Vertically transmitted faecal IgA levels determine extra-chromosomal phenotypic variation

Abstract

SummaryThe proliferation of genetically modified mouse models has exposed phenotypic variation between investigators and institutions that has been challenging to control1-5. In many cases, the microbiota is the presumed culprit of the variation. Current solutions to account for phenotypic variability include littermate and maternal controls or defined microbial consortia in gnotobiotic mice6,7. In conventionally raised mice, the microbiome is transmitted from the dam2,8,9. Here we show that microbially–driven dichotomous fecal IgA levels in WT mice within the same facility mimic the effects of chromosomal mutations. We observed in multiple facilities that vertically-transmissible bacteria in IgA-Low mice dominantly lowered fecal IgA levels in IgA-High mice after cohousing or fecal transplantation. In response to injury, IgA-Low mice showed increased damage that was transferable by fecal transplantation and driven by fecal IgA differences. We found that bacteria from IgA-Low mice degraded the secretory component (SC) of SIgA as well as IgA itself. These data indicate that phenotypic comparisons between mice must take into account the non-chromosomal hereditary variation between different breeders. We propose fecal IgA as one marker of microbial variability and conclude that cohousing and/or fecal transplantation enables analysis of progeny from different dams.

The composition of the zebrafish intestinal microbial community varies across development

“…Our results highlight observations that some of the observed phenotypic variation in animal studies is, in part, owing to variations in the microbiota. For example, it was recently shown that differences in microbial community composition in wild-type mice alter the intestinal IgA levels, thereby differentially influencing susceptibility to a chemically induced model of colitis (Moon et al, 2015). Likewise, it is possible that our observation of greater variation in sIgM transcript abundance in older fish, with little variation in size, is simply a reflection of increasing microbiota variation between individuals in response to widely varying microbial communities.…”

IL-33 regulates the IgA-microbiota axis to restrain IL-1α–dependent colitis and tumorigenesis

“…We and others have shown that gut microbial dysbiosis contributes to susceptibility toward colitis and CAC (36)(37)(38). IgA is known to regulate the gut microbial landscape, and mice deficient in IgA and pIgR are known to harbor a dysbiotic microbiota that contributes to their increased susceptibility to colitis (33,(39)(40)(41). We therefore posited that decreased colonic IgA in Il33 -/-mice would lead them to developing a dysbiotic microbiota.…”

TNFR2 Deficiency Acts in Concert with Gut Microbiota To Precipitate Spontaneous Sex-Biased Central Nervous System Demyelinating Autoimmune Disease

“…It is not known how TNFR2 deficiency impacts A. muciniphilia abundance, but intracellular cross-talk between short-chain fatty acid and sex-hormone signaling and gene regulation is one possibility. Sutterella, also selectively more abundant in male TNFR2 2/2 2D2 mice, has been positively correlated with autism and Down syndrome (84), as well as degradation of secretory IgA (85). In addition to providing a first line of defense against enteric toxins and pathogens, intestinal secretory IgA, promotes Ag clearance, quenches bacterial virulence factors, and changes the composition of the intestinal microbiota (86).…”