Impact of breastmilk on Campylobacter jejuni survival

Campylobacter jejuni is a major cause of bacterial-induced diarrhea worldwide. Infection leads to high rates ofmorbidity and mortality in low-and-middle income countries (LMICs) particularly in young children where up to85% of infants are C. jejuni stool positive by one year of age. Also post-infectious complications such as Guillain-Barr syndrome irritable bowel syndrome reactive arthritis and environmental enteric dysfunction (EED) areincreasingly reported. EED is a subclinical chronic disorder resulting from improper nutrient absorption intestinalinjury and prolonged inflammation that leads to growth stunting impaired cognitive development and furthercomplications. In parallel campylobacters continue to show increasing rates of fluoroquinolone resistanceparticularly ciprofloxacin and are thus high priority pathogens for new antimicrobial development.Through genomics studies examining Campylobacter infection profiles in seven sites in sub-Saharan Africanand South Asia we discovered that exclusively breastfed infants showed a significantly higher abundance of C.jejuni in their stools compared to non-breastfed infants and that breastfed infants were predominantly colonizedwith asaccharolytic (non-carbohydrate metabolizing) strains of C. jejuni while infection with fucose-metabolizingcampylobacters was less frequent. While examining the mechanism behind this selection we discovered thathuman breastmilk is unexpectedly toxic to C. jejuni. This finding was confirmed using 5 different isolates and 5independent breastmilk donor samples. Through directed evolution studies we isolated C. jejuni strains resistantto breastmilk and demonstrated that the milk bioactive agents were derived from proteins and lipids. This studywill investigate how components of human breastmilk can suppress the survival of C. jejuni and in turnwill explore how C. jejuni can develop resistance to those components.The specific aims of this project are to identify the bactericidal lipids and antimicrobial peptides within a pooledcollection of human breastmilk then characterize the mechanisms by which C. jejuni can become resistant tothese components and subsequently test how the identified C. jejuni mutations and toxic milk componentsimpact bacterial colonization in a mouse model of C. jejuni-induced EED.Completion of these aims will fill major gaps in our understanding of EED development and how breastmilkcomponents influence C. jejuni colonization. This study may also identify novel treatments to prevent colonizationwith this pathogen to reduce the burden of disease and mortality.