Editors' ChoiceImmunology

A window of opportunity for immune imprinting

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Science Translational Medicine  03 Apr 2019:
Vol. 11, Issue 486, eaax1719
DOI: 10.1126/scitranslmed.aax1719

Abstract

Host immune responses during a short weaning period determine susceptibility to inflammatory pathologies later in life.

The microbiome has recently gained increasing attention as an important factor shaping the host’s immune system. The intestinal microbiome harbors one of the densest known communities of bacteria on the planet, even exceeding numbers of eukaryotic host cells. This microcosm is strongly influenced by dietary components, starting with the mother’s milk, with subsequent changes during the weaning period, when solid food is gradually introduced. During that time, bacterial numbers strongly increase.

In a thorough investigation, Al Nabhani et al. demonstrated that the intestinal immune system of young mice undergoes a vigorous “weaning reaction” that could be mitigated by antibiotic treatment or germ-free upbringing. Importantly, mice that did not undergo a proper—and timely—weaning reaction between weeks 2 and 4 showed an increased susceptibility to multiple types of inflammatory pathologies later in life, including severe dextran sodium sulftate (DSS)-mediated colitis, exacerbated oxazolone–induced intestinal inflammation, or even increased rates of azoxymethane-induced colorectal cancer. Although this sort of pathological immune imprinting could be prevented when germ-free mice were exposed to specific pathogen-free (SPF) microbiota before weaning at week 2, all later rescue attempts failed. Thus, a missed weaning reaction during a critical time window could not be compensated for later in life, an effect that the authors found was likely in part mediated by the induction of RORγt+ regulatory T cells that depend on the presence of certain microbial antigens, short-chain fatty acids, and retinoic acid. The opening of this short time window that allows a proper weaning reaction may be controlled by components of the mother’s milk, such as a 10-fold drop in epidermal growth factor (EGF) concentration. The factors responsible for window closure, however, still remain to be elucidated, but must be mediated by mechanisms intrinsic to the weaning mouse. Neither delaying introduction of solid food (with prolonged administration of EGF-rich milk), nor prolonged germ-free housing, was able to extend this window.

The results of this study are especially intriguing in light of the so-called hygiene hypothesis, which proposes that early exposure to certain microbes prevents inflammatory pathologies (such as atopy) later in life in humans. Whether a human weaning reaction can be the target of disease-modifying, or even disease preventing measures in at-risk individuals, remains to be shown.

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