Impact of gut colonization with butyrate-producing microbiota on respiratory viral infection following allo-HCT

Abstract

Respiratory viral infections are frequent in patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HCT) and can potentially progress to lower respiratory tract infection (LRTI). The intestinal microbiota contributes to resistance against viral and bacterial pathogens in the lung. However, whether intestinal microbiota composition and associated changes in microbe-derived metabolites contribute to the risk of LRTI following upper respiratory tract viral infection remains unexplored in the setting of allo-HCT. Fecal samples from 360 allo-HCT patients were collected at the time of stem cell engraftment and subjected to deep, 16S ribosomal RNA gene sequencing to determine microbiota composition, and short-chain fatty acid levels were determined in a nested subset of fecal samples. The development of respiratory viral infections and LRTI was determined for 180 days following allo-HCT. Clinical and microbiota risk factors for LRTI were subsequently evaluated using survival analysis. Respiratory viral infection occurred in 149 (41.4%) patients. Of those, 47 (31.5%) developed LRTI. Patients with higher abundances of butyrate-producing bacteria were fivefold less likely to develop viral LRTI, independent of other factors (adjusted hazard ratio = 0.22, 95% confidence interval 0.04-0.69). Higher representation of butyrate-producing bacteria in the fecal microbiota is associated with increased resistance against respiratory viral infection with LRTI in allo-HCT patients.

Graphical abstract

Figure 1.

Timeline depicting longitudinal changes in butyrate-producing bacteria abundance and viral LRTI events following engraftment. Patients are sorted into 3 groups, depending on the abundance of butyrate-producing bacteria in the engraftment sample (triangle). For the most part, abundances were high at the start of allo-HCT, but declined as antibiotics (green lines) were administered. Viral lower respiratory tract events are depicted with their associated respiratory viruses by the purple lines following engraftment. Adeno, adenovirus; Corona, coronavirus; FluA, influenza virus type A; FluB, influenza virus type B; Metapneumo, human metapneumovirus; Paraflu1, parainfluenza virus type 1; Paraflu3, parainfluenza virus type 3; Rhino, rhino-/enterovirus; RSV, respiratory syncytial virus.

Figure 2.

Association between butyrate-producing bacteria abundance and the development of viral LRTI. Kaplan-Meier analysis starting at neutrophil engraftment. Log-rank P values are significant if P < .05.

Figure 3.

Correlation between butyrate-producing bacteria abundance and absolute fecal concentrations of butyrate, acetate, and propionate, and relative abundance of DAT. Kruskal-Wallis P values are significant if P < .05.