Abstract
Necrotizing enterocolitis (NEC) is a life-threatening gastrointestinal disorder afflicting preterm infants, which is currently unpreventable. Fecal microbiota transplantation (FMT) is a promising preventive therapy, but the transfer of pathogenic microbes or toxic compounds raise concern. Removal of bacteria from donor feces by micropore filtering may reduce this risk of bacterial infection, while residual bacteriophages could maintain the NEC-preventive effects. We aimed to assess preclinical efficacy and safety of fecal filtrate transplantation (FFT). Using fecal material from healthy suckling piglets, we compared rectal FMT administration (FMT, n = 16) with cognate FFT by either rectal (FFTr, n = 14) or oro-gastric administration (FFTo, n = 13) and saline (CON, n = 16) in preterm, cesarean-delivered piglets as models for preterm infants. We assessed gut pathology and analyzed mucosal and luminal bacterial and viral composition using 16S rRNA gene amplicon and meta-virome sequencing. Finally, we used isolated ileal mucosa, coupled with RNA-Seq, to gauge the host response to the different treatments. Oro-gastric FFT completely prevented NEC, which was confirmed by microscopy, whereas FMT did not perform better than control. Oro-gastric FFT increased viral diversity and reduced Proteobacteria relative abundance in the ileal mucosa relative to control. An induction of mucosal immunity was observed in response to FMT but not FFT. As preterm infants are extremely vulnerable to infections, rational NEC-preventive strategies need incontestable safety profiles. We show in a clinically relevant animal model that FFT, as opposed to FMT, efficiently prevents NEC without any recognizable side effects.
Highlights
Gut colonization after birth is essential for development of the host immune system
Necrotizing enterocolitis (NEC), a lethal inflammatory and necrotic bowel disease mainly affecting very preterm infants, is a prominent example of a disease that is tightly coupled with gut dysbiosis [2]
The microbiota preceding NEC diagnosis is usually characterized by reduced bacterial diversity, lack of obligate anaerobes and increased relative abundance of single facultative anaerobes often belonging to the family of Enterobacteriaceae [5,6,7]
Summary
Gut colonization after birth is essential for development of the host immune system. Yet, it has become increasingly clear that microbial perturbation resulting in deviation from the normal gut microbiota developmental trajectory is a risk factor and possibly a contributing factor for a range of neonatal diseases. Gut dysbiosis is of particular concern for preterm infants due to their impaired microbial host defense and high susceptibility to life-threatening infections [1]. Major differences between studies of the gut microbiome in preterm infants [3] complicate the elucidation of a clear NEC-associated microbiota, but increased Proteobacteria and reduced Bacteroidetes relative abundances are unifying features of a prediagnostic NEC microbiota across neonatal units [4]. In the search for better bacterial therapies, we recently showed a proof of principle for fecal microbiota transplantation (FMT) against NEC, using cesarean-delivered preterm pigs as recipients and breastfed, term pigs as donors [8]. Any means to reduce the complexity of the donor fecal matrix, while maintaining its therapeutic effects is an advancement towards developing a clinically feasible therapy against NEC. A small case series of Clostridioides difficile infection patients receiving sterile donor fecal filtrate transplanta-
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