Leukotoxin (lkt)-producing Mannheimia haemolytica causes fatal bronchopneumonia in bighorn sheep (BHS). Most BHS pneumonia outbreaks occur following contact with domestic sheep (DS). Experimental commingling studies have confirmed transmission of lkt+ M. haemolytica from DS to BHS resulting in fatal pneumonia in BHS. We hypothesized that elimination or reduction of shedding of lkt+ M. haemolytica by DS will render these two species compatible with each other. An earlier study by us revealed that lkt- Bibersteinia trehalosi inhibits the growth of lkt+ M. haemolytica in vitro. Therefore, the objectives of this study were to: 1. inoculate lkt- B. trehalosi into the nasopharynx of DS; 2. determine whether BHS survive commingling with lkt- B. trehalosi-inoculated DS. Four DS were treated with Ceftiofur to eliminate/reduce nasopharyngeal M. haemolytica, and then inoculated with B. trehalosi to maximize the chances of colonization by B. trehalosi. Subsequently, the treated DS were commingled with four BHS for 106 days. The antibiotic treatment and colonization by B. trehalosi led to a greater reduction of M. haemolytica in the nostrils compared to the pharynx of the DS. Although B. trehalosi colonized the nasopharynx, the DS regained M. haemolytica in three weeks post-treatment. At the time of commingling, all BHS were negative for M. haemolytica. However, M. haemolytica was detected either in nasal or pharyngeal swabs from all four BHS within 14 days of commingling. Unexpectedly, two BHS died due to unrelated causes on day 42 and 84 respectively. No signs of pneumonia were observed on gross- and histo-pathological examination of the lungs. The other two BHS remained healthy until the end of this phase of the study. These observations suggest that reduced shedding of M. haemolytica by DS during first few weeks of commingling enabled the BHS to mount immune response against M. haemolytica, particularly its lkt, and survive.