Proton pump inhibitors induce changes in the gut microbiome composition of systemic lupus erythematosus patients

Abstract

Background: Currently, few studies focus on the association between gut microbiota and systemic lupus erythematosus (SLE), and much less studies consider the effect of drug usage. Proton pump inhibitors (PPIs) are commonly used to treat drug-related gastrointestinal damage in SLE patients. Therefore, the purpose of this study is to examine the gut microbiota of SLE patients using PPIs.

Methods: Fecal samples from 20 SLE patients with PPIs (P-SLE), 20 SLE patients without PPIs (NP-SLE) and 17 healthy controls (HCs) were obtained. The structure of the bacterial community in the fecal samples was analyzed by 16S rRNA gene sequencing. Redundancy analysis (RDA) was performed to observe the relationship between clinical variables and microbiome composition in P-SLE and NP-SLE patients. Based on the Kyoto Encyclopedia of Genes and Genomes (KEGG) database, functional capabilities of microbiota were estimated. Network analysis was performed to analyze the association of metabolic pathway alterations with altered gut microbiota in P-SLE and NP-SLE patients.

Results: P-SLE patients exhibited increased alpha-diversity and an altered composition of the gut microbiota compared with NP-SLE patients. The alpha-diversity of NP-SLE patients was significantly lower than HCs but also of P-SLE patients, whose alpha-diversity had become similar to HCs. Compared with NP-SLE patients, the relative abundances of Lactobacillus, Roseburia, Oxalobacter, and Desulfovibrio were increased, while those of Veillonella, Escherichia, Morganella, Pseudomonas and Stenotrophomonas were decreased in P-SLE patients. RDA indicated that PPI use was the only significant exploratory variable for the microbiome composition when comparing SLE patients. KEGG analysis showed that 16 metabolic pathways were significantly different between NP-SLE and P-SLE patients. These metabolic pathways were mainly associated with changes in Escherichia, Roseburia, Stenotrophomonas, Morganella and Alipipes as determined by the network analysis.

Conclusions: PPI use is associated with an improved microbiome composition of SLE patients as it 1) increases alpha-diversity levels back to normal, 2) increases the abundance of various (beneficial) commensals, and 3) decreases the abundance of certain opportunistic pathogenic genera such as Escherichia. Validation studies with higher patient numbers are however recommended to explore these patterns in more detail.

Keywords: Gut microbiota; Proton pump inhibitors; Systemic lupus erythematosus.

Fig. 1

Diversities of the gut microbiota among P-SLE patients, NP-SLE patients and HCs. A inverse Gini-Simpson index; The middle line in the box plot represents the median value, and the box is drawn from the 25% to75% quartiles. B Principal coordinate analysis (PCoA) of the bacterial community structures in HCs, P-SLE patients and NP-SLE patients. HCs: healthy controls; P-SLE: SLE patients with PPIs; NP-SLE: SLE patients without PPIs

Fig. 2

Characteristics of the microbial composition in SLE patients with PPI use. A Relative abundance of the dominant bacteria at phylum level in the gut microbiota of SLE patients with or without PPIs use and the HCs group; B Relative abundance of the dominant bacteria at phylum level in the gut microbiota of SLE patients with or without PPIs use and the HCs group; C Relative abundance of the dominant bacteria at genus level in the gut microbiota of SLE patients with or without PPIs use and the HCs group. HCs: healthy controls; P-SLE: SLE patients with PPIs; NP-SLE: SLE patients without PPIs

Fig. 3

Compositions of the gut microbiota among SLE patients and HCs. LEfSe analysis was performed to identify differentially abundant taxa by the phylogenetic tree; Linear discriminant analysis (LDA) results were showed by LDA score. HCs: healthy controls; P-SLE: SLE patients with PPIs; NP-SLE: SLE patients without PPIs

Fig. 4

Redundancy analysis based on Bray–Curtis dissimilarity. RDA analysis indicated that only PPIs were significant explanatory variables for microbiome composition (P < 0.05). CRP: C-reactive protein; ESR: Erythrocyte sedimentation rate; HCQ: Hydroxychloroquine; SLEDAI: Systemic Lupus Erythematosus Disease Activity Index 2000; DD: Disease duration; LN: Lupus nephritis; C3: Complement 3; C4: Complement 4; P-SLE: SLE patients with PPIs; NP-SLE: SLE patients without PPIs

Fig. 5

Association network analysis of PPIs, microbiota and KEGG pathways in P-SLE and NP-SLE patients. The diamonds represent PPI, the circles represent species, the squares represent KEGG category, and the different colors of species represent different phyla-level classifications; the thickness of the lines represents the strength of correlation, pink represents positive correlation, and blue represents negative correlation