Long-Term Analysis of Resilience of the Oral Microbiome in Allogeneic Stem Cell Transplant Recipients

Abstract

Stem cell transplantation (SCT) is associated with oral microbial dysbiosis. However, long-term longitudinal data are lacking. Therefore, this study aimed to longitudinally assess the oral microbiome in SCT patients and to determine if changes are associated with oral mucositis and oral chronic graft-versus-host disease. Fifty allogeneic SCT recipients treated in two Dutch university hospitals were prospectively followed, starting at pre-SCT, weekly during hospitalization, and at 3, 6, 12, and 18 months after SCT. Oral rinsing samples were taken, and oral mucositis (WHO score) and oral chronic graft-versus-host disease (NIH score) were assessed. The oral microbiome diversity (Shannon index) and composition significantly changed after SCT and returned to pre-treatment levels from 3 months after SCT. Oral mucositis was associated with a more pronounced decrease in microbial diversity and with several disease-associated genera, such as Mycobacterium, Staphylococcus, and Enterococcus. On the other hand, microbiome diversity and composition were not associated with oral chronic graft-versus-host disease. To conclude, dysbiosis of the oral microbiome occurred directly after SCT but recovered after 3 months. Diversity and composition were related to oral mucositis but not to oral chronic graft-versus-host disease.

Impact of oral microbiota on pathophysiology of GVHD

“…These changes in the early post-transplant period may be due to a significant reduction in defense mechanisms due to the conditioning regimen and associated neutropenia, and they may also be related to OM, antibiotic use, and decreased oral intake. Previous studies have shown that these changes return to approximately the pre-conditioning phase within 1-3 months (134,138).…”

“…Ulcerative oral mucositis after allogeneic HSCT has been observed only in the combination of multi-antibacterial therapy ( 133 ). In the analysis of oral rinses in patients undergoing allogeneic HSCT, the OM-affected group showed a substantial decrease in bacterial microbiota compared to the non-affected group for up to 3 weeks after transplantation ( 134 ). When neutrophil count was included in the regression model, it was found to be a confounding variable, affecting both mucositis and bacterial diversity, while there was no direct effect on diversity.…”

Longitudinal analysis at three oral sites links oral microbiota to clinical outcomes in allogeneic hematopoietic stem-cell transplant

“…Although several dozen core bacterial genera inhabit all oral compartments, different species occupy each oral niche, meaning oral microbes are site-specialists that compose distinct microbiotas in each oral environment [1,59]. We and others have previously reported the impact of allo-HSCT in oral microbiotas and their associations with allo-HSCT complications and outcomes [22][23][24][25][26]30]. However, these studies analyzed single oral sites and were mostly limited to the peri-engraftment period of allo-HSCT.…”

“…Since the immune system regulates microbiota composition [16] and chemotherapy [17], radiotherapy [18], and antibiotics [19] have detrimental effects on the microbiota, drastic alterations in the gut microbiota have been reported in allo-HSCT recipients, including loss of bacterial diversity and blooms of potentially pathogenic species [20]. Recent evidence shows these alterations extend to other microbiotas [21], including the relatively more stable oral microbiota [22][23][24][25][26]. More importantly, the pre-transplant microbiota and the extent of microbiota damage during allo-HSCT are associated with allo-HSCT complications and outcomes, so that gut and oral microbiota provide biomarkers in the allo-HSCT setting [24,25,[27][28][29][30].…”

“…The stability of the oral microbiota [5] and its associations with allo-HSCT outcomes offer a unique opportunity to identify predictive biomarkers and develop therapeutic interventions to promote oral health in allo-HSCT recipients, potentially improving allo-HSCT safety and efficacy. However, so far, oral microbiota studies in allo-HSCT recipients evaluated single oral sites, not leveraging the ease of sampling of different oral compartments [22][23][24][25][26]30]. In addition, although a causal link between post-transplant gut microbiota recovery and improved clinical responses to allo-HSCT has been suggested [15], oral microbiota recovery trajectories after allo-HSCT were not thoroughly characterized and their association with allo-HSCT outcomes remain unknown.…”