In a new study, published in Cell Host & Microbe, researchers identified changes in the gut microbiome that are associated with brain damage in extremely premature infants. The findings suggest that the gut-microbiome-brain axis could be a potential target for future treatments.
Brain damage in premature infants
The incidence of premature births has been rising globally. It is one of the key causes of perinatal morbidity and mortality. Extremely premature infants are at a high risk of brain damage, leading to many suffering from life-long neurodevelopmental issues. The third trimester of pregnancy is a critical period for the establishment, refinement, and maturation of infants’ brain connectivity. However, extremely premature babies are born before the third trimester, meaning their neural circuitry is established outside of the womb. The infants, therefore, have early exposure to the influence of many environmental cues.
The gut microbiome in premature infants
One of the key environmental factors that affects premature infants is the immediate colonisation of their bodies by microorganisms. From the moment infants are born, extra-uterine bacteria begin to establish in the babies’ gut microbiota. Previous studies have shown that the gut microbiota is implicated in early development through interaction with the brain. This relationship is known as the gut-brain axis. In addition, it has been shown that the microorganisms within the gut microbiome in premature infants are not in equilibrium. Nonetheless, it is still unclear exactly how the developing gut microbiota, immune system and brain all interact.
In a recent study, a team of researchers from the University of Vienna analysed the gut microbiota, immune system and neurophysiological development of 60 extremely premature infants. They aimed to discover whether there were any links between the microbiome and brain damage.
Reduced neuroprotectants in infants with brain injury
The researchers found that one week after birth, infants with brain damage had higher levels of γδ T cells in their blood than healthy infants. Human γδ T cells, which have a distinct T cell receptor, are involved in the initiation of immune responses. The team found a positive correlation between elevated levels of γδ T cells and decreased levels of two neuroprotectants. These were specifically brain-derived neurotrophic factor (BDNF) and platelet-derived growth factor-BB (PDGF-BB). BDNF plays an important role in neuronal survival, growth and plasticity, which is essential for learning and memory. Meanwhile, PDGF-BB plays a significant role in cell growth, division and blood vessel formation. These results suggest that the increase of γδ T cells in premature infants underlies reduced levels of neuroprotectants. This in turn influences brain development.
Increased levels of Klebsiella in the gut microbiome
As the microbiome is an important determinant of our immune response, the team next analysed the gut flora of premature infants. The group found that infants with brain damage had on average 1.7 times more bacteria of the genus Klebsiella in their gut microbiota four weeks post-delivery than infants without brain damage. In particular, levels of Klebsiella pneumoniae correlated significantly with severe brain injury. Interestingly, the specific strain of K. pneumoniae isolated possessed several virulence factors, including antibiotic resistance genes.
Crucially, the researchers found a positive association between Klebsiella levels and γδ T cell levels. Conversely, the team discovered a negative association between Klebsiella levels and neuroprotectant levels. Altogether, these results suggest that Klebsiella overgrowth in the gut microbiome is directly involved in the dysregulation of the gut microbiota-immune-brain axis which leads to brain injury.
Conclusions and future work
Overall, these results show that the development of the gut microbiome is a key factor in whether premature infants develop brain injuries. The team identified Klebsiella levels specifically as a key factor in the assembly of a distinctive microbiome associated with severe brain damage. The findings demonstrate that the gut-microbiota-immune-brain axis may be an attractive target for future treatment methods.
The researchers will continue to follow the children studied in this work over several years. This will provide valuable insights into how early development of the gut-immune-brain axis affects children’s motor and cognitive skills over time.
“In fact, we have been able to identify certain patterns in the microbiome and immune response that are clearly linked to the progression and severity of brain injury,” co-author David Berry said. “Crucially, such patterns often show up prior to changes in the brain. This suggests a critical time window during which brain damage of extremely premature infants may be prevented from worsening or even avoided.”
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