Abstract
BackgroundMelioidosis, caused by the Gram-negative bacterium Burkholderia pseudomallei, is an emerging cause of pneumonia-derived sepsis in the tropics. The gut microbiota supports local mucosal immunity and is increasingly recognized as a protective mediator in host defenses against systemic infection. Here, we aimed to characterize the composition and function of the intestinal microbiota during experimental melioidosis.Methodology/Principal findingsC57BL/6 mice were infected intranasally with B. pseudomallei and sacrificed at different time points to assess bacterial loads and inflammation. In selected experiments, the gut microbiota was disrupted with broad-spectrum antibiotics prior to inoculation. Fecal bacterial composition was analyzed by means of IS-pro, a 16S-23S interspacer region-based profiling method. A marked shift in fecal bacterial composition was seen in all mice during systemic B. pseudomallei infection with a strong increase in Proteobacteria and decrease in Actinobacteria, with an increase in bacterial diversity. We found enhanced early dissemination of B. pseudomallei and systemic inflammation during experimental melioidosis in microbiota-disrupted mice compared with controls. Whole-genome transcriptional profiling of the lung identified several genes that were differentially expressed between mice with a normal or disrupted intestinal microbiota. Genes involved in acute phase signaling, including macrophage-related signaling pathways were significantly elevated in microbiota disrupted mice. Compared with controls, alveolar macrophages derived from antibiotic pretreated mice showed a diminished capacity to phagocytose B. pseudomallei. This might in part explain the observed protective effect of the gut microbiota in the host defense against pneumonia-derived melioidosis.Conclusions/SignificanceTaken together, these data identify the gut microbiota as a potential modulator of innate immunity during B. pseudomallei infection.
Highlights
Melioidosis is a frequent cause of community-acquired sepsis in Southeast Asia and northern Australia [1, 2]
The intestinal microbiota has been suggested to be a modulator of innate immune defenses against bacterial infections
We investigated in mice whether the intestinal microbiota affects the clinical course of melioidosis and vice versa
Summary
Melioidosis is a frequent cause of community-acquired sepsis in Southeast Asia and northern Australia [1, 2]. Pneumonia is the presenting symptom in most adult patients [3] and results in a rapidly progressive illness with a high mortality up to 40% [1, 3]. The disease is caused by Burkholderia pseudomallei, a facultative intracellular Gram-negative bacterium that is commonly found in the soil from countries located between 20 ̊ north latitude and 20 ̊ south latitude [1, 2, 4]. The global burden of melioidosis is probably much larger than previously anticipated: it was recently estimated that each year 165,000 (95% credible interval 68,000–412,000) people suffer from this debilitating disease resulting in 89,000 (36,000–227,000) fatalities [5]. Melioidosis, caused by the Gram-negative bacterium Burkholderia pseudomallei, is an emerging cause of pneumonia-derived sepsis in the tropics. We aimed to characterize the composition and function of the intestinal microbiota during experimental melioidosis.
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