Bacterial metabolites shape neonatal immune system

There is growing evidence that allergic disorders may be linked to disturbances in the maternal or neonatal microbiota. Two recent studies in Nature Microbiology and Nature Communications provide further insight into how microbiota-derived metabolites can shape regulatory T (T_reg) cell development in early life, thereby affecting susceptibility to allergy.

Credit: S. Bradbrook/Springer Nature Limited

Infants who are at high risk of developing allergy show distinct changes in their gut microbiota. Their faeces also lack anti-inflammatory bacterial metabolites, such as short-chain fatty acids (SCFAs), and are enriched in monohydroxy fatty acids, including 12,13-diHOME. 12-13-diHOME is a poorly characterized metabolite of linoleic acid (a fatty acid humans derive from the diet) and was shown to be induced in the airways of asthmatics following exposure to allergens; it was also found to inhibit T_reg cell induction by dendritic cells (DCs) in vitro. The source of faecal 12,13-diHOME in high-risk neonates is unknown, but Levan et al. hypothesized that it may be derived from the microbiota and influence susceptibility to allergy by affecting DC induction of T_reg cells.

In preliminary experiments, Levan et al. showed that 12,13-diHOME can reach the lungs after peritoneal injection and that this treatment leads to fewer T_reg cells, increased serum IgE and exacerbated airway inflammation in a mouse model of allergic airway disease. They also detected higher concentrations of 12,13-diHOME in the stools of 1-month-old infants who subsequently developed asthma or allergy. Linoleic acid is initially metabolized to 12,13-EpOME and then converted to 12,13-diHOME by epoxide hydrolase (EH) enzymes, which are encoded by humans, bacteria and fungi. The authors used shotgun metagenomic sequencing to screen neonatal stool samples for sequence reads with EH homology. They did not detect any human or fungal EH genes in the stool samples but found ~1,400 putative bacterial EH genes. Notably, bacterial EH genes were more abundant in the stools of the infants who developed allergy.

They selected 11 of the most frequently detected bacterial genes for functional analyses and found that only 3 of these (1 gene from Enterococcus faecalis and 2 genes from Bifidobacterium bifidum) could convert 12,13-EpOME to 12,13-diHOME. When they orally delivered Escherichia coli strains that had been engineered to overexpress these three functional EH (3EH) genes and linoleic acid to mice, the animals showed higher plasma concentrations of 12,13-diHOME as well as increased inflammation and decreased T_reg cell numbers in a model of allergic airway inflammation. Finally, the authors screened samples from two human cohorts and found that a higher 3EH copy number in neonatal faeces is associated with the development of allergy and asthma during childhood.

The study by Hu et al. examined the link between metabolites from the maternal microbiota and fetal immune development in pre-eclampsia, a condition that has been associated with higher rates of allergy in the offspring. They found that fetal thymic development and output of T_reg cells is impaired in pre-eclampsia, with follow-up studies showing that this T_reg cell deficiency was still seen after 4 years in children born to mothers with pre-eclampsia. They additionally observed that lower maternal levels of serum acetate (a microbiota-derived SCFA that has been shown to support tolerogenic immune responses) were associated with the development of pre-eclampsia. Experiments in germ-free mice indicated that supplementation of mothers with acetate could rescue thymic cellularity and increase FOXP3 expression in T_reg cells in pups. Therefore, disturbances in the maternal microbiota that affect the generation of acetate may impair T_reg cell development, thereby increasing the risk of pre-eclampsia in the mother and allergic disorders in infants.

allergic disorders may be linked to disturbances in the maternal or neonatal microbiota

Both of these studies indicate how early-life exposure to microbial metabolites can have a crucial role in shaping the immune system.