Impact of short-term proton pump inhibitors vs . histamine-2 receptor antagonists on gut microbiota in patients with acute coronary syndrome: A multicenter randomized trial

Abstract

Background: Several randomized controlled studies have suggested that the prophylactic use of proton pump inhibitors (PPIs) in intensive care unit (ICU) patients could not reduce the incidence of gastrointestinal bleeding (GIB) and may increase adverse events such as intestinal infection and pneumonia. Gut microbiota may play a critical role in the process. PPIs have been widely prescribed for GIB prophylaxis in patients with acute coronary syndrome (ACS). This study aimed to determine the short-term effects of PPI and histamine-2 receptor antagonist (H2RA) treatment on gut microbiota of ACS patients.

Methods: The study was designed as a single-blind, multicenter, three-parallel-arm, randomized controlled trial conducted at three centers in Beijing, China. We enrolled ACS patients at low-to-medium risk of GIB and randomized (2:2:1) them to either PPI ( n = 40), H2RA ( n = 31), or control group ( n = 21). The primary outcomes were the alterations in gut microbiota after 7 days of acid suppressant therapy. Stool samples were collected at baseline and 7 days and analyzed by 16S ribosomal RNA (rRNA) gene sequencing.

Results: There were no significant changes in the diversity of gut microbiota after the short-term use of acid suppressants, but the abundance of Fusobacterium significantly increased and that of Bifidobacterium significantly decreased, especially in PPI users. In addition, the abundance of some pathogenic bacteria, including Enterococcus and Desulfovibrio, was significantly elevated in the PPI users. The fecal microbiota of the PPI users included more arachidonic acid metabolism than that of control group.

Conclusions: PPIs may increase the risk of infection by adversely altering gut microbiota and elevating arachidonic acid metabolism, which may produce multiple proinflammatory mediators. For ACS patients at low-to-medium risk of GIB, sufficient caution should be paid when acid-suppressant drugs are prescribed, especially PPIs.

Registration: www.chictr.org.cn (ChiCTR2000029552).

Keywords: Acute coronary syndrome; Gut microbiota; Histamine-2 receptor antagonists; Proton pump inhibitors.

Figure 1

Flow chart of screening participants for comparing the impact of short-term Proton pump inhibitors and Histamine-2 receptor antagonists on gut microbiota in patients with acute coronary syndrome. H2RA: Histamine-2 receptor antagonist; PPI: Proton pump inhibitor.

Figure 2

Characteristics of gut microbial diversity in ACS patients with acid suppressant use. (A) Four metrics of alpha diversity (observed species, Chao1 estimator richness, Shannon index, and Simpson index) were calculated. Two-tailed Wilcoxon rank sum tests were performed to assess differences between the PPI-user, H2RA-user, and control groups. (B) PCoA of an unweighted UniFrac analysis plot based on the relative taxa abundance in the gut microbiota of ACS patients. Each symbol represents a sample. ACS: Acute coronary syndrome; C: Control; H, H2RA: Histamine-2 receptor antagonist; P, PPI: Proton pump inhibitor; PCoA: Principal coordinate analysis.

Figure 3

Characteristics of the microbial composition in ACS patients with acid suppressant use. (A) Relative abundance of the dominant bacteria at phylum level in the gut microbiota of ACS patients with PPI use, H2RA use, and the control group. (B) Relative abundance of the dominant bacteria at genus level in the gut microbiota of ACS patients with PPI, H2RA use, and the control group. ACS: Acute coronary syndrome; C: Control; H, H2RA: Histamine-2 receptor antagonist; P, PPI: Proton pump inhibitor.

Figure 4

Variations in the gut microbiota in ACS patients with acid suppressant use. (A) LEfSe comparison of the gut microbiota of ACS patients with H2RA use and the control group. Enriched taxa in samples with an LDA score >2.0 are shown. (B) LEfSe comparison of the gut microbiota of ACS patients with PPI use and the control group. Enriched taxa in samples with an LDA score >2.0 are shown. (C) Violin plots showing several bacteria genus that differ between the gut microbiota of PPI-users, H2RA-users, and the control group. ^*P <0.05. ACS: Acute coronary syndrome; C: Control; H, H2RA: Histamine-2 receptor antagonist; LDA: Linear discriminant analysis; LEfSe: Linear discriminant effect size; P, PPI: Proton pump inhibitor.

Figure 5

Variations of arachidonic acid metabolism and nicotinate and nicotinamide metabolism in ACS patients with acid suppressant use. (A) Comparison of arachidonic acid metabolism and nicotinate and nicotinamide metabolism of ACS patients with PPI use, H2RA use, and the control group. (B) Interaction of arachidonic acid metabolism and nicotinate and nicotinamide metabolism with changed bacteria genus. ^*P <0.05; ^§P <0.01. ACS: Acute coronary syndrome; C: Control; H, H2RA: Histamine-2 receptor antagonist; P, PPI: Proton pump inhibitor.