Fecal filtrate transplantation protects against necrotizing enterocolitis

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.

The Roles of the Virome in Cancer

“…We and others have shown that during FMT, phages are transmitted [100][101][102]119]. In some indications, sterile fecal filtrates (containing phages, but not bacteria) may even be more efficient than FMT, as shown recently for necrotizing enterocolitis of preterm infants [120]. The role of phages and eukaryotic viruses in determining the responder status to immunotherapy has not been investigated to date.…”

The gut virome: A new microbiome component in health and disease

“… 120 Another study also evaluated the effect of FMT versus FVT in preventing piglets from necrotising enterocolitis and found that FVT was superior to FMT without any recognised side effects. 121 A significant alteration in the gut microbiome was observed after FVT, including an increase in the diversity of the gut virome and a decrease in the relative abundance of Proteobacteria in the ileal mucosa. 121 Recently, transfer of the caecal virome from lean mice to obese recipient mice was also shown to decrease weight gain and blood glucose parameters, and decrease the expression of genes related to T2D.…”

“… 121 A significant alteration in the gut microbiome was observed after FVT, including an increase in the diversity of the gut virome and a decrease in the relative abundance of Proteobacteria in the ileal mucosa. 121 Recently, transfer of the caecal virome from lean mice to obese recipient mice was also shown to decrease weight gain and blood glucose parameters, and decrease the expression of genes related to T2D. 19 In this HFD-induced obese mice study 19 and another targeted phage transfer study, 122 phage transfer was shown to mediate the shift of the metabolic profile in plasma or faeces, suggesting that FVT and phage transfer may change the metabolic repertoire of the bacteria communities/mammalian host and/or regulate the expression profile of metabolic genes in the bacteriome.…”

“… Disease Model Donor Route Effect Year Refs. Antibiotics-induced dysbiosis Murine model Autochthonous stool Orogastric administration The gut bacteriome was reshaped towards pre-antibiotic treated mice 2020 18 Recurrent Clostridioides difficile infection (rCDI) Patients with rCDI (n=5) Stool from healthy donors Nasojejunal infusion Restored normal stool habits; eliminated symptoms of CDI for a minimum period of six months 2016 16 Recurrent Clostridioides difficile infection (rCDI) Patients with rCDI (n=4) Uncertain Oral take capsules of lyophilized sterile faecal filtrate (LSFF) 75% (3/4) patients achieved no CDI recurrence at the end of eighth weeks 2019 120 Necrotizing Enterocolitis Caesarean-delivered preterm piglets Breastfed, term pigs Rectal or orogastric administration Orogastric FVT increased gut virome diversity, reduced Proteobacteria relative abundance and completely resolved NEC 2021 121 Obesity Type 2 Diabetes (T2D) Murine model Low-fat (LF) diet-fed mice (lean mice) Orogastric administration Alleviated symptoms of T2D and obesity; mediate the shift of the metabolic profile among obesity mice. 2020 19 …”

Fecal virome transfer improves proliferation of commensal gut Akkermansia muciniphila and unexpectedly enhances the fertility rate in laboratory mice

“…Other studies using sterile filtered feces have reported to alleviate symptoms of type-2-diabetes (T2D) and obesity in mice [17], and to prevent the development of necrotizing enterocolitis [18] in preterm piglets. These changes in phenotype may be driven by a phage-mediated modulation of the GM [17][18][19][20][21]. In all cases, when transferring the fecal viral components, a significant change in the bacterial diversity and composition was observed, with the bacterial GM-component of the recipients becoming more like the GM of the donors.…”