Table 1.

Summary of Pathophysiology-directed Therapeutic Approach for Disorders for Gut-Brain Interactions

Drug name		Function/pathway	Pathophysiological mechanisms	Clinical outcome	DGBI types
Prokinetics	Prucalopride	5-HT4R agonist	Altered gut motility	Improved GI symptoms as assessed by the GCSI.	Gastroparesis, FD, chronic constipation
				Improved solid gastric emptying.
	Felcisetrag	Selective 5-HT4R agonist	Altered gut motility	Accelerated transit of solids throughout the gut in patients with idiopathic or diabetic gastroparesis.	Gastroparesis
				Stimulate motility and secretion through enhanced release of acetylcholine from excitatory motor neurons and interneurons.
	Alosetron	5-HT3R antagonist	Altered gut motility	Improved stool consistency and bowel movements.	IBS-D
	Ondasetron
	Ramosetron
	Cilansetron
	Buspirone	5-HT1R agonist	Altered gut motility	Fundus relaxation, improve gastric accommodation.	FD
	Tandospirone
	Relamorelin	Ghrelin receptor agonist	Altered gut motility	Stimulates nodose afferents and DMV neurons and accelerates gastric emptying.	Gastroparesis
	Metoclopramide	Dopamine-2 receptor antagonists	Altered gut motility	Improved gut motility.	FD, gastroparesis
	Domperidone
	Itopride
	Acotiamide	Muscarinic receptor antagonists	Altered gut motility	Inhibits acetylcholinesterase and antagonizes the presynaptic muscarinic receptors, present on cholinergic nerve endings, which leads to an increase in acetylcholine levels in the synaptic cleft.	FD
Antibiotics	Neomycin	Modulating gut microbiota profile	Gut microbiota dysbiosis	Shifting the microbial community composition.	IBS
	Rifaximin			Improvement in constipation, SIBO and dyspeptics symptoms.
Probiotics	Bifidobacterium animalis DN-173010154, Bifidobacterium lactis DN-173	Modulating gut microbiota profile	Gut microbiota dysbiosis	Shifting the microbial community composition.	IBS
	Lactobacillus gasseri			Improved symptoms and gut transit.
Bile acid sequestrants	Obeticholic acid	FXR agonist	Bile acid alterations	Stimulate the synthesis and subsequent release of FGF-19 from ileal epithelial cells and inhibit bile acid synthesis by hepatocytes.	IBS-D
	Tropifexor
	Cholestyramine			Improve stool form and symptoms of diarrhea.
Bile acid transporter inhibitor	Elobixibat	IBAT antagonist	Bile acid alterations	Efficacious treatment for constipation, improving gut transit and symptoms via increasing colonic bile acids.	IBS-C
	Cholestipol
Anti-inflammatory agents	Mesalazine	Gut immune homeostasis	Low grade inflammation	Sustained therapy response and benefits for a subgroup of patients with IBS.	IBS
			Visceral hypersensitivity
	Ketotifen	Mast cell stabilizer	Visceral hypersensitivity	Increased the threshold for discomfort in patients with IBS with visceral hypersensitivity, and reduced IBS symptoms.	IBS
	Ebastine	Histamine receptor-1 antagonist	Visceral hypersensitivity	Reduced visceral hypersensitivity and abdominal pain in patients with IBS.	IBS
Acid suppressive therapy	Pantoprazole	Proton pump inhibitors	Gut immune dysfunction	Reduced duodenal eosinophilia, mast cells, and intestinal permeability in patients with FD.	FD
			Epithelial barrier dysfunction
			Visceral hypersensitivity
Neuromodulators	Amitriptyline	TCA	Gut-brain dysregulation	Affect gastrointestinal motility through anticholinergic and serotonergic mechanisms. TCAs reduce visceral hypersensitivity. Antidepressant therapy might lead to neurogenesis.	IBS, FD
	Mirtazapine	Tetracyclic antidepressants	Gut-brain dysregulation	Upregulates the levels of orexigenic hormones and downregulated the levels of anorexigenic hormones.	FD
	Escitalopram	SSRI	Gut-brain dysregulation	Treating depressive symptoms with these molecules modulates the severity of GI symptoms indirectly via a positive effect on depression.	IBS
	Venlafaxine	SNRI
	Duloxetine
Intestinal Secretagogues	Lubiprostone	CCl2 agonist	Abnormal secretion	Increased fecal water content.	IBS-C, chronic constipation
				Creates an ion gradient that promotes water and sodium secretion into the intestinal lumen.
	Linaclotide	Guanylate cyclase-C receptor agonist	Abnormal secretion	Increase water secretion via targeting cGMP leads to the secretion of chloride and bicarbonate into the intestinal lumen.	IBS-C
Visceral Analgesics	Oliceridine	Biased μ-Opioid receptor ligands	Visceral hypersensitivity	Management of moderate to severe acute pain in adults for whom alternative treatments other than opioids had failed.	IBS
	Olorinab	Cannabinoid type 2 receptor agonist	Visceral hypersensitivity	Potential analgesic effects in patients with IBS.	IBS

DGBIs, disorders of gut-brain interactions; 5-HTR, 5-hydroxytriptamine receptor; GI, gastrointestinal; GCSI, gastroparesis cardinal symptom index; FD, functional dyspepsia; DMV, dorsal motor nucleus of the vagus; IBS-D, diarrhea-predominant irritable bowel syndrome; SIBO, small intestinal bacterial overgrowth; IBS, irritable bowel syndrome; FXR, farnesoid X receptor; FGF-19, fibroblast growth factor 19; IBAT, ileal bile acid transporter; IBS-C, constipation-predominant irritable bowel syndrome; TCA, tricyclic antidepressant; SSRI, serotonin reuptake inhibitor; SNRI, serotonin norepinephrine reuptake inhibitor; CCl2, type 2 chloride channel; cGMP, cyclic guanosine monophosphate.