Antenatal Dietary Butyrate Supplementation Reduces Postnatal Gastrointestinal Injury in a Murine Model of Colitis

Purpose: Determine whether optimizing the antenatal diet, with either direct or indirect butyrate supplementation, reduces the severity of intestinal injury in offspring with colitis. Butyrate is a short-chain fatty acid that has been shown to enhance intestinal barrier function, regulate intestinal mucosal immunity and reduce intestinal inflammation. Butyrate levels can be increased by ingestion of butyrate, a HF diet or certain probiotics. Therefore, we hypothesize that consuming a diet that increases butyrate levels prenatally will reduce the severity of intestinal injury in offspring with colitis. Methods: Mating pairs of C57BL/6 mice were fed either 1% butyrate, high fiber (HF) diet or probiotics with or without a HF diet during pregnancy. Probiotics administered included Lactobacillus rhamnosus (LGG) in one group and Lactococcus lactis subspecies cremoris (LLC) in the other group. Antenatal dietary supplementation was discontinued at the time of delivery. Pups were fed a regular diet after weaning. Acute colitis (3% enteral dextran sodium sulfate, DSS, for 5-7 days) or chronic colitis (2% DSS for 7 days, followed by 7-10 days of recovery and another 7 days of 2% DSS) was induced in the offspring at 6-8 weeks of life. Intestinal injury was measured by measuring disease activity index (DAI) score in each mouse. Fluorescently labelled dextran molecule (FITC-Dextran) was used to evaluate the postnatal intestinal permeability of the offspring at various time points. Results: Antenatal butyrate supplementation reduced intestinal injury in offspring with acute or chronic colitis. Antenatal HF diet had no protective effect on offspring with acute colitis but did reduce injury score in offspring with chronic colitis. Antenatal LLC supplementation had no protective effect on offspring with chronic colitis. Offspring exposed to antenatal LLC with HF diet had higher injury scores than those exposed to antenatal LLC alone. The intestinal permeability of offspring exposed to antenatal butyrate improved over the first two weeks of life while the control group had no change. There was no difference in the intestinal permeability between the offspring exposed to antenatal butyrate and the control group at the end of an acute colitis model. Conclusions: Our results highlight the importance of the antenatal diet on fetal gut development. Overall, direct antenatal butyrate supplementation had the most consistent protective effects on the offspring with DSS induced colitis. The offspring exposed to antenatal butyrate had improved intestinal barrier function in the neonatal period but not at peak colonic injury. Our results suggest that antenatal butyrate has an impact on fetal gut development and this impact leads to lasting protective effects on the offspring’s postnatal gut health. Antenatal butyrate supplementation may impact fetal gut development by several potential mechanisms, including modification of the offspring’s microbiome through modification of the maternal microbiome or through epigenetic changes.