Mayer EA. Gut feelings: the emerging biology of gut-brain communication. Nat Rev Neurosci 2011; 12: 453-466.

Box | The brain–gut axis is a system of hierarchical homeostatic reflexes

Prefrontal cortex (PFC); input to the insula (INS); anterior cingulate cortex (ACC); periaqueductal grey (PAG); nucleus tractus solitarius (NTS); rostro–ventro–lateral medulla (RVLM); ventromedial medulla (VMM); dorsal motor nucleus of vagus (DMNV); ANS, autonomic nervous system; medullary catecholaminergic nuclei (A1, A2 and A5)

Mayer EA. Gut feelings: the emerging biology of gut-brain communication. Nat Rev Neurosci 2011; 12: 453-466.

Figure | Gut to brain communication. | Endocrine,immune and neuronal afferent signalling from the gut tothe CNS.

5 hydroxytryptamine (5 HT); ; spinal, vagal and intrinsic primary afferents ‑ ‑(IPANs), enteroendocrine (EE) cells; Enterochromaffin (EC) cells

Mayer EA. Gut feelings: the emerging biology of gut-brain communication. Nat Rev Neurosci 2011; 12: 453-466.

Figure | Gut to brain communication. | Encoding of multiple luminalsignals by EE cells.

GPR40, G protein-coupled receptor 40; T1R, taste receptor type 1 member; TLRs, toll-like receptors; Gαgust’ Gα protein subunit, gustducin; PLCβ2, phospholipase Cβ; PIP2, aquaporin PIP2 member; InsP3, Inositol 1,4,5 trisphosphate; [Ca2+]I intracellular calcium concentration; TRPM5, transient receptor potential cation channel subfamily M member 5; VSCC,voltage-sensitive Ca2+ channel; DAG, diacylglycerol; PKC, protein kinase C; GI peptide, gastrointestinal peptide;

Mayer EA. Gut feelings: the emerging biology of gut-brain communication. Nat Rev Neurosci 2011; 12: 453-466.

Figure | Gut–brain signalling related to food intake.PFC, prefrontal cortex;

OLF, olfaction; aINS, anterior insula; OFC, orbitofrontal cortex; ACC, anterior cingulate cortex; HIPP, hippocampus; AMYG, amygdala; VTA, ventral tegmental area, NAc, nucleus accumbens; LH, lateral hypothalamus; PeF, pernifornical hypothalamus; ARC, arcuate nucleus; AP, area postrema; NTS, nucleus tractus solitarius; cNTS, caudal NTS; rNTS, rostral NTS;

Mayer EA. Gut feelings: the emerging biology of gut-brain communication. Nat Rev Neurosci 2011; 12: 453-466.

Figure | Gut signalling systems, gut sensations and meta-representations of suchsensations.

OFC, orbitofrontal cortex, AMYG, amygdala; HIPP, hippocampus; aINS, anterior insula; CRF, corticotropin releasing factor; SP, substance P; CKK, cholecystokinin; NPY, neuropeptide Y; PYY, peptide YY

Mayer EA. Gut feelings: the emerging biology of gut-brain communication. Nat Rev Neurosci 2011; 12: 453-466.

Figure: Interoceptive memeory and prediction error in chronic disease

ANS, autonomic nervous system; ACC, anterior cingulate cortex; AMYGamygdala; HIPP, hippocampus; OFC orbitofrontalcortex; PFC prefrontal cortex.

Amines

AcetylcholineNorepinephrineSerotonin (5-hydroxytryptamine)

Amino acidsy-Aminobutyric acid

PurinesATP

GasesNitric oxide

Carbon monoxidePeptides

Calcitonin gene—related peptideCholecystokininGalaninGastrin-releasing peptideNeuromedin UNeuropeptide YNeurotensinOpioids

DynorphinEnkephalinsEndorphins

Peptide YYPituitary adenylyl cyclase—activating peptide

SomatostatinSubstance PThyrotropin-releasing hormone

Vasoactive intestinal contractor (an endothelin)Vasoactive intestinal polypeptide

Verdu E, Armstrong D, Murray J. Between celiac disease andirritable bowel syndrome: the “no man’s land” of gluten sensitivity.Am J Gastroenterol 2009

Several studies in patients with IBS have detected low-grade inflammatory changes involving CD3 + cells, mast cells and reduced mucosal expression of SERT (5-HT transporter).

Excess serotonin production in response to a carbohydrate meal has also been described and may be a mechanism for dyspeptic symptoms in celiac disease.

Prolonged 5-HT activity, owing to reduced SERT activity, would be expected to lead to activation of afferent pathways, increased acetylcholine (Ach) release, and activation of peristaltic and secretory reflexes, which may affect gut function and symptom generation.

Verdu E, Armstrong D, Murray J. Between celiac disease andirritable bowel syndrome: the “no man’s land” of gluten sensitivity.Am J Gastroenterol 2009

Rome II Criteria for IBS Diagnosis

The included patients had suffered from recurrent abdominaldiscomfort or pain at least 3 days per month in theprevious 3 months, associated with 2 or more of the following:(1) improvement with defecation;(2) onset associated with a change in stool frequency; or (3) onset associated with a changein stool appearance.

Longstreth GF; Thompson WG , Chey WD et al. Functional bowel disorders. Gastroenterology 2006 ; 130 : 1480 – 1 9

Verdu E, Armstrong D, Murray J. Between celiac disease andirritable bowel syndrome: the “no man’s land” of gluten sensitivity.Am J Gastroenterol 2009;

“[…] Gluten-sensitive individuals, who have IBS symptoms and IgG antibodies to gluten, are orphans, living in no man ’ s land, acknowledged neither by functional disease specialists nor by celiac disease specialists.”

DBPC, double-blind placebo-controlled oral food challenge; FH, food hypersensitivity; IBS, irritable bowel syndrome

A Carroccio, I Brusca, P Mansueto; Fecal Assays Detect Hypersensitivity to Cow’s Milk Protein and Gluten in Adults With Irritable Bowel Syndrome; Clinical Gastroenterology and HepatologyVolume 9, Issue 11 , Pages 965-971, November 2011

The concept that the gut and the brain are closely connected, and that this interaction plays an important part not only in gastrointestinal function but also in certain feeling states and in intuitive decision making, is deeply rooted in our language. Recentneurobiological insights into this gut–brain crosstalk have revealed a complex, bidirectional communication system that not only ensures the proper maintenance of gastrointestinalhomeostasis and digestion but is likely to have multiple effects on affect, motivation and higher cognitive functions, including intuitive decision making. Moreover, disturbances of this system have been implicated in a wide range of disorders, including functional andinflammatory gastrointestinal disorders, obesity and eating disorders.

Mayer EA. Gut feelings: the emerging biology of gut-brain communication. Nat Rev Neurosci 2011; 12: 453-466.