Review 1: "Commensal Bacteria can Inhibit the Growth of P. Aeruginosa in Cystic Fibrosis Airway Infections Through a Released Metabolite"

Sarah E Clark

Commensal bacteria can inhibit the growth of P. aeruginosa in cystic fibrosis airway infections through a released metabolite

by Andrew Tony-Odigie, Alexander H. Dalpke, Sébastien Boutin, and Buqing Yi

Show Description
Published on Feb 04, 2023
www.biorxiv.org

Description

Abstract In cystic fibrosis (CF), infections with Pseudomonas aeruginosa or other typical pathogens play a critical role in eliciting disease progression, leading to tissue damage and finally loss of lung function. Previous observations showed that the presence of various commensal bacteria and a higher airway microbiome diversity were associated with better lung function and less severe disease burden. Thus, the hypothesis was raised that commensal bacteria might be able to interfere with pathogenic bacteria. In this study, we aimed to identify airway commensal bacteria that inhibit the growth of P. aeruginosa.Through a screening experiment of co-culture with P. aeruginosa PAO1, we could identify more than 30 CF commensal strains from various species that inhibited the growth of P. aeruginosa. With multiple selected strains, we further verified the results with P. aeruginosa CF isolates and several other pathogens isolated from CF patients, and most of the identified commensal strains showed consistent results strongly inhibiting the growth of diverse CF pathogens.The underlying mechanisms of the growth-inhibition effects were first investigated through genomic analysis by comparing strains with and without growth-inhibition effects, which revealed that genes responsible for carbohydrate transport and metabolism were highly enriched in the inhibitory commensals. Metabolite analysis and functional analysis showed that commensals with inhibitory effects produce large amounts of acetate. Exogenous addition of acetate under a low pH inhibited the growth of P. aeruginosa, indicating acetate produced and released by commensals may affect the growth of P. aeruginosa living in the same microenvironment.In summary, through co-culture of P. aeruginosa with commensals, we could identify that a variety of airway commensal strains can inhibit the growth of P. aeruginosa by producing acetate. The data provide insights into possible novel strategies for controlling infections in people with CF and also emphasize the importance of preserving airway commensals when designing infection treatment strategies.

RR:C19 Evidence Scale rating by reviewer:

Reliable. The main study claims are generally justified by its methods and data. The results and conclusions are likely to be similar to the hypothetical ideal study. There are some minor caveats or limitations, but they would/do not change the major claims of the study. The study provides sufficient strength of evidence on its own that its main claims should be considered actionable, with some room for future revision.

***************************************

Review:

This paper addresses the inhibitory potential of commensal bacteria found in the CF airway. The authors identify several Streptococcus strains, including isolates of S. mitis, S. oralis, and S. cristatus, isolated from CF sputum samples which were shown to inhibit growth of Pseudomonas aeruginosa in vitro using an mcherry reporter strain and OD600 measurements. In contrast, other Streptococcus strains and isolates outside this genus were not inhibitory using this assay. In addition to P. aeruginosa, co-cultures with inhibitory S. mitis and S. cristatus isolates (but not a non-inhibitory strain S. intermedius) reduced OD600 growth over time for several other CF pathogens including S. aureus and K. pneumoniae. The inhibitory effect against P. aeruginosa was observed in conditioned media from the Streptococcus strains, and was resistant to heat inactivation or treatment with proteinase K. In the conditioned media, low pH and acetate were identified as the top candidates responsible for P. aeruginosa growth inhibition. Supporting this, exogenous acetate under low pH was sufficient to inhibit P. aeruginosa growth. It is unclear whether low pH and acetate also support growth inhibition of the other CF pathogens tested in the co-culture setting, as this was not addressed. Critical questions remain undefined, such as how much acetate is present in the lungs of people with CF and whether this environment has a low pH, both of which are key factors required for the inhibitory mechanism. The authors also do not address literature concerning P. aeruginosa inhibition of Streptococcus species, which would impact the Streptococcus inhibitory mechanism they describe in vivo. Nevertheless, the authors identify a potential benefit for Streptococcus commensals against a wide range of CF bacterial pathogens.