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The Effect of Omeprazole on the Development of Experimental Autoimmune Encephalomyelitis in C57BL/6J and SJL/J Mice

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The Effect of Omeprazole on the Development of Experimental Autoimmune Encephalomyelitis in C57BL/6J and SJL/J Mice

Scott A Sands et al. BMC Res Notes.

Abstract

Background: Gastric disturbances such as dyspepsia are routinely encountered by multiple sclerosis (MS) patients, and these conditions are often treated with gastric acid suppressors such as proton pump inhibitors, histamine H2 receptor antagonists, or antacids. The proton pump inhibitor omeprazole can alter the gut flora and immune responses, both of which can influence the course of experimental autoimmune encephalomyelitis (EAE), an animal model of MS. The objective of the current study was to examine the effect of omeprazole treatment on the development of EAE. Bacterial microbiome analysis of mouse fecal pellets was determined in C57BL/6J EAE mice chronically treated with omeprazole, and spleen immune cell content, clinical scores, weight, rotarod latency, and histopathology were used as outcome measures in C57BL/6J and SJL/J mice with EAE.

Results: Omeprazole treatment resulted in decreases in Akkermansia muciniphila and Coprococcus sp. and an increase in unidentified bacteria in the family S24-7 (order Bacteroidales) in C57BL/6J mice with EAE. Omeprazole did not alter spleen immune cell content compared to vehicle in EAE mice, but differences independent of treatment were observed in subsets of T cells between early and advanced disease in C57BL/6J mice as well as between the two strains of mice at an advanced disease stage. Omeprazole caused no difference in clinical scores in either strain, but significantly lowered weight gain compared to vehicle in the C57BL/6J mice with EAE. Omeprazole also did not alter rotarod behavior or hindbrain inflammatory cell infiltration compared to vehicle in both strains of mice with EAE. Rotarod latency did reveal a negative correlation with clinical scores during active disease in both mouse strains, but not during clinical remission in SJL/J mice, suggesting that rotarod can detect disability not reflected in the clinical scores.

Conclusions: Despite alterations in the gut microbiota and weight gain in the C57BL/6J EAE model, omeprazole had no effect on multiple measures of disease activity in C57BL/6J and SJL/J mice with EAE, supporting the notion that omeprazole does not substantially influence disease activity in MS patients.

Figures

Figure 1
Figure 1
Next-generation sequencing of fecal microbiota from omeprazole and saline treated C57BL/6J mice. Pellets were collected on Day 40 post-encephalitogen during active disease from a subset of omeprazole (n = 5) and saline (n = 5) treated C57BL/6J mice. Sequences were annotated against a database of known 16S rRNA gene sequences and binned at all taxonomic levels (phylum, class, order, etc.). Operational taxonomic units (OTUs) represented in these graphs were statistically different following omeprazole treatment in C57BL/6J mice. Overall distribution in saline (A) and omeprazole (B) treated mice and more detailed analyses of three different OTUs (C-E) are shown. Black bars - saline treatment; white bars - omeprazole treatment. Additional information is provided in Additional file 1: Table S1.
Figure 2
Figure 2
Evaluation of spleen immune cell content in omeprazole and saline treated C57BL/6J mice. Quantitation of spleen immune cells from flow cytometry analysis in saline and omeprazole treated C57BL/6J mice was performed on Day 18 post-encephalitogen (A, B), which was at an early clinical stage (clinical scores: saline 2.36 +/- 0.84, n = 7 vs. omeprazole 1.21. +/- 0.15, n = 7; p = 0.15) and Day 46 post-encephalitogen (C, D), which was during an advanced disease stage (clinical scores: saline 4.14 +/- 0.7, n = 7 vs. omeprazole 4.14 +/- 0.14, n = 7; p = 1.0). No differences in the percent of naïve (CD44loCD62Lhi), CM (CD44hiCD62Lhi) or EM (CD44hiCD62Llo) CD4+ or CD8+ cells (from parent CD4+ or CD8+ populations) were observed following omeprazole treatment vs. saline during both stages of EAE. Black bars, saline treatment; white bars, omeprazole treatment.
Figure 3
Figure 3
Comparison of omeprazole and saline treated C57BL/6J mice with EAE. Average clinical scores (A) revealed no significant differences between groups, but weight differences (B) revealed that omeprazole treated EAE mice (n = 12) had significantly less weight gain relative to Day 7 than saline EAE mice (n = 12). Rotarod latency at Day 14 (C), Day 25 (D), and Day 40 (E) post-encephalitogen, with no differences observed between omeprazole and saline groups. A strong negative correlation was observed between clinical score and rotarod latency during active disease at Day 40 post-encephalitogen (r2 = -0.747, p < 0.005), but not at Day 14 or Day 25. Black squares, saline treatment; white squares, omeprazole treatment. Histological examination revealed no major differences in inflammatory cell infiltrates in the hindbrains of both saline (F) and omeprazole (G) C57BL/6J mice during active disease. Bar = 50 μm.
Figure 4
Figure 4
Evaluation of omeprazole and saline treated SJL/J mice with EAE. Quantitation of percent of naïve, CM or EM CD4+ or CD8+ cells (relative to respective parent CD4+ or CD8+ populations) was performed on spleen cells from saline (n = 5) and omeprazole (n = 5) treated SJL/J mice during active disease (A, B). No significant differences were observed following omeprazole treatment compared to saline in the relative percentages of all T cell populations examined. Average clinical scores (C) and weight difference from the day prior to disease onset (D) in saline and omeprazole treated SJL/J mice. No significant differences were observed between groups (n = 15 for the omeprazole group and n = 16 for the saline group at the start of the study, with 5 mice per group sacrificed at Day 15 and used for splenocyte analysis, above). Rotarod latency plotted vs. clinical scores during active disease, Day 14 post-encephalitogen (E) and remission, Day 21 post-encephalitogen (F). No differences were observed following omeprazole treatment vs. saline at either disease stage. A negative correlation was observed between clinical score and rotarod latency on Day 14 post-encephalitogen (r2 = -0.653, p < 0.005).

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