The maternal microbiome regulates infant respiratory disease susceptibility via intestinal Flt3L expression and plasmacytoid dendritic cell hematopoiesis

Sikder, M. A. A.; Rashid, R. B.; Ahmed, T.; Sebina, I.; Howard, D. R.; Ullah, M. A.; Rahman, M. M.; Lynch, J. P.; Curren, B.; Werder, R. B.; Simpson, J.; Bissell, A.; Morrison, M.; Walpole, C.; Radford, K. J.; Kumar, V.; Woodruff, T. M.; Tan, H.; Ali, A.; Kaiko, G. E.; Upham, J. W.; Hoelzle, R. D.; O Cuiv, P.; Holt, P. G.; Dennis, P. G.; Phipps, S.

doi:10.1101/2023.01.05.522516

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bioRxiv · 10.1101/2023.01.05.522516

The maternal microbiome regulates infant respiratory disease susceptibility via intestinal Flt3L expression and plasmacytoid dendritic cell hematopoiesis

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Abstract

Severe lower respiratory infection (sLRI) are a major cause of infant morbidity and mortality, and predispose to later chronic respiratory diseases such as asthma. Poor maternal diet during pregnancy is a risk factor for sLRI in the offspring. Here we demonstrate in mice that a maternal low-fibre diet (LFD) disrupts plasmacytoid and conventional dendritic cell (DC) hematopoiesis in the offspring, predisposing to sLRI and subsequent asthma. The LFD alters the composition of the maternal milk microbiome and assembling infant gut microbiome, ablating the induction of a developmental wave of the non-redundant DC growth factor Flt3L by neonatal intestinal epithelial cells. Therapy with a propionate-producing bacteria isolated from the milk of high-fibre diet-fed mothers, or supplementation with propionate, confers protection against sLRI by restoring gut Flt3L expression and pDC hematopoiesis. Our findings identify a microbiome-dependent Flt3L axis in the gut that regulates pDC hematopoiesis in early life and confers disease resistance. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=51 SRC="FIGDIR/small/522516v1_ufig1.gif" ALT="Figure 1"> View larger version (15K): org.highwire.dtl.DTLVardef@1a39990org.highwire.dtl.DTLVardef@1b6fe67org.highwire.dtl.DTLVardef@f8440dorg.highwire.dtl.DTLVardef@13bc67e_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Sikder, M. A. A., Rashid, R. B., Ahmed, T., Sebina, I., Howard, D. R., Ullah, M. A., Rahman, M. M., Lynch, J. P., Curren, B., Werder, R. B., Simpson, J., Bissell, A., Morrison, M., Walpole, C., Radford, K. J., Kumar, V., Woodruff, T. M., Tan, H., Ali, A., Kaiko, G. E., Upham, J. W., Hoelzle, R. D., O Cuiv, P., Holt, P. G., Dennis, P. G., Phipps, S.. 2023-01-06. The maternal microbiome regulates infant respiratory disease susceptibility via intestinal Flt3L expression and plasmacytoid dendritic cell hematopoiesis. https://doi.org/10.1101/2023.01.05.522516

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