Donor-dependent fecal microbiota transplantation efficacy against necrotizing enterocolitis in preterm pigs

Abstract

The development of necrotizing enterocolitis (NEC), a life-threatening inflammatory bowel disease affecting preterm infants, is connected with gut microbiota dysbiosis. Using preterm piglets as a model for preterm infants we recently showed that fecal microbiota transplantation (FMT) from healthy suckling piglet donors to newborn preterm piglets decreased the NEC risk. However, in a follow-up study using donor stool from piglets recruited from another farm, this finding could not be replicated. This allowed us to study donor-recipient microbiota dynamics in a controlled model system with a clear difference in NEC phenotype. Preterm piglets (n = 38) were randomly allocated to receive control saline (CON), or rectal FMT using either the ineffective (FMT1) or the effective donor stool (FMT2). All animals were followed for four days before necropsy and gut pathological evaluation. Donor and recipient colonic gut microbiota (GM) were analyzed by 16 S rRNA gene amplicon sequencing and shotgun metagenomics. As expected, only FMT2 recipients were protected against NEC. Both FMT groups had shifted GM composition relative to CON, but FMT2 recipients had a higher lactobacilli relative abundance compared to FMT1. Limosilactobacillus reuteri and Lactobacillus crispatus strains of FMT recipients showed high phylogenetic similarity with their respective donors, indicating engraftment. Moreover, the FMT2 group had a higher lactobacilli replication rate and harbored specific glycosaminoglycan-degrading Bacteroides. In conclusion, subtle species-level donor differences translate to major changes in engraftment dynamics and the ability to prevent NEC. This could have implications for proper donor selection in future FMT trials for NEC prevention.

A Gently Processed Skim Milk‐Derived Whey Protein Concentrate for Infant Formula: Effects on Gut Development and Immunity in Preterm Pigs

“…These differences correlate to the observed glycation products in the ingredients. The preterm gut microbiome is characterized by a facultative dysbiosis often caused by a prolonged dominance of Enterobacteriaceae and Enterococcaceae [84][85][86] including the genera Enterococcus, which was found to be especially abundant in HTS-SPC pigs. As such, a high consumption of MRPs may further delay the colonization of commensal obligate anaerobic bacteria and thereby increase the risk of potential pathogens crossing the intestinal wall.…”

Treatment of preterm brain injury via gut‐microbiota–metabolite–brain axis

“…In a rat model of NEC, FMT before or after induction of NEC significantly alleviated inflammation, oxidative stress, and intestinal mucosal damage, suggesting that FMT may be a potential therapy for NEC 141 . Experimental FMT in neonatal preterm piglets reduced NEC risk, but the effect was donor‐specific 142 . This process may be related to the promotive effect of early FMT intervention on the development of the innate and adaptive immune systems and the maturation of the GM in piglets 143 .…”

Necrotizing enterocolitis: Bench to bedside approaches and advancing our understanding of disease pathogenesis

“…Pigs share many features of anatomy and physiology with humans, rendering them one of the more popular choices when exploring NEC pathogenesis. Additionally, the piglet's larger size affords the ability to study preterm neonates ( 148 , 149 ). Piglets are a good model for testing preclinical drugs, effects of various diet formulations, and pathological manifestation on NEC ( 150 ).…”