Alternative Diagnoses in Pediatric Fecal Microbiota Transplant Referral Patients.

ABSTRACT: The incidence of Clostridioides difficile infection (CDI) has been increasing in the United States. About 10-20% recur after initial treatment, with increasing recurrence following subsequent treatment courses. This sequence can lead to recurrent CDI (rCDI), refractory to conventional therapeutics resulting in the most common indication for fecal microbiota transplantation (FMT). FMT is the most effective microbial therapeutic to date and can cure rCDI in 80-90% of cases. There is growing concern, however, for pathogen transmission through FMT, underscoring the importance of careful recipient selection. In adults referred for FMT with a tentative diagnosis of rCDI, alternative diagnoses were recognized in 25% of patients, but such observation in children is lacking. In this single-center retrospective study, alternative diagnoses (eg, constipation/overflow diarrhea, inflammatory bowel disease) were found in 13 (22.4%) of 58 children who were referred for FMT evaluation for rCDI. Of the patients who were diagnosed with rCDI, 16 (27.6%) did not require FMT.

Microbiome associations of therapeutic enteral nutrition.

One of the most effective forms of therapeutic enteral nutrition is designated as "exclusive enteral nutrition" (EEN). EEN constitutes the monotonous enteral delivery of complete liquid nutrition and has been most explored in the treatment Crohn's disease (CD), a form of inflammatory bowel disease. While EEN's mechanisms of action are not clearly understood, it has been shown to modify the composition of the intestinal microbiome, an important component of CD pathogenesis. The current literature on the intestinal microbiome in healthy individuals and CD patients is reviewed with respect to EEN therapy. Further investigations in this field are needed to better understand the role and potential for EEN in chronic human disorders.

Prenatal methyl-donor supplementation augments colitis in young adult mice.

Inflammatory bowel diseases (IBD) have become highly prevalent in developed countries. Environmentally triggered exaggerated immune responses against the intestinal microbiome are thought to mediate the disorders. The potential dietary origins of the disease group have been implicated. However, the effects of environmental influences on prenatal developmental programming in respect to orchestrating postnatal microbiome composition and predilection towards mammalian colitis have not been examined. We tested how transient prenatal exposure to methyl donor micronutrient (MD) supplemented diets may impact predilection towards IBD in a murine dextran sulfate sodium (DSS) colitis model. Prenatal MD supplementation was sufficient to modulate colonic mucosal Ppara expression (3.2 fold increase; p=0.022) and worsen DSS colitis in young adulthood. The prenatal dietary exposure shifted the postnatal colonic mucosal and cecal content microbiomes. Transfer of the gut microbiome from prenatally MD supplemented young adult animals into germ free mice resulted in increased colitis susceptibility in the recipients compared to controls. Therefore, the prenatal dietary intervention induced the postnatal nurturing of a colitogenic microbiome. Our results show that prenatal nutritional programming can modulate the mammalian host to harbor a colitogenic microbiome. These findings may be relevant for the nutritional developmental origins of IBD.

Cellulose supplementation early in life ameliorates colitis in adult mice.

Decreased consumption of dietary fibers, such as cellulose, has been proposed to promote the emergence of inflammatory bowel diseases (IBD: Crohn disease [CD] and ulcerative colitis [UC]) where intestinal microbes are recognized to play an etiologic role. However, it is not known if transient fiber consumption during critical developmental periods may prevent consecutive intestinal inflammation. The incidence of IBD peaks in young adulthood indicating that pediatric environmental exposures may be important in the etiology of this disease group. We studied the effects of transient dietary cellulose supplementation on dextran sulfate sodium (DSS) colitis susceptibility during the pediatric period in mice. Cellulose supplementation stimulated substantial shifts in the colonic mucosal microbiome. Several bacterial taxa decreased in relative abundance (e.g., Coriobacteriaceae [p = 0.001]), and other taxa increased in abundance (e.g., Peptostreptococcaceae [p = 0.008] and Clostridiaceae [p = 0.048]). Some of these shifts persisted for 10 days following the cessation of cellulose supplementation. The changes in the gut microbiome were associated with transient trophic and anticolitic effects 10 days following the cessation of a cellulose-enriched diet, but these changes diminished by 40 days following reversal to a low cellulose diet. These findings emphasize the transient protective effect of dietary cellulose in the mammalian large bowel and highlight the potential role of dietary fibers in amelioration of intestinal inflammation.

Maternal micronutrients can modify colonic mucosal microbiota maturation in murine offspring.

Epidemiologic data suggest that early nutritional exposures may inflict persistent changes in the developing mammalian "super-organism" (i.e., the host and its residing microbiota). Such persistent modifications could predispose young adults to inflammatory bowel diseases (IBD). We recently observed that the dietary supplementation of four micronutrients to dams augmented colitis susceptibility in murine offspring in association with mucosal microbiota composition changes. In this study the effects of the four micronutrients on the microbiota of dams and female mice was examined. Additionally, age dependent microbiota composition shifts during pediatric development were delineated from the previous offspring data sets. Maternal and adult female microbiota did not separate secondary to the nutritional intervention. Significant microbiota composition changes occurred from postnatal day 30 (P30) to P90 at the level of 1 phylum and 15 genera. Most of these changes were absent or opposite in the maternally supplemented offspring. Nutritionally induced alterations in mucosal microbiota maturation may be contributors to colitis susceptibility in mammals.

Maternal methyl-donor supplementation induces prolonged murine offspring colitis susceptibility in association with mucosal epigenetic and microbiomic changes.

Developmental epigenetic changes, such as DNA methylation, have been recognized as potential pathogenic factors in inflammatory bowel diseases, the hallmark of which is an exaggerated immune response against luminal microbes. A methyl-donor (MD) diet can modify DNA methylation at select murine genomic loci during early development. The components of the MDs are routinely incorporated into prenatal human supplements. Therefore, we studied the effects of maternal MD supplementation on offspring colitis susceptibility and colonic mucosal DNA methylation and gene expression changes in mice as a model. Additionally, we investigated the offspring mucosal microbiomic response to the maternal dietary supplementation. Colitis was induced by dextran sulfate sodium. Colonic mucosa from offspring of MD-supplemented mothers following reversal to control diet at weaning was interrogated by methylation-specific microarrays and pyrosequencing at postnatal days 30 (P30) and P90. Transcriptomic changes were analyzed by microarray profiling and real-time reverse transcription polymerase chain reaction. The mucosal microbiome was studied by high throughput pyrosequencing of 16S rRNA. Maternal MD supplementation induced a striking susceptibility to colitis in offspring. This phenotype was associated with colonic mucosal DNA methylation and expression changes. Metagenomic analyses did not reveal consistent bacteriomic differences between P30 and P90, but showed a prolonged effect of the diet on the offspring mucosal microbiome. In conclusion, maternal MD supplementation increases offspring colitis susceptibility that associates with persistent epigenetic and prolonged microbiomic changes. These findings underscore that epigenomic reprogramming relevant to mammalian colitis can occur during early development in response to maternal dietary modifications.