Pharyngeal Microbial Signatures Are Predictive of the Risk of Fungal Pneumonia in Hematologic Patients

Abstract

The ability to predict invasive fungal infections (IFI) in patients with hematological malignancies is fundamental for successful therapy. Although gut dysbiosis is known to occur in hematological patients, whether airways dysbiosis also contributes to the risk of IFI has not been investigated. Nasal and oropharyngeal swabs were collected for functional microbiota characterization in 173 patients with hematological malignancies recruited in a multicenter, prospective, observational study and stratified according to the risk of developing IFI. A lower microbial richness and evenness were found in the pharyngeal microbiota of high-risk patients that was associated with a distinct taxonomic and metabolic profile. A murine model of IFI provided biologic plausibility for the finding that loss of protective anaerobes such as Clostridiales and Bacteroidetes, along with an apparent restricted availability of tryptophan, is causally linked to the risk of IFI in hematologic patients, and indicates avenues for antimicrobial stewardship and metabolic re-equilibrium in IFI.

Targeted Drug Delivery Technologies Potentiate the Overall Therapeutic Efficacy of an Indole Derivative in a Mouse Cystic Fibrosis Setting

“…As the dysbiotic expansion of Enterobacteriacae is associated with a worse outcome in children with CF [ 30 , 31 ], and contributes to infectious pathology in the lung [ 32 ], preliminary as they are, these data indicate a specific 3-IAld-dependent regulation of local microbial composition that could be of benefit in CF. Moreover, the expansion of L. reuteri , known to provide epithelia barrier function at mucosal surfaces [ 33 ], points to the unique ability of 3-IAld to dually act at the microbe/host interface.…”

A Shifted Composition of the Lung Microbiota Conditions the Antifungal Response of Immunodeficient Mice

“…It has been noted that the microbiome may also be involved in protection against Aspergillus [15,16]. In this regard, we have recently shown that the composition of the oropharyngeal microbiome could predict the risk of fungal pneumonia in hematological patients [17]. In particular, an increased risk of fungal pneumonia was associated with the loss of protective anaerobes such as Clostridiales and Bacteroidota and the expansion of pathogenic Proteobacteria, as confirmed in a murine model of aspergillosis [17].…”

“…We have previously shown that strictly anaerobic bacteria, such as Prevotella oris and Peptostreptococcus anaerobius, representative members of Bacteroidota and Firmicutes (order Clostridiales), respectively, protected against infection in a murine model of aspergillosis [17]. Since anaerobic bacteria produce SCFAs, we evaluated the presence of butyric acid and isobutyric acid in in vitro cultures and found that Prevotella oris and Peptostreptococcus anaerobius produced the two SCFAs both in the presence and in the absence of Aspergillus (Figure 1).…”

“…Since strictly anaerobic bacteria protected against aspergillosis by preventing the expansion of pathogenic Proteobacteria [17], we evaluated whether tipping the balance between anaerobic bacteria and Proteobacteria could affect the susceptibility to infection. For this purpose, upon administration of the Proteobacteria Klebsiella pneumoniae in mice with aspergillosis, we found a higher fungal burden (Figure 3A) and a more severe histopathology (Figure 3B) in Klebsiella-exposed mice as compared to wild-type mice, confirming that Proteobacteria may negatively affect the course of the infection.…”

“…In this regard, we have recently shown that the composition of the oropharyngeal microbiome could predict the risk of fungal pneumonia in hematological patients [17]. In particular, an increased risk of fungal pneumonia was associated with the loss of protective anaerobes such as Clostridiales and Bacteroidota and the expansion of pathogenic Proteobacteria, as confirmed in a murine model of aspergillosis [17]. However, the mechanisms at the basis of the protection as well as how the microbiota integrates with the immune system during the response to infection have not been investigated.…”