METATRANSCRIPTOMIC ACTIVITY OF ORAL-TYPICAL MICROBES IN PROTON PUMP INHIBITOR USAGE

Background: Proton pump inhibitor (PPI) use has been linked to alterations in gut microbial communities, but prior studies have been limited to describing broad differences in microbial abundance. The underlying mechanisms and functional dynamics of these communities as assessed by community-wide transcriptomics (“metatranscriptomics”) remain poorly understood, particularly in the context of host physiologic changes due to long-term acid suppression (e.g., parietal cell hyperplasia) that could favorably alter the local milieu for microbial growth and transcription. Methods: We analyzed stool metagenomes and metatranscriptomes for 307 participants in the long-running Health Professionals Follow-up Study. We defined oral-typical species as those with a greater mean relative abundance in oral vs. gut samples using the Human Microbiome Project (Lloyd-Price et al, Nature 2017). Results: Using multivariable linear modeling, we observed eight differentially abundant species between PPI ever and never-users (Fig. A), with an enrichment of oral-typical microbes in PPI users that remained significant even after adjusting for indication of use (i.e., GERD). The expansion of oral-typical species was broadly observed in both PPI and an active comparator group of histamine-2 receptor antagonist (H2RA) users (Fig. B), supporting the hypothesis that acid suppression leads to the translocation of oral-typical bugs into the gut. The abundance of oral species in the gut significantly increased with greater duration of PPI use, but was uncoupled to length of H2RA use (Fig. C). Next, we analyzed the association between long-term PPI use (≥6 years) and expression of biochemical pathways by oral bacteria. We found that even after controlling for gene copy number, the transcription of 14 MetaCyc pathways was significantly decreased with long-term PPI use, primarily those involved in nucleotide and amino acid biosynthesis and carbohydrate degradation (Fig. D). Specifically, we observed a depletion in the expression of L-isoleucine biosynthesis, which could stimulate gastric acid secretion, in long-term PPI users mostly contributed by Streptococcus spp. This suggests that oral-typical species that translocate to the gut may employ adaptive strategies, such as downregulation of L-type amino acid biosynthesis, which could partially counteract the effect of PPIs by increasing gastric acid secretion. Conclusion: Our findings demonstrated a dose-dependent association between PPI use and increased introgression and eventual colonization of oral species in the gut. Our analysis of community-wide transcription revealed that long-term PPI use leads to altered expression of L-isoleucine biosynthesis, which may increase microbial acid secretion and serve as evidence of a potential microbial response to a host selective pressure (i.e., medication-induced acid suppression).