Intestinal Dysbiosis and the Developing Lung: The Role of Toll-Like Receptor 4 in the Gut-Lung Axis

Abstract

Background: In extremely premature infants, postnatal growth restriction (PNGR) is common and increases the risk of developing bronchopulmonary dysplasia (BPD) and pulmonary hypertension (PH). Mechanisms by which poor nutrition impacts lung development are unknown, but alterations in the gut microbiota appear to play a role. In a rodent model, PNGR plus hyperoxia causes BPD and PH and increases intestinal Enterobacteriaceae, Gram-negative organisms that stimulate Toll-like receptor 4 (TLR4). We hypothesized that intestinal dysbiosis activates intestinal TLR4 triggering systemic inflammation which impacts lung development. Methods: Rat pups were assigned to litters of 17 (PNGR) or 10 (normal growth) at birth and exposed to room air or 75% oxygen for 14 days. Half of the pups were treated with the TLR4 inhibitor TAK-242 from birth or beginning at day 3. After 14 days, pulmonary arterial pressure was evaluated by echocardiography and hearts were examined for right ventricular hypertrophy (RVH). Lungs and serum samples were analyzed by western blotting and immunohistochemistry. Results: Postnatal growth restriction + hyperoxia increased pulmonary arterial pressure and RVH with trends toward increased plasma IL1β and decreased IκBα, the inhibitor of NFκB, in lung tissue. Treatment with the TLR4 inhibitor attenuated PH and inflammation. Conclusion: Postnatal growth restriction induces an increase in intestinal Enterobacteriaceae leading to PH. Activation of the TLR4 pathway is a promising mechanism by which intestinal dysbiosis impacts the developing lung.

The Role of Gut Microbiota in Lung Cancer: From Carcinogenesis to Immunotherapy

“…At present, many studies have shown that the intestinal flora is closely associated with many diseases featuring chronic systemic inflammation ( 71 – 73 ). Intestinal bacteria not only influence immune and inflammatory responses at the local mucosal level but also lead to chronic pulmonary inflammation via gut-lung axis communication ( 52 , 74 ). Gut dysbiosis can lead to damage to intestinal mucosal barrier function and increase intestinal mucosal permeability ( 75 , 76 ); invading microorganisms and metabolites can cause local and systematic inflammation.…”

“…For example, Stephen Wedgwood et al. found that gut dysbiosis characterized by a significant increase in Enterobacteriaceae activates TLR4 in the intestine and causes inflammation, increases the level of IL-1β in peripheral circulation, transduces inflammatory signals to the lungs, and activates the NF-κB pathway, leading to pulmonary inflammation ( 74 ). Similarly, Jia Tang et al.…”

Revisited Hyperoxia Pathophysiology in the Perioperative Setting: A Narrative Review

“…In premature neonates, the association between hyperoxia and postnatal growth restriction, alters the microbiota of the distal small bowel and cecum, leading to an increase in pro-inflammatory Gram-negative Enterobacteriaceae: the recognition of lipopolysaccharide in the cell wall of Enterobacteriaceae by the host TLR-4 is important in the pathogenesis of necrotizing enterocolitis. TLR4 signaling is also involved in lung injury and inflammation (70). Moreover, hyperoxia might have a positive role during colon surgery.…”

Gut microbiota and bronchopulmonary dysplasia

“…One possible reason is that hyperoxia alters the gut microbiota, leading to the pathogen invasion and inflammation involved in BPD development. For example, hyperoxia exposure dramatically elevated amounts ofEnterobacteriaceae 43 , Proteobacteria andEpsilonbacteraeota 44 in mouse intestines. Another murine intestinal tract showed that hyperoxia reversed the antibiotic-induced decreases in Bacteroidales andAlistipes and incerases ofAkkermansia 41 .…”

“…For example, MAE increases the number of CD45-positive cells and granulocytes, leading to over-immunity, resulting in lung injury 38 . Besides this, metabolites produced by the gut microbiota, such as lipopolysaccharide, recognized by TLR4 via the pathogen-associated molecule patterns pathway, caused an increase in interleukin-1β, which further activated nuclear factor kappa-B and formed an inflammatory cascade leading to lung injury 43 . Surprisingly, gut microbiota and its metabolites also seem to be associated with pulmonary fibrosis 78 .…”