Table 5.

Studies reporting gastrointestinal side effects associated with AST

Study	Study characteristic	Key findings
Dysbiosis
Jackson et al.39	Population-based cohort analysis N = 1,827 individuals from the TwinsUK study	Significantly lower abundance in gut commensals and lower microbial diversity were reported in PPI users
Hojo et al.40	Observational study N = 20 patients with reflux esophagitis who received 8-week PPI therapy	A significant increase in Lactobacillus species and Streptococcus species in fecal samples was observed following 4 and 8 weeks of treatment with PPIs, respectively
Horvath et al.41	Cohort study N = 50 patients with cirrhosis on long-term PPI therapy and 40 control patients with cirrhosis without PPI therapy	Patients on long-term PPI therapy showed a significant increase in Streptococcus salivarius, Veillonella parvula, and the genus Streptococcus, which performed well as biomarkers for dysbiosis
Clostridium difficile infection
Barletta and Sclar, 201442	Retrospective case-control study N = 400 ICU patients	PPI use was an independent risk factor for development of CDI in ICU patients (p = 0.012) The heightened risk was particularly associated with two or more days of PPI therapy
Trifan et al.43	Systematic review and meta-analysis of 56 studies N = 3,56,683 patients	PPI use increased the risk of CDI (OR, 1.99; p < 0.001)
Tariq et al.44	Systematic review and meta-analysis N = 7,703 patients with CDI	A higher rate of recurrent CDI (22.1%) was observed in patients receiving AST
Park et al.45	Single-center, cohort study N = 3,09,073 hospitalized patients, n = 1,25,922 PPI users, n = 1,83,151	PPI use was associated with a 1.8-fold increase in CDI risk High-dose PPI increased the risk of CDI by two-fold
Seo et al.46	Retrospective, observational, comparative cohort study N = 67,915 patients with CDI	There was a significantly higher risk of CDIs among patients taking PPIs compared with those on H2RAs HR for CDI development was 2.22 times higher in the PPI group compared with the group of patients receiving H2RAs
Inghammar et al.47	Nationwide cohort study N = 3,583 cases of community-associated CDI	PPI users showed a 2.03-fold increased risk of community-associated CDI compared with nonusers
D'Silva et al.48	Systematic review and meta-analysis N = 57,477 patients with CDI	Significantly higher odds of recurrent CDI were observed in patients who received PPIs (OR, 1.69)
Lee et al.49	Retrospective cohort study N = 16,820 ICU patients	A higher proportion of patients receiving PPI developed CDI compared with H2RAs (3.0 vs 0.8%, p < 0.001) Both intravenous (OR, 2.4) and oral (OR, 2.3) use of PPI were associated with higher odds of developing CDI compared with H2RAs
Inflammatory bowel disease
Xia et al.50	Pooled analysis NHS, n = 82,869; NHS II, n = 5,141; and UK Biobank, n = 4,69,397	PPI use was consistently associated with a significantly increased risk of IBD A high risk of IBD was also observed in regular PPI users compared with H2RAs alone
Shastri et al.51	Systematic review and meta-analysis of eight studies N = 1,57,758 participants	PPI use increased the risk of IBD (adjusted OR, 2.43), including ulcerative colitis and Crohn's disease together, collagenous colitis, and lymphocytic colitis
Onwuzo et al.52	Cross-sectional population-based analysis N = 45,586,150	PPI use increased the odds of ulcerative colitis (OR, 2.02; p < 0.001) as well as Crohn's disease (OR, 2.79; p < 0.001) development
Choden et al.53	Longitudinal, retrospective cohort analysis N = 46,234 patients with IBD, n = 6,488 PPI users, n = 39,746 nonusers	PPI use in IBD patients was associated with higher odds of hospital admissions (OR, 1.95) and surgeries (OR, 1.46) Worse clinical outcomes were observed in IBD patients on concomitant PPI therapy
Bacterial peritonitis
Min et al.54	Retrospective cohort study N = 1,554 cirrhotic patients with ascites	PPI group patients had a higher annual SBP incidence rate compared with nonusers PPI use was an independent risk factor for SBP (HR, 1.396)
Xu et al.55	Comprehensive meta-analysis N = 8,204 cirrhotic patients with ascites	PPI use was significantly associated with an increased risk of SBP (OR, 2.17) and overall bacterial infection (OR, 1.98) in cirrhotic patients with ascites
Zang et al.56	Retrospective study N = 1,092 patients with chronic liver diseases/cirrhosis with acute insults (the HBV-reactivation)	PPI users with elevated MELD scores were at an increased risk of SBP
Dahabra et al.57	Retrospective cohort analysis N = 1,07,750 patients with SBP	PPI use was strongly associated with an increased risk of SBP (OR, 4.24; p < 0.0001) compared with nonusers
Fundic gland polyps
Ally et al.58	Retrospective cohort study N = 385 patients who underwent upper endoscopy	Chronic PPI therapy lasting for more than 48 months was an independent predictor of FGP (OR, 4.7; p = 0.001)
Tran-Duy et al.59	Systematic review with a meta-analysis of 12 studies N = 87,000 patients with FGP	Long-term PPI use (≥12 months) was associated with a significantly increased risk of FGP (OR, 1.43)
Martin et al.60	Systematic review and meta-analysis of 12 studies N = 40,218 patients with FGP	PPI usage increased the odds of FGP development (OR, 2.46; p = 0.001) This association was more pronounced in individuals on PPI therapy for at least six months (OR, 4.71) or 12 months (OR, 5.32)
Velazquez-Dohorn et al.61	Case-control analysis N = 133 patients with gastric polyps	PPI administration for at least one year was linked to the development of gastric FGP (OR, 7.7)
Microscopic colitis
Keszthelyi et al.62	Retrospective case-control study N = 136 cases of microscopic colitis	Histological diagnosis of microscopic colitis was significantly associated with exposure to PPIs compared with controls (38 vs 13%; p < 0.001; adjusted OR, 4.5)
Masclee et al.63	Population-based nested case-control study N = 1,458,410 subjects	The use of PPIs (OR-adjusted 10.6) and NSAIDs (OR-adjusted 5.6) increased the risk of microscopic colitis
Bonderup et al.64	Nationwide case‐control study N = 10,652 patients with a diagnosis of microscopic colitis	There was a robust association between current PPI use and both collagenous colitis (adjusted OR, 6.98) and lymphocytic colitis (adjusted OR, 3.95)

AST, acid suppression therapy; CDI, Clostridium difficile infections; FGP, fundic gland polyps; H2RAs, histamine-2-receptor antagonists; HBV, hepatitis B virus; HR, hazard ratio; IBD, inflammatory bowel disease; NHS, Nurses' Health Study; MELD, model for end-stage liver disease; OR, odd ratio; SBP, spontaneous bacterial peritonitis