Lactobacillus rhamnosus(LR) ameliorates acute respiratory distress syndrome (ARDS) via modulating the lung “Innate Lymphoid Cells (ILCs)-Mononuclear Phagocytic System (MPS)”

Abstract Acute-respiratory-distress-syndrome (ARDS), the ultimate manifestation of acute-lung-injury (ALI) is a life-threatening respiratory failure with a significantly higher incidence and mortality worldwide. Recent discoveries have emphasized the existence of a potential nexus between gut and lung-health wherein physiology of the gut is directly linked with the outcomes of the lung pathologies. These discoveries fuel novel approaches including probiotics for the treatment of several respiratory disorders including ALI/ARDS. Lactobacillus rhamnosus (LR) is a preferred probiotic of choice as it has been reported to exhibit potent anti-inflammatory activities in various inflammatory diseases. In the present study, we investigated the prophylactic-potential of LR in lipopolysaccharide (LPS)-induced ALI/ARDS mice model, which mimics the pathophysiology of several respiratory disorders including respiratory tract infections, COVID-19, influenza, pneumonia, asthma, tuberculosis, cystic fibrosis, chronic obstructive pulmonary disease (COPD) etc. Our in vivo findings revealed that pretreatment with LR significantly attenuated lung inflammation and improved the pathophysiology of lung-tissues in ALI/ARDS mice. We observed that LR-administration suppressed the LPS-induced inflammatory cell infiltration in the lungs via ameliorating vascular-permeability (edema) of the lungs. Acute and chronic lung-disorders, including ARDS, are largely governed by innate-immune response. Interestingly, we observed that LR via modulating different ILCs (first responder to infections) subsets viz. ILC1, ILC2 and ILC3 prevent lung-fibrosis and maintain vascular permeability in LPS induced ALI/ARDS mice model. Of note, we observed a significant-enhancement in the percentage of inflammatory IL-17 producing CD3 - Rorγt + NKp46 - ILC3-fraction along with a significant reduction in IL-22 (responsible for vascular integrity) producing CD3 - Rorγt + NKp46 + ILC3 in both the BALF and lung-tissues. These ILCs would further augment the activation and recruitment of mononuclear phagocytic system (MPS-monocytes, macrophages and DCs) along with neutrophils and eosinophils in the lungs and BALF in ALI/ARDS mice model. Furthermore, gene expression and protein-analysis demonstrated that LR treatment significantly reduces the expression of inflammatory-cytokines in lung tissue and serum, thereby suggesting its potent immunomodulatory activity in attenuating ALI/ARDS. Summarily, our research convincingly establishes the prophylactic-role of LR in the prevention and management of respiratory-distress syndromes driven by the diverse inflammatory insults via modulating the lung’s “ILCs-MPS” axis with significant clinical-implications for the management of COVID-19, Influenza, COPD etc.