Carbohydrate malabsorption as a potentiator of infectious antibiotic-associated diarrhea

About This Grant

PROJECT SUMMARY Antibiotic-associated diarrhea is a common and potentially life-threatening adverse event that affects the tolerability and therefore efficacy of these drugs. Most cases have been postulated to be due to malabsorption of nutrients secondary to the disruption of microbial communities capable of catabolizing them, while a minority but clinically serious number of cases are due to infection with toxin-producing pathogens. This study proposes a previously unappreciated link between malabsorptive and infectious antibiotic-associated diarrhea through the compromising effect of antibiotics on immunoglobulin A (IgA) levels in the intestine. IgA is an important immune mediator capable of neutralizing bacterial toxins, and selective IgA deficiency following antibiotic treatment is a common clinical occurrence. The Stappenbeck lab, i.e., the research environment this fellowship will be completed in, has an extensive and recent publication history regarding the function of IgA in the context of infection and how these functions are compromised by actions of the microbiota. Preliminary data generated in this lab suggests that water accumulation in the lower intestine underlies reduced fecal IgA concentrations following vancomycin treatment, and that the degree of this water accumulation positively correlates with dietary carbohydrate intake. The overarching hypothesis of this proposal is that vancomycin-induced disruption of microbial carbohydrate catabolism underlies water accumulation and dilution of luminal IgA in the lower intestine (Aim 1), and that this dilution of luminal IgA renders the host susceptible to toxin-mediated damage in the colon (Aim 2). Aim 1 focuses on establishing dietary carbohydrate catabolism as a necessary function of the microbiota in maintaining proper water balance and thereby normal IgA concentrations in the lower intestine. This will be experimentally tested by investigating the relative contribution of vancomycin-sensitive microbes to carbohydrate catabolism in vivo, and the functional relevance of this contribution through rescue experiments involving microbes capable or incapable of catabolizing dietary carbohydrates. Aim 2 focuses on the clinical implications of reduced colonic IgA concentrations following vancomycin treatment through in vitro and in vivo neutralization and challenge assays using bacterial toxins relevant to infectious antibiotic-associated diarrhea. The aims in this proposal have been made with close consideration of the goals detailed in the training plan, those being i) furthering technical abilities in the study of microbes and their effects on immunity, ii) providing the basis for improvement of written and verbal scientific communication, and iii) serving as a foundation in addressing clinical problems through experimental investigation. Successful completion of these aims will both prepare the applicant for a future career as a physician-scientist in the long-term, while also clarifying mechanisms underlying antibiotic-associated diarrhea and immunodeficiency to benefit human health in the short-term.