Personalized medicine in functional gastrointestinal disorders: Understanding pathogenesis to increase diagnostic and treatment efficacy

Table 1 Commonly encountered gastrointestinal diseases and their phenotypic presentations (symptoms and pathophysiology) and management principles

Disease phenotype	Symptoms	Pathophysiology	Diagnosis	Treatment options or selections
Functional dyspepsia	Postprandial fullness, early satiety; Epigastric pain, epigastric burning	Alterations in gastric emptying and/or gastric accommodation	Gastric emptying study; Gastric accommodation studies (SPECT, MR imaging)	Reduced GE and/or GA → prokinetic or gastric relaxants; Normal GE and GA → central pain modulator
Outlet dysfunction constipation	Constipation, abdominal pain	Pelvic floor dyssynergia	Anorectal manometry with balloon expulsion test; MR defecography	Pelvic floor rehabilitation with biofeedback training
Slow transit constipation	Constipation, abdominal pain	Decreased colonic motility	Colon transit studies with radiopaque markers or scintigraphy or wireless motility capsule	Prokinetic agents; Secretory + stimulant laxatives; Total colectomy with ileo-rectal anastomosis
Bile acid diarrhea	Diarrhea; Abdominal pain	Increased bile acid synthesis/ decreased bile acid absorption	Total fecal bile acids; Fecal bile acid composition; Serum 7-α-hydroxy-4-cholesten-3-one	Bile acid binders

GE: Gastric emptying; GA: Gastric accommodation; SPECT: Single-photon emission computed tomography; MR: Magnetic resonance.

Table 2 Pharmacological treatments (current or in-development) for indications based on accurate phenotyping of gastrointestinal disorders

Drug	Mechanism of action	Indication	Typical doses	Phases of trials completed	Study design	Important results
Relamorelin	Synthetic ghrelin analog	Diabetic gastro-paresis	10 µg b.i.d. SQ	Phase 2 (Phase 3 on-going); Multicenter, randomized, double-blind, placebo-controlled, parallel-group study; 2 wk single-blind, placebo run-in[18]	Diabetic gastroparesis patients (n = 393); Placebo (n = 104) vs relamorelin [10 µg (n = 98), 30 µg (n = 109), 100 µg (n = 82)] twice daily × 12 wk	Symptoms of diabetic gastroparesis (but not vomiting frequency) significantly reduced vs placebo in all relamorelin groups; Significant acceleration of GE from baseline vs placebo; Dose-related worsening of glycemic control in relamorelin arm[18]
Acotiamide	Acetyl-cholinesterase inhibitor	Functional dyspepsia	100 mg t.i.d.	Phase 3 Multicenter, single arm, open label safety trial[66]	Functional Dyspepsia patients (n = 207); Acotiamide three times daily × 1 yr	Improved postprandial fullness, early satiation, quality of life, work productivity; No significant adverse effects[66]
Colesevelam	Bile acid sequestrants	BAD	625-1875mg b.i.d.	FDA approved for DM2 and hyperlipidemia; Single center, unblinded single-dose trial in IBS with BAD[67]	IBS-D with prior evidence of increased bile acid synthesis/excretion (n = 12): colesevelam 1875 mg twice daily × 10 d	Increased fecal total bile acid, and deoxycholic acid excretion by sequestration by BA binder; Increased serum C4; More solid stool consistency[67]
Colestipol		BAD	5 g daily initially, + 5 g/ mo increase up to 30 g daily	FDA approved for primary hypercholesterolemia	No large trials for primary therapy in treatment of bile acid diarrhea[68]	Can consider in those who do not tolerate colesevelam or cholestyramine[68]
Prucalopride	5-HT4 receptor agonist	CC	1 mg (> 65 yr); 2 mg (< 65 yr) q.d.	FDA approved; Multiple Phase 3: multicenter, randomized, placebo-controlled, parallel group trials[69]	Chronic constipation patients (n = 620); Placebo vs prucalopride 2 mg vs prucalopride 4 mg	Significant increase in patients with three or more spontaneous, complete bowel movements/week with 2 mg prucalopride vs placebo NNT = 5[69]
Tegaserod		IBS-C and CC	2 or 6mg bid	FDA approved for patients with low cardiovascular risk; Multiple phase 3 and 4 trials with several; Systematic reviews and Meta-analyses showing consistent efficacy[70]	9242 patients in 11 trials (3 only females, 8 studies with constipation predominant patients); Tegaserod 0.5-12 mg twice daily for 4 to 20 wk	Relative risk of symptoms persisting = 0.85% (95%CI: 0.80-0.90, I2 = 57%); NNT = 10[70]
Alosetron	5-HT3 receptor antagonist	IBS-D	0.5-1.0 mg b.i.d.	FDA approved; Multiple phase 3 and 4 trials with several; Systematic reviews and Meta-analyses showing consistent efficacy[70]	4987 IBS patients in 8 trials (5 with only female participants); Alosetron (dose range studied 0.1 to 8 mg) twice daily compared to placebo	Relative risk of symptoms persisting = 0.79; (95%CI: 0.69-0.90, I2 = 85%) NNT = 8[70]

BAD: Bile acid diarrhea; CC: Chronic constipation; IBS: Irritable bowel syndrome; IBS-C: IBS-constipation; IBS-D: IBS-diarrhea; FDA: Food and Drug Administration; DM2: Type 2 diabetes mellitus; GE: Gastric emptying; NNT: Number needed to treat; CI: Confidence interval.