Gut microbiota dysbiosis promotes inflammation
An essential aspect in the development of BPD is inflammation activation. Recruitment of neutrophils and macrophages to preterm immature lungs in response to chemokines contributes to the production of several inflammatory factors such as interleukin-1, interleukin-6, interleukin-8, TNF-α and transforming growth factor-β (TGF-β), resulting in lung injury68, an essential pathological process in BPD. In addition, recent studies have shown that the decrease of interleukin-17A69, as a microbial signal-related cytokine38, and anti-inflammatory factor interleukin-1070, is strongly associated with BPD.
Notably, the gut microbiota appears to exert an extraordinarily vital function in regulating lung inflammation. The gut microbiota drives the secretion of interleukin-1β, interleukin-6, and TGF-β71,72, and its dysregulation causes a decrease in both interleukin-17A and interleukin-22, while altering interleukin-6 and TNF-α signaling38. For example, gut microbiota dysbiosis caused significantly elevated levels of interleukin-6 in bronchoalveolar lavage fluid from mice with lipopolysaccharide-induced lung inflammation73. Furthermore, findings suggest that the metabolic state of alveolar macrophages is significantly altered in response to gut microbiota dysbiosis74. In contrast, supplementation with acetate, generated by the gut microbiota, dramatically diminished the levels of inflammation in the lungs of neonatal mice exposed to hyperoxia75. Moreover, fecal microbiota transplantation attenuated inflammatory cell infiltration and interstitial lung exudates in acute lung injury in rats by downregulating the expression of TNF-α, interleukin-1β, interleukin-6, and TGF-β176. Similarly, fecal microbiota transplantation has been shown to alleviate radiation-induced lung inflammation77. Additionally, mice with gut microbiota dysbiosis that received fecal microbiota transplantations showed earlier recovery of both TNF-α and interleukin-10 levels following Streptococcus pneumoniaeinfection74.
Furthermore, the gut microbiota probably affects BPD by influencing the expression of specific immune genes in the blood33. For example, MAE increases the number of CD45-positive cells and granulocytes, leading to over-immunity, resulting in lung injury38. 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 injury43.
Surprisingly, gut microbiota and its metabolites also seem to be associated with pulmonary fibrosis78. For example, TLR4 recognizes the damage-associated molecular pattern signal produced by the gut microbiota and activates myeloid differentiation 2/TLR4-dependent fibroblasts under the drive of myeloid differentiation 2, resulting in lung fibrosis79.
Collectively, gut microbiota dysbiosis initiates inflammation partly via direct transfer of bacteria to the lungs80 and partly through the release of specific immune signals such as polysaccharide A, sphingolipids, which are taken up by immune cells triggering an inflammatory response. Moreover, gut microbiota dysregulation causes impaired intestinal epithelial integrity, allowing microorganisms and metabolites to directly enter the bloodstream, leading to systemic inflammation. When the developing lungs receive these abnormal or amplified inflammatory signals, they alter the lungs perception of their surroundings, leading to chronic inflammation32.
Gut microbiota dysbiosis affects growth
It is widely accepted that malnutrition is one of the most critical factors leading to the occurrence and deterioration of BPD. Previous studies have shown that adequate early energy and protein supply are significantly negatively correlated with BPD risk28,81. For VLBW or extremely premature (EPT) infants, elimination of undernutrition as a means of recovery from BPD may be beneficial. Notably, there appears to be a strong correlation and partial overlap between postnatal growth restriction, gut microbiota dysbiosis, and BPD, especially between gut microbiota and preterm infant nutrition, although the causal relationship between the three still needs to be confirmed82.
Mice receiving gut microbiota from malnourished infants developed growth disturbances and metabolic abnormalities, whereas mice receiving gut microbiota from healthy infants did not. Interestingly the mice received the gut microbiota from undernourished infants gained in terms of growth advancement when the two groups of mice cohabited83. A microbiota-directed complementary food study showed improvements in the nutritional status of gnotobiotic animals and promoted growth, bone formation, neurodevelopment, and enhanced immune function were observed in malnourished children84. Furthermore,Lactobacillus plantarum helped maintain weight and length in germ-free mice exposed to chronic malnutrition by partially eliminating peripheral tissue resistance to growth hormone and insulin-like growth factor-1, thus illustrating the importance of the gut microbiota in promoting growth85.
Actinobacteria , Proteobacteria , and Firmicutes at the phylum level of gut microbiota were remarkably correlated with nutritional intake. Actinobacteria and Proteobacteriacorrelate with lipid intake, Firmicutes with protein, and all three are associated with carbohydrates, these presumably facilitate increased calories uptake and growth19. In addition, the gut microbiota is involved in energy metabolism as it regulates the levels of several organic acids such as pyruvate, citric acid, fumaric acid and malic acid, and is intrinsic to lipid metabolism as the microbiota regulates lipase activity12. For example, gut microbiota dysbiosis releases specific signals to accelerate lipolysis and fatty acid oxidation, which is probably a contributor to slow growth in malnourished infants86. Moreover, SCFA (butyrate, acetate and propionate) and other specific substances (trimethylamine, indolepropionic acid) secreted by the gut microbiota contribute crucially to various nutrient metabolic processes including food fermentation and transformation. Specifically, butyrate helps collect energy, propionate senses gluconeogenesis and satiety signals, acetate is involved in cholesterol and fat metabolism, gut microbial enzymes regulate bile acid metabolism, and indolepropionic acid fights free radicals29.
Recent studies indicated that growth disorders were strongly associated with reducing gut microbiota diversity and maturity.Staphylococcaceae and Enterobacteriaceae were the dominant bacteria observed during the growth decline phase, whereasStreptococcus and Bifidobacterium were present in relatively high proportions during the growth catch-up period86. An obvious consideration is the weakened ability of Enterobacteriaceae (a significant member within theGammaproteobacteria family) to decompose human milk oligosaccharides and engender less butyrate and vitamins, which cripples intestinal digestion and absorption87. Furthermore, Yee et al.88 showed a relationship between the growth of 83 VLBW infants and longitudinal gut microbiota changes. They discovered that weight gain was related to the alpha diversity of the microbiota, and length gain was related to the fluctuation amplitude of beta diversity and maturity. Gut microbiota dysbiosis impedes VLBW growth through multiple pathways, such as weakened or disrupted synthesis of polysaccharides and amino acids, consequently making it more susceptible to pathogens87.
It is of note that weight-gain at different age stages is possibly influenced by the composition of the gut microbiota at specific times. For example, the gut microbiota during early postnatal days impacts the weight of preterm infants at one month of age. In these cases the abundance of Staphylococcus and Enterococcus wasnegatively correlated with weight-gain, whereas Weissella was positively associated with weight-gain89. Similarly, the diversity and maturity of the gut microbiota at month 6 postnatally were correlated with weight-gain at 6-12 months of age, during which time Proteobacteria and Bacteroidetes were positively correlated with weight-gain, whereas Actinobacteria were negatively correlated with weight-gain90.
These data suggest that gut microbiota plays a critical role in growth. Gut microbiota dysbiosis and malnutrition are in turn involved in BPD potentially through mechanisms such as altering epigenetics, promoting inflammation and oxidative stress, changing intestinal permeability, modifying vascular and lymphatic vessel development, and by affecting micronutrients82.