod:
  • 5-HT₄ receptor agonist; also prokinetic
  • Previously used for IBS-C; voluntarily withdrawn in 2007 after increased cardiovascular complications in 18,000-patient database (0.11% vs 0.01% placebo)
  • Re-approved in 2019 by FDA only for women <65 years with no history of ischaemic cardiovascular disease and ≤1 cardiovascular risk factor

6. Antidepressants

• Mechanism:
  • Slow jejunal migrating motor complex transit propagation
  • Delay orocecal and whole-gut transit (motor inhibitory effect)
  • Alter visceral afferent neural function → reduce visceral sensation
  • Alter GI motility
• Beneficial effects are INDEPENDENT of effects on depression — occur faster and at lower doses
• Primarily benefit IBS-D patients (improvements observed in IBS-D; no improvement in IBS-C)
• Agents: Amitriptyline, imipramine, clomipramine (start 25–50 mg at bedtime, then adjust)
• Side effects: dry mouth, drowsiness (usually mild)
• Caution: Patients with somatisation tolerate poorly — use lower doses

• Paroxetine: Accelerates orocecal transit → potentially useful in IBS-C
• Citalopram: Blunts perception of rectal distension; reduces gastrocolonic response magnitude; one small RCT showed pain reduction (not confirmed in subsequent RCT)
• SSRIs: efficacy needs further confirmation; may be combined with a prokinetic (domperidone) or smooth muscle relaxant (mebeverine) for combined central and end-organ effect

7. Antiflatulence Therapy

• Behavioural: Eat slowly; do not chew gum or drink carbonated beverages; avoid flatogenic foods; exercise; lose excess weight
• Low FODMAP diet: Most effective for reducing gas and bloating
• Rifaximin: May help a subgroup with predominant bloating
• Beano (oral β-glycosidase): May reduce rectal passage of gas (but not bloating or pain)
• Pancreatic enzymes: Reduce bloating, gas, and fullness during/after high-calorie, high-fat meals
• Simethicone (surfactant): Conflicting data

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E. Modulation of Gut Flora

1. Antibiotics

• Rifaximin (550 mg twice daily × 2 weeks):
  • Non-absorbed oral antibiotic; acts strictly on the gut lumen
  • Most thoroughly studied antibiotic for IBS
  • Double-blind, placebo-controlled study: substantial improvement of global IBS symptoms over placebo
  • Systemic review and meta-analysis of 5 studies: more effective than placebo for global symptoms and bloating (OR 1.57; NNT = 10.2)
  • The only antibiotic with demonstrated sustained benefit beyond therapy cessation in IBS patients
  • Favourable safety and tolerability profile vs. systemic antibiotics
  • Mechanism: Uncertain — likely gut flora modulation
  • Still insufficient data to recommend routine use
• Neomycin (500 mg twice daily × 10 days): Double-blind study showed more effective than placebo; less studied than rifaximin
• Doxycycline: Cheaper alternative to rifaximin for SIBO; can offer symptomatic benefit

2. Probiotics

• Defined as live microorganisms conferring health benefit when administered in adequate amounts
• Meta-analysis of 10 studies: significant relief of pain and bloating with B. breve, B. longum, L. acidophilus vs. placebo
• No change in stool frequency or consistency
• Two studies found Bifidobacterium infantis led to symptomatic improvement vs. placebo
• Role not yet clearly established; large-scale studies in well-phenotyped patients needed
• Future focus: subgroups (especially IBS-D); personalised microbiome correction

3. Prebiotics

• Nondigestible food ingredients stimulating gut bacterial growth/activity
• 3 of 4 RCTs found prebiotics worsened or did not improve IBS symptoms — consistent with adverse effects of a high-carbohydrate diet on IBS

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F. Psychological Interventions (Reserved for Most Difficult / Refractory Cases)

• Cognitive Behavioural Therapy (CBT): Most widely studied psychotherapy for IBS; may improve bowel symptoms, quality of life, and psychological distress; refer to clinical psychologist or psychiatrist
• Gut-directed hypnotherapy
• Relaxation therapy
• Formal psychotherapy
• Anxiety and affective disorders may also require specific treatment

Central and end-organ targeted treatment approaches should be combined — e.g., SSRI paroxetine combined with a prokinetic (domperidone) or smooth muscle relaxant (mebeverine)

