1. Pathophysiology of irritable bowel syndrome
Prof Gerald J Holtmann, MD, Prof Alexander C Ford, MD, Prof Nicholas J Talley, MD 
The Lancet Gastroenterology & Hepatology 
Volume 1, Issue 2, Pages (October 2016)
DOI: /S (16)
Copyright © 2016 Elsevier Ltd Terms and Conditions

2. Figure 1 Histological presentation of colonic spirochaetosis
Colonic spirochaetosis indicated by blue fringe arrows on haematoxylin and eosin staining and, inset, Warthin Starry staining.
The Lancet Gastroenterology & Hepatology 2016 1, DOI: ( /S (16) )
Copyright © 2016 Elsevier Ltd Terms and Conditions

3. Figure 2
Immunostaining of colonic mucosa in a patient with irritable bowel syndrome
Increased mast cells in colonic mucosa in the lamina propria in a patient with IBS (CD117 immunostaining).
The Lancet Gastroenterology & Hepatology 2016 1, DOI: ( /S (16) )
Copyright © 2016 Elsevier Ltd Terms and Conditions

4. Figure 3 Association between anxiety scores and TNFα concentration
Association between the release of TNFα from peripheral blood mononuclear cells and anxiety scores as measured with HADS. HADS=hospital anxiety and depression score. Figure adapted from Liebregts and colleagues.24 Anxiety is related to circulating TNFα, suggesting a possible mechanism by which subtle intestinal inflammation in IBS might induce or worsen mood disturbance.
The Lancet Gastroenterology & Hepatology 2016 1, DOI: ( /S (16) )
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5. Figure 4
A proposed gut–brain disease model in irritable bowel syndrome
Adapted from Talley and Fodor with permission.97 Different people have distinct gut microbiota; the hypothesis is that the differences set in motion an inflammatory cascade in those who are genetically predisposed and subject to a specific environmental hit. A new insult (eg, acute infectious gastroenteritis or a food antigen) could damage intestinal permeability, leading to a cascade of microbes upregulating mast cells through the T-helper-2-cell pathway. Toll-like receptors (TLR) on mast cells may interact directly with relevant microbes. Mast cells accumulate in the lamina propria and release histamine (which interacts with histamine 1–4 receptors), proteases (PAR1 receptor), and probably serotonin (5-HT3 and 5-HT4 receptors). Chemical signalling, via receptors, results in neural excitation and smooth muscle contraction, leading to abdominal pain, abnormal intestino-abdominal reflex responses (that, combined with fermentation by gas-producing bacteria in the lumen, triggers bloating), and disturbed intestinal transit (manifest as diarrhoea or constipation, or both, depending on the balance of upregulatory and downregulatory responses). Cytokines and chemokines are released into the circulation inducing extra-intestinal symptoms
The Lancet Gastroenterology & Hepatology 2016 1, DOI: ( /S (16) )
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6. Figure 5
Potential factors that determine the manifestation of irritable bowel syndrome symptoms
Multiple interacting pathways can affect the manifestation of IBS. Environmental factors dominate, but genetic makeup is also likely to be crucial for the onset and manifestation of symptoms.
The Lancet Gastroenterology & Hepatology 2016 1, DOI: ( /S (16) )
Copyright © 2016 Elsevier Ltd Terms and Conditions