Project Grant R21CA281729

THE ROLE OF EARLY LIFE EXPOSURE TO ANTIBIOTICS ON RISK OF EARLY ONSET COLORECTAL CANCER - PROJECT SUMMARY/ABSTRACT THE INCIDENCE OF EARLY ONSET COLORECTAL CANCER (EOCRC) HAS INCREASED IN THE PAST FOUR DECADES AND IS PREDICTED TO INCREASE BY 140% BY 2030.4,5 IT IS THE SECOND MOST COMMON CANCER AND THIRD LEADING CAUSE OF CANCER DEATHS IN INDIVIDUALS UNDER 50 YEARS OLD IN THE USA.4,6,7 IN A RECENT REVIEW47, WE PROPOSED THAT INCREASED RISK OF EOCRC IS DRIVEN BY EXPOSOMES WHOSE ENTRY INTO THE GLOBAL ENVIRONMENT PRECEDES AND MIMICS THE WORLDWIDE INCREASE IN EOCRC INCIDENCE. EXPOSURE TO THESE SUSPECTED EXPOSOMES HAS BEEN INCREASING IN THE PAST 40 YEARS (AS HAS EOCRC), AND THEY ALL IMPACT GUARDIANS OF THE COLON (INFLAMMATION, THE MICROBIOME, AND EPIGENETIC/GENETIC CHANGES); EXPOSURE IS GLOBAL AND OCCURS DURING DEVELOPMENT - POTENTIALLY DURING CHILDHOOD. IN THIS PROJECT, WE FOCUS ON THE ROLE OF EXPOSURE TO ANTIBIOTICS DURING DEVELOPMENT AND ITS ON IMPACT EOCRC IN APPROPRIATE PRE-CLINICAL MODELS. ANTIBIOTIC OVERUSE HAS BECOME A SERIOUS PUBLIC HEALTH CONCERN, WITH OVER A MILLION DOSES PRESCRIBED ANNUALLY IN THE US.50,23 ITS USE IN INFANTS IS HIGH; OVER 50% ARE DIRECTLY EXPOSED FOR >5 DAYS.17 INDIRECT EXPOSURE IN PREGNANCY AFFECTS INFANT GUT MICROBIOTA AT BIRTH19,20; AND AT AN EARLY AGE, EXPOSURE CAN LEAD TO MULTIPLE HEALTH DISORDERS - INCLUDING CRC.21,22,23 REPEATED EXPOSURES CONTRIBUTE TO ANTIBIOTIC RESISTANCE AND ALTERED GUT MICROBIOTA WITH PRO-INFLAMMATORY AND PRO-CARCINOGENIC OUTCOMES28-32, SUGGESTING THAT THERE MAY BE WINDOWS OF DEVELOPMENTAL VULNERABILITY. HOWEVER, EPIDEMIOLOGIC AND ANIMAL STUDIES HAVE SHOWN CONFLICTING RESULTS, WITH NONE CONDUCTED ON THE IMPACT OF ANTIBIOTICS COMMONLY PRESCRIBED TO INFANTS AND CHILDREN ON THE COLON, CREATING A SUBSTANTIAL GAP IN OUR KNOWLEDGE ON THE MECHANISMS BY WHICH ANTIBIOTICS IMPACT EOCRC. WE WILL ADDRESS THIS GAP BY TESTING THE HYPOTHESIS THAT EXPOSURE EARLY IN LIFE TO ANTIBIOTICS COMMONLY PRESCRIBED TO CHILDREN CAUSES A TOXIC COLON (ASSOCIATED WITH DYSBIOSIS, INFLAMMATION, AND ALTERED GENETIC SIGNATURES) THAT PROMOTE MUTATIONS LEADING TO EOCRC. USING MOUSE MODELS OF CRC, WE WILL TEST THIS HYPOTHESIS IN TWO SPECIFIC AIMS: AIM 1. TO IDENTIFY DEVELOPMENTAL WINDOWS OF SUSCEPTIBILITY TO ANTIBIOTICS; AIM 2. TO DETERMINE IF DYSBIOSIS CAUSED BY ANTIBIOTICS DRIVES EOCRC. UPON COMPLETION, WE WILL KNOW: (1) THE IMPACT OF ANTIBIOTICS ON EOCRC RISK; (2) DEVELOPMENTAL WINDOWS OF COLON SUSCEPTIBILITY TO ANTIBIOTICS; (3) WHAT MICROBES DRIVE EOCRC; AND (4) WHETHER THESE MICROORGANISMS PROMOTE INCREASED MUTATION AS A MECHANISM CAUSING CRC. THE ACQUIRED KNOWLEDGE WILL BE CRITICAL IN DEVELOPING NOVEL STRATEGIES TO IDENTIFY INDIVIDUALS AT RISK, INTERVENTIONS TO MINIMIZE RISK OF EOCRC, AND INFORMED DECISIONS TO MITIGATE RISK AFTER USE OF ANTIBIOTICS THAT ARE INDISPENSABLE AGAINST INFECTIONS, AND MORE IMPORTANTLY, PROVIDE THE FOUNDATION FOR FUTURE STUDIES TO IDENTIFY COMPONENTS OF HUMAN MICROBIOME THAT MEDIATE INCREASED RISK FOR EOCRC.