Senior Research Associate Evolve Biosystems Davis, California, United States
Background: Preterm infants are exposed to interventions such as C-section delivery, antibiotics, and formula feeding that can foster early dysbiotic colonization of the gut microbiome, significantly altering the concentrations of bacterial metabolites available for cellular function. This can lead to a cascade of adverse effects that to which premature infants are particularly vulnerable. Previous research shows that B.infantis EVC001-fed infants produce significantly increased levels of total organic acids, specifically acetate and lactate acting as an essential energy source for intestinal cell proliferation.
Objective: Given previous findings that show infants colonized with B. infantis EVC001 have significantly increased concentrations of energetically favorable organic acids, such as acetate and lactate, we investigated the effect of B. infantis EVC001 metabolites on intestinal proliferation and integrity in premature intestinal epithelial cell models.
Design/Methods: Pooled fecal water (FW) from infants colonized with B. infantis EVC001 or those who were not (control), as well as major bacterial metabolites (acetate, lactate, butyrate, and formate) at physiological concentrations were added to premature human intestinal cells and organoids, and analyzed to assess proliferation, membrane integrity, and cytotoxicity.
Results: Intestinal primary cells exposed to B. infantis EVC001 fecal water significantly increased enterocyte proliferation as shown by ATP expression compared to medium alone and control FW (P< 0.01). Furthermore, organoids exposed to B. infantis EVC001 FW significantly increased ATP production as compared to control infants suggesting impaired ATP production in control infants (P< 0.0001). EVC001 FW treatment significantly decreased the release of lactate dehydrogenase, a biomarker of damaged cell membrane integrity as compared to control FW(P< 0.05). Physiological concentrations of acetate and lactate from EVC001-fed infants significantly increased intestinal epithelial cell integrity in intestinal epithelial cells compared to the lower levels found in control infants (P< 0.01). Conclusion(s): This study provides evidence that EVC001 FW and specific bacterial metabolites, lactate and acetate significantly increased ATP production, and lowered LDH concentrations, while control FW negatively affected cell growth; suggesting metabolites produced by B. infantis EVC001 promote enterocyte growth and improve intestinal integrity in premature infants.
Schematic of proposed mechanism of action.B.infantis EVC001 promotes enterocyte proliferation by providing metabolites which increase ATP production and support membrane integrity by reducing cytotoxictiy within premature infant inestinal cell models
Authors/Institutions: Stephanie G. Chew, Evolve Biosystems, Davis, California, United States; Guo-Zhong Tao, Stanford Medicine, Stanford, California, United States; Johann S. Prambs, Evolve Biosystems, Davis, California, United States; Amy M. Ehrlich, University of Copenhagen, Copenhagan, , Denmark; Karl G. Sylvester, Stanford University School of Medcine, Stanford, California, United States; Bethany M. Henrick, Evolve Biosystems, Davis, California, United States
