What is the pathophysiology of irritable bowel syndrome (IBS)?

Pathophysiology of Irritable Bowel Syndrome

IBS is fundamentally a disorder of dysregulated brain-gut-microbiome interactions, not a single disease entity, characterized by multiple interrelated pathophysiological mechanisms that vary in their relative contribution across individual patients. 1, 2

Core Pathophysiological Mechanisms

Gut-Brain Axis Dysregulation

The bidirectional neurohumoral communication system connecting the gut and brain represents the primary pathophysiological framework for understanding IBS. 1 This system operates through three key components:

• Autonomic nervous system dysfunction: Acute or chronic stress triggers corticotrophin-releasing factor production, which directly impairs gut function and generates gastrointestinal symptoms. 1
• HPA axis dysregulation: The stress-buffering system becomes fundamentally impaired in IBS, with high amygdala activity contributing to this dysfunction, making the gut more susceptible to stressful events and less able to recover from them. 1, 2
• Reduced stress resilience: Both psychological and physiological resilience to stress are diminished in IBS patients, underlying their heightened susceptibility and impaired recovery from stress. 1

Visceral Hypersensitivity

Enhanced perception of pain and discomfort from normal gut stimuli represents one of the most important pathophysiological factors in IBS. 2, 3 This hypersensitivity involves:

• Altered processing of afferent signals from the gut, with abnormal activation of specific brain regions following painful rectal stimulation. 4
• Enhanced visceral perception that can be modulated by external factors including stress and nutrients. 3
• Central nervous system alterations in pain perception and modulation of visceral signals. 1

Altered Gut Reactivity

Motility and secretory changes occur in response to both luminal stimuli (meals, gut distention, inflammation, bacterial factors) and environmental provocations (psychosocial stress): 1

• IBS with constipation (IBS-C): Reduced motility, fewer high-amplitude propagating contractions, and delayed colonic transit. 2
• IBS with diarrhea (IBS-D): Increased motility, more high-amplitude propagating contractions, and accelerated transit. 2
• These motor patterns differ systematically between IBS subgroups based on predominant bowel habits. 3

Immune Dysregulation and Low-Grade Inflammation

Post-infectious IBS develops in approximately 10% of patients following infectious enteritis, representing a distinct pathophysiological subgroup. 2, 4 Key inflammatory mechanisms include:

• Low-grade mucosal inflammation resulting from compromised epithelial barrier function, dysbiosis, or altered stress levels. 2
• Inflammatory infiltration and mast cell activation in proximity to colonic nerves, contributing to abdominal pain frequency and severity. 4
• Persistent gut inflammatory and immune factors following bowel infection or inflammation. 1

Microbiome Alterations

The gut microbiome has emerged as an integral component of gut-brain communication through its influence on endocrine, neural, and immune pathways. 1 Specific findings include:

• Distinct microbiome compositions between IBS patients with and without psychological comorbidity. 1, 2
• Animal model evidence showing that fecal transplantation from humans with IBS and anxiety into mice induces behavioral abnormalities, gastrointestinal motility changes, immune activation, and gut barrier dysfunction. 1
• Altered gut microflora contributing to symptom generation in at least a subset of IBS patients. 4

Genetic and Shared Pathophysiological Mechanisms

Genome-wide analysis of over 250,000 people with IBS identified shared genetic risk factors with depression and anxiety disorders, indicating common pathophysiological mechanisms rather than one condition causing the other. 1 Additional findings include:

• Reduced brain volume and changes in resting brain functional connectivity across brain regions implicated as shared mechanisms linking IBS with depression and anxiety. 1
• HPA axis dysregulation serving as a key pathophysiological mechanism for both IBS and depression, explaining their frequent co-existence. 1

Integrative Disease Model

IBS requires understanding as a systems-based disorder where peripheral gut alterations dominate in some patients while disturbed central processing of peripheral signals predominates in others. 3 The relative contribution of gut versus brain factors is unique to each patient, with cluster-based modeling identifying subgroups with varying degrees of gastrointestinal symptoms, extra-intestinal symptoms, and psychological comorbidity. 1

Critical Clinical Implications

• No specific physiological mechanism is unique to or characterizes all IBS patients; rather, at least three interrelated factors (altered gut reactivity, visceral hypersensitivity, and brain-gut axis dysregulation) affect symptoms to varying degrees in different individuals. 1
• Psychological factors can trigger and perpetuate the core pathophysiological mechanisms (disordered motility, visceral hypersensitivity, altered mucosal/immune/microbial integrity), but IBS is not a psychological disorder—the physical gastrointestinal symptoms are real. 1
• Anxiety specifically related to gastrointestinal symptoms can be a key driver of symptom severity and impaired quality of life. 1

Common Pitfalls to Avoid

• Do not conceptualize IBS as a single disease entity: It represents multiple physiological subgroups contributing to a common symptom complex, requiring identification of specific pathophysiological mechanisms in each patient for targeted treatment. 1
• Do not dismiss the physical basis of symptoms: Although psychosocial factors influence symptom experience and healthcare-seeking behavior, the symptoms have a clear physiological basis involving measurable alterations in gut function, brain processing, and immune-microbiome interactions. 1
• Do not assume uniform pathophysiology: The challenge is determining for each individual patient which interacting factors are identifiable and remediable, as the optimal treatment approach will be unique based on their specific pathophysiological profile. 1