Functional gastrointestinal disorders and gut-brain axis: What does the future hold?

Table 1 Different factors that influence the brain - Gut interaction in functional gastrointestinal disorders

Nature of link	Evidence	Comments
Dysbiosis	Kassinen et al[82]; Tojo et al[83]; Chassard et al[84]; Cryan et al[85]	Disturbance in the complex community of microbiota seems to influence gut-brain axis by modulating neuroendocrine, neuroimmunal and visceral sensory system.
Altered mucosal secretions	Mazmanian et al[86]; Xue et al[87]	Secretion is modulated by complex interaction of intrinsic and extrinsic factors acting on gut mucosa. Dysregulation of the epithelial cells due to autonomic reactivity may lead to 5-HT release contributing to altered secretion
Disturbance in motility	Randich et al[13]; Dass et al[88]; Barbara et al[89]	Products of metabolism of gut bacteria, such as short-chain fatty acids modulate enteric system and influence the rate of gut transit
Visceral hypersensitivity	O'Mahony et al[22]; Akbar et al [34]	Patients with IBS have been found to have an increased concentration of pain-sensing receptors such as TPRV1 compared to the controls.
Altered processing of visceral signals	Lemann et al[90]; Mertz et al[91]	There is increased activation of certain cerebral areas in IBS patients compared to the controls. Altered processing of the visceral pain in the central nervous system has been a recurring theme in many studies.
Immune dysfunction	Chadwick et al[92]; Dinan et al[24]; Keely et al[93]	Patients with prolonged Infectious diarrhea are much more prone to developing IBS. Also, biopsies of patients with IBS have shown increased immune cells in the mucosa[92].
Psychological disturbances	Creed et al[17]; Gwee et al[94]; Drossman et al[95]; Monnikes et al[2,12]	Patients with FGIDs have co-existing psychosocial symptoms such as stress, anxiety and depression and thus a biopsychosocial model has been proposed for FGIDs
Early life stress	O'Mahony et al[22]; Bailey et al[96]	Early life-stress can alter the composition of gut microbiota

5-HT: 5-hydroxytryptamine; FGID: Functional Gastrointestinal diseases; IBS: Inflammatory bowel disease; TRPV1: Transient receptor potential vallinoid 1.

Table 2 Methods used to study brain - Gut interaction in functional gastrointestinal disorders

Link to be tested	Name of the test	Evidence	Comments
Microbiota-gut-brain axis
	Germ-free mice	Abrams et al[45]	This has been the most widely used technique to study the gut-brain axis. Germ-free mice are compared with healthy to look for changes in desired characteristics or behaviors
	Antibiotic-treated mice	Verdú EF et al[59]	Antibiotics are used to induce changes in the composition of microbiota and then these treated mice are compared with untreated mice to look for the desired characteristics. Antibiotics are useful for selectively eliminating certain bacteria from the gut, allowing the growth of other strains.
	Mice treated with probiotics	Mohle et al[64]	Once germ-free mice have been studied, they can be injected with probiotics to establish the reciprocity of the relationship that has been studied.
The interactions between visceral, peripheral and central pathways
	Functional MRI (fMRI)	Tillisch et al[72]; Aziz et al[73]; Mayer et al[75], and Labus et al[76]	fMRI measures the changes in oxygenated and deoxygenated hemoglobin where oxygenated hemoglobin denotes the group of neurons that have increased activity. They are useful in studying the complex relationship between visceral stimuli and brain response.
	PET imaging	Tillisch[72]	PET imaging has the advantage of probing a particular receptor by developing a radiolabeled ligand. This important feature can be used to assess specific receptor activities during pain and stress response in control and FGID patients.
	Structural MRI (sMRI)	Seminowicz et al[77]	Whole and regional brain images using sMRIs have been used to study differences between individuals with FGIDs and control groups

FGIDs: Functional gastrointestinal diseases; MRI: Magnetic resonance imaging; PET: Positron emission tomography.