A new study in infants challenges the long-standing belief about the pathogen’s effects in the youngest pediatric population. Senior author Joseph Zackular, PhD, provides insights around his work including how it reshapes gut development and offers potential intervention strategies to shield neonates.
C difficile colonization in infants has long been assumed to be harmless, but Joseph Zackular, PhD, researcher in the Department of Pathology and Laboratory Medicine and co-director of the Center for Microbial Medicine at Children’s Hospital of Philadelphia (CHOP), and his team challenged this assumption and went to work examining if this toxin-producing pathogen could alter the gut. Zackular was the senior author in a study published earlier this month in
Zackular says this pathogen’s origin story comes from the infant population when C difficile was discovered in a healthy baby in the 1930s.
In their study, Zackular et al utilized a neonatal mouse model, which showed, “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. Despite transient colonization, exposure to C difficile early in life led to persistent changes into adulthood. 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. Human infant intestinal epithelial cells were sensitive to C difficile toxins, and biopsies from colonized infants exhibited altered intestinal stem cell behavior,” the authors wrote.1
“We showed that even without overt disease, exposure to this toxin-producing pathogen leaves a lasting biological imprint on the developing gut and immune system,” Zackular said.2
In their geographic analysis, Zackular et al found infant C difficile colonization was more common in infants from industrialized communities than nonindustrial ones. In industrialized nations, an estimated 40–70% of infants are colonized without the bacterium producing obvious symptoms.1-2
Zackular says the pathogen is likely circulating much more broadly in industrialized communities and remains difficult to kill off.
“We hypothesize that babies aren't exposed to C difficile as readily in underdeveloped or unindustrialized communities because C difficile isn't circulating like it is in the United States where we have these healthcare systems that are designed to have patients that come into the hospital, and a pathogen like C diff that produces spores can really circulate...This is why it's such a problem in adults and why it's the number one healthcare-associated pathogen.”
With their findings, Zackular would like to see 2 follow-up developments: determining if preventative measures are necessary and expanding the research to other pathogens.
“This study has reshaped how we're thinking about what asymptomatic really is and whether we should be rethinking what it means to be exposed to a pathogen early in life asymptomatically,” Zackular said. “This study is making us think that exposure to toxin-producing pathogens, although asymptomatic early in life, might be, reshaping developmental trajectories or long-term health, and our big push is that asymptomatic doesn't necessarily mean silent.”
If further research deems interventions necessary, Zackular would like to see prevention strategies such as maternal vaccination or monoclonal antibodies be utilized to mitigate C difficile. He believes in taking the same strategy currently being deployed in protecting newborns against RSV and pertussis by immunizing expecting mothers.
“A vaccine targeting C difficile may shield neonates from toxin-mediated effects on the developing gut. It could be a precise and feasible intervention to protect infants from C difficile during this critical developmental window.”
“We had an mRNA vaccine for C difficile that we developed recently in preclinical studies. This was published 2 years ago, and so we used that strategy in this study to see as a model if we could vaccinate the mothers, and if this would provide protection to the babies…There's other vaccines that are currently coming through the pipeline, including a phase 3 clinical trial that's being redone by Pfizer with a toxoid-based vaccine.”
“Our evidence suggests that it seems to be leading to potentially negative effects, but we don't know that. There's a lot of work to be done…But you could envision if this truly is problematic, that there's an opportunity for us to vaccinate mothers, we could do testing in infants, and then provide antibodies directly to the infants that maybe have high-risk strains or have strains that are producing a lot of toxin—or if they're at increased risk for negative consequences like autoimmunity or inflammatory disorders.”
Zackular would also like to expand these findings into future research to see if other pathogens are affecting infants and young children.
“We're really excited to continue to pursue this and understand, is this specific to C diff? Is this something that might be more generalized to other early life colonizing toxin-producing pathogens? And if so, how can we take this information and integrate it into pediatric care to improve the lives of children?”
