The maternal microbiome regulates infant respiratory disease susceptibility via intestinal Flt3L expression and plasmacyoid dendritic cell haematopoiesis
Sikder M.A.A. et al. (BioRxiv) DOI: 10.1101/2023.01.05.522516
Plasmacytoid Dendritic cells (pDC)
Sever lower respiratory tract infections (sLRI) are a group of illnesses that increase the risk of developing asthma. sLRI prevalence in early life coincides with the development of the infant microbiome and perturbing this axis increase sLRI severity. However, the underlying mechanisms linking the infant microbiome and sLRI development remain elusive.
Plasmacytoid dendritic cells (pDC) are important regulators of the immune response in sLRI with their depletion perturbing Treg expansion leading to more severe disease. A recent preprint (not peer-reviewed) by Sikder et al., identify a microbiome-dependent axis in the gut that is essential for pDC hematopoiesis during early life and conferring sLRI resistance.
The maternal microbiome was perturbed using low (LFD) versus high-fibre diet (HFD) during pregnancy and the pre-weaning period. Offspring were then exposed to either the pneumonia virus of mice (PVM) or rhinovirus and in both instances LFD offspring developed more type 2 inflammation, airway remodeling and had reduced pDC and Treg expansion. On exposure to an aeroallergen, cockroach extract (CRE), LFD-offspring also developed asthma with HFD-offspring remaining protected from CRE-induced asthma.
Next the authors investigated how changes in the maternal diet were mediating these effects. Fecal microbiome transplants from HFD mothers to LFD pups failed to reduce sLRI severity or rescue pDC numbers. However, cross fostering experiments whereby newly born pups were switched from LFD-fed mothers to HFD-mothers could confer protection against sLRI, reduce inflammation and induce pDC and Treg expansion. These results suggest that the maternal milk microbiome is essential for conferring sLRI resistance. Indeed, bacterial isolates obtained from the milk of HFD-fed mothers or supplementation with the microbial short chain fatty acid, propionate, could also confer sLRI resistance. Depletion of pDC using the diphtheria toxin reversed propionate-induced sLRI resistance highlighting these effects were mediated through pDC.
Mechanistically, the expression of the non-redundant DC growth factor, Flt3L, was found to be reduced in the bone marrow, colon, feces, and serum in LFD-fed offspring. Of interest HFD-offspring displayed a burst of Flt3L expression in the feces during early development and the authors went on to show that intestinal epithelial cells (IEC) express surface bound Flt3L that is cleaved by ADAM10. Furthermore, propionate appears essential for this neonatal intestinal expression of Flt3L. Indeed, sLRI protection induced by propionate in LFD-fed offspring was ablated by anti-Flt3L treatment.
The results of this study suggest that the maternal milk microbiome is essential in establishing the early infant microbiome leading to an critical wave of IEC Flt3L expression essential for pDC and Treg expansion and conferring resistance to sLRI and later development of asthma.
1. In response to acute infection, the authors show that ADAM10 inhibition ablated pDC and Treg cell expansion predisposing otherwise healthy HFD-reared pups to a sLRI. Importantly, however ADAM10 affects a broad array of proteins and hence there are limitations to the systemic use of ADAM10 inhibitor. In general, the data is consistent with the notion that gut-derived Flt3L promotes postnatal DC hematopoiesis and confers protection against sLRI.
2. As propionate can mediate its anti-inflammatory effects through the inhibition of histone deacetylases (HDACs) the authors treated mice with the pan-HDAC inhibitor, TSA and showed that Flt3L levels were restored similar to HFD-reared pups . While these experiments do implicate a mechanism of action whereby propionate regulates Flt3L in IECs though deacetylation of histones. More experiments for example ChIP on the Flt3L promoter for certain epigenetic modifiers would be needed to clarify these claims
The authors identify for the first time that intestinal epithelia cells (IEC) as a critical source of Flt3L during early development that appears crucial for dendritic cell haematopoiesis. They also show that the maternal microbiome is critical for this axis mediated through the milk microbiota. This is a significant and novel finding that is robustly shown using different experimental models including cross fostering and milk isolate transfer. Finally, the authors show that it is propionate, the short chain fatty acid, that is the essential component of this IEC-Flt3L-dendritic cell axis. From a general immunology point of view, this preprint brings new knowledge about the mechanism regulating dendritic cell haematopoiesis and how they can be perturbed by changes in the environment and microbiota and has broad implications for many diseases where DC play a crucial part in antigen presentation and T-cell activation.
Reviewed by Lily Keane as part of the cross-institutional journal club of the Immunology Institute of the Icahn School of Medicine, Mount Sinai and the Kennedy Institute of Rheumatology, University of Oxford.