A new Escherichia coli strain called ST131-H30 – unknown prior to 2000 – is now the single most common cause of E. coli infections such as urinary tract infections, particularly those associated with resistance to first- line antibiotics. Veterans are especially vulnerable to ST131-H30, which causes 25-30% of all their E. coli infections, and 70-75% of those involving fluoroquinolone (e.g., ciprofloxacin) resistance. Gut colonization is an important upstream step in ST131-H30 infections, and therefore is a key part of the ST131-H30 epidemic. We have found that, in veterans and their household members, gut colonization with fluoroquinolone-resistant E. coli (12-13% overall) is quite prolonged (possibly years), is significantly longer for ST131-H30 than other resistant E. coli, and is attributable more to strain persistence than frequent transmission. This suggests the possibility of reducing gut colonization with ST131-H30 by identifying modifiable risk factors, host immune factors, bacterial traits, and characteristics of the gut microbiota that correlate with prolonged H30 colonization and loss of colonization, to inform the development of appropriate interventions. Accordingly, we propose to augment our current longitudinal fecal surveillance of H30-colonized veterans and household members by: · identifying epidemiological risk factors for presence and loss of H30 colonization · identifying humoral and cell-mediated immune correlates of presence and loss of H30 colonization · identifying genomic differences between initial vs. final, and shorter vs. longer-persisting, fecal ST131- H30 isolates · identifying shifts in the gut microbiota (i.e., bacterial community and E. coli population) that correspond with presence and loss of H30 colonization. The results of these studies can be expected to provide essential information needed for the design of interventions (e.g., risk factor modification, vaccines, anti-colonization drugs, and pre- or probiotics) to reduce gut colonization with the ST131-H30 strains that cause infections in veterans. Such interventions should help to reduce the enormous disease burden from infections caused by multi-resistant E. coli, mainly ST131-H30.