Oral and Gut Microbiota Dysbiosis is Associated with Mucositis Severity in Autologous Hematopoietic Stem Cell Transplantation: Evidence from an Asian Population

Abstract

Mucositis is a debilitating complication of hematopoietic stem cell transplant (HSCT). It is unclear how changes in the composition of microbiota, which are modulated by geographical location and ethnicity, may influence immune regulation leading to the development of mucositis, and the study of both oral and gut microbiota in a single population of autologous HSCT in the Asian region is lacking. The study aimed to characterize the oral and gut microbiota changes, and the impact on both oral and lower gastrointestinal (GI) mucositis, with its associated temporal changes in a population of adult autologous HSCT. Autologous HSCT patients aged 18 years old and above were recruited from Hospital Ampang, Malaysia, between April 2019 to December 2020. Mucositis assessments were conducted daily, whilst blood, saliva and fecal samples were collected prior to conditioning regimen, on Day 0, Day+7 and 6-month post-transplant. Longitudinal differences in alpha and beta diversities were determined using Wilcoxon signed-rank test and Permutational Multivariate Analysis of Variance, respectively. Changes in relative abundances of bacteria across timepoint were assessed using the Microbiome Multivariate Analysis by Linear Models function. The combined longitudinal effects of clinical, inflammatory and microbiota variables on mucositis severity were measured using the generalized estimating equation. From the 96 patients analyzed, oral mucositis and diarrhea (representing lower GI mucositis) were reported at 58.3% and 95.8%, respectively. Alpha and beta diversities were significantly different between sample types (p<0.001) and across timepoints, with alpha diversity reaching statistical significance at Day 0 in fecal (p<0.001) and Day+7 in saliva samples (p<0.001). Diversities normalized to baseline by 6-month. Significant microbiota, clinical and immunological factors were associated with increasing mucositis grades. Increasing relative abundances of saliva Paludibacter, Leuconostoc and Proteus, were associated with higher oral mucositis grades, whilst increasing relative abundances of fecal Rothia and Parabacteroides were associated with higher GI mucositis grades. Meanwhile, increasing relative abundances of saliva Lactococcus and Acidaminococcus, and fecal Bifidobacterium were associated with protective effects against worsening oral and GI mucositis grades, respectively. This study provides real-world evidence and insights into the dysbiosis of the microbiota in patients exposed to conditioning regimen during HSCT. Independent of clinical and immunological factors, we demonstrated significant associations between relative bacteria abundances with the increasing severities of oral and lower GI mucositis. The findings presented in our study offer a potential rationale to consider the inclusion of preventive and restorative measures targeting oral and lower GI dysbiosis as interventional strategies to ameliorate mucositis outcome in HSCT patients.