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.