Transplantation-Associated Long-Term Immunosuppression Promotes Oral Colonization by Potentially Opportunistic Pathogens without Impacting Other Members of the Salivary Bacteriome

Abstract

e Solid-organ transplant recipients rely on pharmacological immunosuppression to prevent allograft rejection. The effect of such chronic immunosuppression on the microflora at mucosal surfaces is not known. We evaluated the salivary bacterial microbiome of 20 transplant recipients and 19 nonimmunosuppressed controls via 454 pyrosequencing of 16S rRNA gene amplicons. Alpha-diversity and global community structure did not differ between transplant and control subjects. However, principal coordinate analysis showed differences in community membership. Taxa more prevalent in transplant subjects included operational taxonomic units (OTUs) of potentially opportunistic Gammaproteobacteria such as Klebsiella pneumoniae, Pseudomonas fluorescens, Acinetobacter species, Vibrio species, Enterobacteriaceae species, and the genera Acinetobacter and Klebsiella. Transplant subjects also had increased proportions of Pseudomonas aeruginosa, Acinetobacter species, Enterobacteriaceae species, and Enterococcus faecalis, among other OTUs, while genera with increased proportions included Klebsiella, Acinetobacter, Staphylococcus, and Enterococcus. Furthermore, in transplant subjects, the dose of the immunosuppressant prednisone positively correlated with bacterial richness, while prednisone and mycophenolate mofetil doses positively correlated with the prevalence and proportions of transplant-associated taxa. Correlation network analysis of OTU relative abundance revealed a cluster containing potentially opportunistic pathogens as transplant associated. This cluster positively correlated with serum levels of C-reactive protein, suggesting a link between the resident flora at mucosal compartments and systemic inflammation. Network connectivity analysis revealed opportunistic pathogens as highly connected to each other and to common oral commensals, pointing to bacterial interactions that may influence colonization. This work demonstrates that immunosuppression aimed at limiting Tcell-mediated responses creates a more permissive oral environment for potentially opportunistic pathogens without affecting other members of the salivary bacteriome.

Human Microbiota Characterization in the Course of Renal Transplantation

“…Diaz et al compared the salivary microbiota of transplant recipients and healthy controls and observed relatively higher fractions of potentially opportunistic pathogens belonging to the Gammaproteobacteria in transplant subjects (25). Different immunosuppressants were correlated with increased microbiota richness (the corticosteroid prednisone) or specific microbiota members (increase in Candida spp.…”

Microbiology, Genomics, and Clinical Significance of the Pseudomonas fluorescens Species Complex, an Unappreciated Colonizer of Humans

“…P. fluorescens has been implicated as a cause of acute bacterial cystitis (192)(193)(194), both with (192) and without (193) the presence of an indwelling urinary catheter. In a study comparing the oral microbiomes of 20 solid organ transplant recipients and 19 nonimmunosuppressed control subjects, P. fluorescens was abundant in the saliva of nearly 50% of transplant subjects while being nearly absent from nontransplant controls (1). In another study of 258 stomach wall biopsy specimens acquired from patients with various upper gastrointestinal disorders, 93% had evidence of the presence of P. fluorescens (identified via both culture-dependent and -independent methods) (2).…”

“…One interesting feature is that a number of these studies have identified the bacterium Pseudomonas fluorescens as a lowabundance member of the indigenous microbiota of various body sites, including the mouth, stomach, and lungs (1)(2)(3)(4)(5). P. fluorescens has generally been considered nonpathogenic for humans, an assessment dating back to its earliest descriptions, by A. Baader and C. Garre, in Ü ber Antagonisten unter den Bacterien (1887) (6):…”

The Microbiome, Systemic Immune Function, and Allotransplantation

“…The salivary microbiome in kidney and heart transplant recipients is disrupted compared with normal oral flora in favor of colonization with opportunistic pathogens, including Pseudomonas, Acinetobacter, and Enterobacteriaceae species (58). Such changes are termed "dysbiosis."…”