In recent preclinical models, the inhalation of a mixture of living Lactobacilli bacteria attenuated pulmonary inflammation and improved lung function and structure for the chronic lung diseases bronchopulmonary dysplasia and chronic obstructive pulmonary disease. This study , published in the journal Nature Communications , determined the mechanism of this live biotherapeutic product—a powder mixture of living Lactobacilli bacteria—to reduce neutrophilic inflammation and reduce a broad swath of inflammatory markers in BPD and COPD, says Charitharth Vivek Lal, M.D.
, a University of Alabama at Birmingham neonatologist who co-led the research with Amit Gaggar, M.D., Ph.
D., a UAB pulmonologist. Their findings "provide a paradigm for the progression of structural lung disease," Lal said, because it identifies the Lactobacilli as critical to regulating lung protease activity that is linked to the destruction caused by matrikine generation, extracellular matrix turnover and chronic neutrophilic inflammation that damages air sacs in the lungs.
A possible protective role for Lactobacilli in the lung and the possible use of Lactobacilli to treat chronic lung disease had its foundation in 2016 when Lal and UAB colleagues discovered that the airways of infants with severe bronchopulmonary dysplasia had decreased numbers of Lactobacilli, increased numbers of proteobacteria and increased concentrations of proteobacterial endotoxin. In this latest study, the UAB researchers provide a mechanism of action for the Lactobacilli treatment to decrease downstream disease development and showed safety and effectiveness of the live biotherapeutic treatment in a mouse pup model for BPD and three mouse models of COPD. Bronchopulmonary dysplasia develops in some extremely premature infants after damage induced by high oxygen tension or mechanical ventilation needed to keep them alive.
COPD occurs in older people, especially smokers, and kills about 130,000 Americans a year and about 3 million more worldwide. "Inhaled live biotherapeutic products show promise in addressing common pathways of disease progression that in the future can be targeted at a variety of lung diseases," Lal said. "Preclinical animal data is suggestive, and safety of the potential drug in humans will be tested in a forthcoming clinical trial.
Human adult safety data in COPD will help de-risk the pathway to approval for use of the drug in bronchopulmonary disease infants." The UAB researchers hypothesized that mouse models of BPD would show heightened levels of acetylated proline-glycine-proline, or Ac-PGP, an extracellular matrix-derived peptide, as had been seen in premature infants with BPD. This was demonstrated in BPD mouse models, and gain- or loss-of-function studies showed the impact of Ac-PGP.
Intranasal instillation of Ac-PGP increased neutrophilic inflammation and lung degradation. When an inhibitor of Ac-PGP was given with the Ac-PGP, markers of neutrophilic inflammation decreased and lung structure improved. Researchers then showed that a proprietary Lactobacilli blend of L.
planatarum, L. acidophilus and L. rhamnosus performed best in synergy to reduce the inflammatory proteinase MMP-9, which helps release the Ac-PGP from extracellular matrix.
Furthermore, supernatant from Lactobacilli growth medium also reduced MMP-9 at a similar magnitude as live Lactobacilli bacteria. More information: Teodora Nicola et al, A Lactobacilli-based inhaled live biotherapeutic product attenuates pulmonary neutrophilic inflammation, Nature Communications (2024). DOI: 10.
1038/s41467-024-51169-0.