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G. Drug Table by Dominant Symptom (Table 327-4)

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H. Management Summary by Severity

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8. COMPLICATIONS (WITH PATHOPHYSIOLOGY)

A. Severely Impaired Quality of Life

• Pathophysiology: Chronic, unpredictable abdominal pain and bowel dysfunction from persistent visceral hypersensitivity and brain–gut dysregulation create continuous functional impairment; comorbid anxiety and depression (up to 80%) further diminish coping capacity
• ~25% of UK IBS patients take 7–13 days off work per year
• Significantly higher healthcare utilisation and costs: ~£45.6 million/year (UK); ~$8 billion/year (USA)

B. Psychiatric Comorbidity and Psychological Deterioration

• Up to 80% of referred IBS patients have abnormal psychiatric features — anxiety, depression, somatisation, panic attacks
• Pathophysiology — a vicious cycle:
  • Anxiety and stress → ↑ proinflammatory cytokine release → ↑ intestinal permeability → immune activation → ↑ visceral hypersensitivity → worsened GI symptoms → ↑ anxiety → cycle perpetuates itself
  • Bidirectional brain–gut axis dysfunction: psychological state amplifies visceral hypersensitivity; abnormal visceral sensations worsen psychological state
  • Altered HPA axis function and autonomic nervous system dysregulation
  • Proinflammatory cytokines from gut mucosal inflammation reach the brain and modulate mood and affect processing

C. Extra-GI Complications (Systemic) — Due to Systemic Immune/Neurological Mechanisms

• Fibromyalgia: IBS coexists with fibromyalgia; shared nociplastic pain mechanism (central sensitisation); cytokine-mediated diffuse musculoskeletal pain
• Chronic Fatigue Syndrome (CFS): Coexists with IBS; cytokine/chemokine release from mucosal inflammation → fatigue, muscle pain; altered immune activation
• Temporomandibular Joint (TMJ) dysfunction: Shared central sensitisation mechanisms; diffuse pain amplification across multiple body systems
• Pathophysiology shared by all three: Systemic cytokines and chemokines released from low-grade gut mucosal inflammation → extra-GI symptom generation; diffuse central sensitisation extending the pain network beyond the visceral afferent pathway to affect musculoskeletal and other organ systems

D. Nutritional Consequences of Restrictive Diets

• Low FODMAP, gluten-free, and other exclusion diets — if unsupervised — risk nutritional deficiencies (vitamins, minerals, fibre from excluded food groups)
• Pathophysiology: Elimination of entire food groups without adequate substitution leads to micronutrient deficiencies; fermentable carbohydrates in FODMAPs also serve as important prebiotics for healthy gut flora
• Management of this complication: all dietary restrictions should be implemented under dietitian guidance

E. Risk of Narcotic/Opioid Misuse — Narcotic Bowel Syndrome

• Patients with severe, refractory, chronic pain may escalate opioid use despite its harm
• The document states: "Narcotics should always be avoided" in pain/gas/bloat syndrome
• Pathophysiology: Opioid-induced GI dysmotility → constipation (worsening IBS-C); paradoxical narcotic bowel syndrome — opioids cause worsening, not improvement, of abdominal pain due to opioid-induced bowel hypersensitivity; escalating doses needed → dependency and addiction risk

F. Drug-Specific Complications from IBS Treatments

G. Delayed or Missed Organic Disease Diagnosis

• Over-confident labelling of IBS may delay diagnosis of:
  • Colorectal carcinoma (especially in alarm features not investigated)
  • Inflammatory bowel disease (Crohn's disease, ulcerative colitis)
  • Coeliac disease — particularly in IBS-D; serology testing is cost-effective when coeliac prevalence >1%; years of unnecessary morbidity can be prevented by appropriate testing
  • Microscopic colitis — requires biopsy to diagnose
  • Bile acid diarrhoea — up to 30% of IBS-D patients
• Pathophysiology of the harm: Overlapping symptom profiles between IBS and organic disease; absence of alarm features does not exclude all organic pathology; chronic untreated coeliac disease → progressive villous atrophy → malabsorption → nutritional deficiencies and risk of GI lymphoma

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MASTER SUMMARY TABLE

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