|Abstract:||Post-weaning diarrhea, caused by enterotoxigenic Escherichia coli, is one of the most common causes of mortality and morbidity in commercial pig production. With recent global concern over antibiotic resistance, the development of nutritional technologies to support animal health during times of infection is more important than before. An experiment was conducted to evaluate the combined dietary effects of a whole yeast cell product, CitriStim, and an essential oil, capsicum, on performance and immune indices in weanling pigs inoculated with an F18, enterotoxigenic E. coli strain. Growth performance, fecal bacteria counts, frequency of diarrhea, clinical blood outcomes, intestinal cytokine gene expression, T cell profiles, and recall nitric oxide (NO) production from isolated peripheral blood mononuclear cells (PBMC) stimulated with E. coli lipopolysaccharide (LPS) were evaluated throughout the experiment. The pigs challenged with ETEC showed clear signs of infection, such as diarrhea and F18 E.coli at 5 days post-inoculation (DPI), while the control animals showed no signs of infection and had no detectable levels of F18 E. coli throughout the study. Both capsicum and whole yeast cells had minimal impact on body weight gain, however pigs fed the capsicum only diet were more efficient than those fed the whole yeast cell only diet. Total fecal bacterial counts were higher during the acute phase of infection (0 – 5 DPI) in pigs fed the combination of additives (P = 0.05) compared with all other experimental groups. Pigs fed the capsicum-only diet also had higher total fecal bacterial counts (P = 0.05) compared with pigs fed the control or whole yeast cell-only diet. The combination of additives elicited lower total bacteria counts than either additive alone (P = 0.03) at 10 DPI, suggesting a possible return to gut homeostasis. Blood leukocyte counts at 7 DPI were increased in pigs fed the combination of additives (P = 0.04), while cytotoxic and memory T cell proportions were lower in these pigs at the same post-inoculation time-point (P = 0.02). To better quantify extent of the inflammatory response mounted against E. coli infection, PBMC were isolated from each pig, exposed to purified E. coli LPS, and measured for NO production, an indicator of macrophages reactivity. Nitric oxide production was higher (P = 0.02) in macrophages from pigs fed the whole yeast cell-only diet, while capsicum was effective at reducing the amount of NO produced by macrophages challenged with LPS after 24 h compared to cells isolated from pigs fed the whole yeast cell-only diet. Cytokine mRNA expression for 4 different cytokines did not differ among all ETEC-challenged groups. This indicates that cytokine levels were down regulated to low levels by the recovery phase of infection. In conclusion, these findings indicate that while feeding whole yeast cells and capsicum alone is not effective at improving growth performance in weanling pigs, these additives have potential to more efficiently reduce the untoward effects of enterotoxigenic E. coli infection, as evidenced by the lower bacterial counts and lower T cell proportions. The ability of these additives to reduce mortality and loss of growth makes them a viable option as alternatives to antibiotics for producers, and can be marketed as natural feed ingredients.