Although the highly contagious bacterium Clostridioides difficile (C. diff) causes severe disease in adults, it has been reported to not cause symptoms in infants. Based on that, the assumption has been that infant colonization was not a serious health issue. That said, the consequences of early-life colonization on host development remain unknown. Now, in a new study, researchers at Children’s Hospital of Philadelphia (CHOP) are challenging that long-held assumption, with new findings suggesting that the bacterium can reshape the developing infant gut and may have long-term consequences.
This work was published in Science in the paper, “Early-life colonization with Clostridioides difficile remodels the developing gut.”
C. diff causes symptoms ranging from diarrhea to deadly colonic inflammation caused by the production of toxins. It spreads quickly via spores and commonly infects vulnerable populations, including the elderly, those taking antibiotics, and patients in hospitals or nursing homes. Around half a million patients are infected in the U.S. annually, resulting in approximately 30,000 fatal cases.
However, one population always seemed to be resistant to the damaging effects of the bacterium: infants. An estimated 40–90% of infants in industrialized countries are colonized with C. diff without the bacterium producing obvious symptoms.
“For decades, C. diff colonization in infants has been assumed to be harmless,” notes Joseph Zackular, PhD, researcher in the Department of Pathology and Laboratory Medicine and co-director of the Center for Microbial Medicine at CHOP. “But we asked: does asymptomatic really mean inconsequential? Could a toxin-producing pathogen actually be reshaping the developing gut without causing obvious symptoms?”
Researchers used a combination of preclinical models, human infant intestinal biopsies, and lab grown organoids to study the effects of C. diff colonization early in life.
The study found that the presence of C. diff in an otherwise healthy preclinical neonatal model led to a remodeling of the developing epithelium and a reshaping of the mucosal immune system. More specifically, the authors write that “in a neonatal mouse model, C. difficile colonization drove proinflammatory and tissue repair responses in the intestinal epithelium, enriching injury-associated intestinal stem cell populations and skewing differentiation toward secretory lineages.”
These effects were observed long into adulthood and increased the risk of some viral infections, suggesting that C. diff colonization in infants may have a potential long-term effect on health. The impact of C. diff on the developing epithelial layer was also observed in human infants colonized with C. diff. Epithelial responses were toxin dependent, as “colonization with nontoxigenic strains or maternal vaccination with a C. difficile–targeted messenger RNA–lipid nanoparticle vaccine protected neonates.”
This means that an early life exposure to C. diff, although seemingly benign, could have profound effects on healthy development of the gut.
“The infant gut epithelium is still building itself, so C. diff doesn’t just injure it; it can alter the developmental trajectory of the tissue in ways that may last into adulthood,” said Kathryn Hamilton, PhD, a researcher in the Department of Pediatrics and co-director of the Gastrointestinal Epithelium Modeling (GEM) Program at CHOP.
With these findings challenging long-held assumptions, there is enthusiasm to explore whether this exposure can increase the risk of developing metabolic or autoimmune disorders. The study also points to a clear path forward. Much like maternal vaccines already in clinical use to protect newborns against RSV and pertussis, immunizing mothers with a vaccine targeting C. diff shielded neonates from toxin-mediated effects on the developing gut. This shows that a maternal vaccination strategy could be a precise and feasible intervention to protect infants from C. diff during this critical developmental window.
“Our findings challenge a long-held assumption in pediatric medicine: that C. diff colonization in infants is benign,” Zackular said. “We show that even without overt disease, exposure to this toxin-producing pathogen leaves a lasting biological imprint on the developing gut and immune system, and that a maternal vaccine can protect against it.”
