Fecal microbiota transplantation prevents gut bacterial dysbiosis and necrotizing enterocolitis in preterm pigs

Background and aims. Necrotizing enterocolitis (NEC) is a severe gastrointestinal complication affecting preterm infants, and related to inappropriate gut microbial colonization and formula feeding. Fecal microbiota transplantation (FMT) supports microbe-host homeostasis in other gastrointestinal diseases, but remains to be studied in preterm infants. Using preterm pigs as models, we hypothesized that FMT prevents formula-induced bacterial dysbiosis and NEC. Methods. Cesarean-delivered, formula-fed preterm pigs were administered combined oral + rectal administration of donor feces (n=41), or exclusively rectal donor feces (n=22), and compared with corresponding controls (n=42 and 23, respectively). After five days, NEC lesions were recorded, together with gut bacterial composition, metabolites and mucosal barrier structure. Results. FMT induced a maturational shift in the neonatal gut bacterial composition, increasing obligate and decreasing facultative anaerobic bacterial abundance without affecting total colonic bacterial load. FMT reduced abnormally high lactate levels (p<0.001) and increased propionate production (p<0.05), thereby normalizing colon luminal pH (p<0.01). Further, FMT reduced NEC incidence by 75% (p<0.05), which was associated with preservation of goblet cell mucin stores (p<0.05) and a reduced mucosal immune response. Only rectal FMT increased colon bacterial diversity (p<0.05) and microbe-host signaling pathways (all q<0.05), while reducing mucosa bacterial adhesion (p<0.05), whereas oral + rectal FMT led to a 10-fold increase in stomach bacterial load (p<0.001), increased mucosa adhesion (p<0.05) and a 2.5-fold increased mortality rate (p<0.01). Conclusion. FMT prevents NEC in preterm pigs, possibly by improving bacterial colonization, reducing distal gut luminal acidification, barrier rupture and mucosal inflammation. Rectal FMT administration is the superior administration route because oral FMT may increase bacteremia and sepsis risk.