UC Irvine

Diarrheal disease is the second leading cause of death in children under five, killing over 500,000 children every year, and disproportionally impacting low- and middle-income countries (LMIC). Additionally, diarrheal diseases contribute to long-lasting morbidities for millions of others reducing quality of life through malnutrition, poor growth rates, and reduced vaccine efficacy. A wide range of enteric pathogens (Rotavirus, Norovirus, Campylobacter, Shigella, Giardia, etc.) are responsible for diarrheal diseases in children under five. However, these known pathogens only account for 40-50% of cases in LMIC leaving a substantial number that cannot be attributed to a specific pathogen and making targeted intervention impossible. It also remains unclear why children who grow up in the same environment have different susceptibility to enteric pathogens. One potential explanation is that the resident commensal microbes, which are largely inherited from mothers at least early in life, play a protective or detrimental role in disease susceptibility. Either through direct interaction with pathogens or influence on immune development. However, the role of the commensal gut microbiome in the susceptibility to and severity of diarrheal disease is unclear. This is in part due to high variability within the “Healthy” human gut microbiome, a lack of longitudinal studies that include pre-symptom samples, and difficulty in collecting samples in resource-limited settings. In this dissertation, we describe and utilize an infant macaque model of naturally acquired diarrheal disease to investigate questions that are either difficult or impossible to study in humans. We use a combination of clinical, microbiological, and immunological assays on primary samples to describe novel findings regarding the causes and consequences of diarrheal disease in infants. We first show that the gut microbiome of infant macaques develops predictably and with similar features to humans in LMIC suggesting that our model could provide valuable insight into a disease that primarily impacts the developing world. Second, using samples from host sites not accessible in humans we found that growth faltering independent of acute diarrhea was associated with immune dysfunction in the colon and mixing of small and large intestine microbial communities. Next, we identify and genomically characterize four previously unknown and yet to be cultured campylobacter species that are likely to contribute to idiopathic disease in humans. Finally, we examine both the fecal and vaginal microbiome of reproductive-age female macaques to shed light on the dynamics of these communities while exploring their potential impact on infant health. Together these experiments have yielded valuable insight into the causes and consequences of diarrheal disease and have led to potential targets for both pathogen detection and treatments.