RT Journal Article
SR Electronic
T1 Epigenetic alterations in gut and brain of adult rats after oral administration of miR-320-3p and miR-375-3p at mid-lactation, and preventive potential of miR-320-3p on early weaning stress
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2022.06.20.496755
DO 10.1101/2022.06.20.496755
A1 Gabriel A Tavares
A1 Amada Torres
A1 Gwenola Le Drean
A1 Maïwenn Queignec
A1 Blandine Castellano
A1 Laurent Tesson
A1 Séverine Remy
A1 Ignacio Annegone
A1 Sandra L de Souza
A1 Bruno Pitard
A1 Bertrand Kaeffer
YR 2022
UL http://biorxiv.org/content/early/2022/06/20/2022.06.20.496755.abstract
AB Aim To investigate if the artificial delivery of microRNAs naturally present in the breastmilk can impact the gut and brain of young rats according to weaning.Methods Animals from a new transgenic rat line expressing green-fluorescent protein in the endocrine lineage (cholecystokinin expressing cells) received at Day-12, near neural diversification, a single oral bolus of mir-320-3p or miR-375-3p, embedded in DiOleyl-Succinyl-Paromomycin (DOSP), and were further early (Day-15) or regularly (Day-30) weaned. Relevant miRNA (miR-320-3p, miR-375-3p, miR-375-5p, miR-16-5p, miR-132-3p, miR-504), polr3d, hspb6, inflammation, enteroendocrine, and circadian clock-related mRNAs, chromatin complexes, and duodenal cell density were assayed at 8h post-inoculation and at Day-45.Results The miR-320-3p/DOSP induced immediate effects on H3K4me3 chromatin complexes with polr3d promoter (p<0.05) but no long-term effects. On regular weaning, at Day-45, both miR-320-3p and 375-3p were down-regulated in the stomach, up-regulated in the hypothalamus (p<0.001) but only miR-320-3p was up-regulated in the duodenum. After early weaning, the miR-320-3p and miR-375-3p levels were down-regulated in the stomach and the duodenum, but up-regulated in the hypothalamus and the hippocampus. Combining miR-320-3p/DOSP with early weaning enhanced miR-320-3p and chromogranin A expression in the duodenum. In the hippocampus, the miR-504 was down-regulated for both sexes, but in the brain stem, up regulated only for females, along with miR-320-3p and miR-16-5p levels. In the hypothalamus, clock levels were up regulated for both sexes. In the miR-375-3p/DOSP group, the density of enteroendocrine duodenal cells increased. The long-term effect of miR-375-3p/DOSP was more limited, according to the fourfold lower number of predicted targets than with miR-320-3p.Conclusion Addressing oral miRNA-320-3p loads to duodenal cell lineage is paving the way for the design of new therapeutics, manipulating long term consequences of early life stress.Competing Interest StatementThe authors have declared no competing interest.