Post-weaning diarrhea remains a threat to swine production in the US despite the use of antibiotic feed additives and other alternative therapies utilized in post-weaning diets. Colicins are proteins produced by, and effective against E. coli, including the enterotoxigenic Escherichia coli (ETEC) responsible for post-weaning diarrhea. The addition of 16.5 of a mg/kg highly purified Colicin E1 (ColE1) to a post-weaning ration reduced the duration and severity of diarrhea caused by a combination of two F18+ ETEC strains over a five day study. Semi-quantitative real time PCR of the ileum revealed lower levels of mRNA expression for inflammatory cytokines IL-1beta and TNFbeta in the 16.5 mg/kg ColE1 fed group as compared to the control animals. These data, taken together with a lower number of ETEC challenge bacteria recovered from ColE1 fed animals 24 hours after oral challenge, suggests that the dietary ColE1 was able to reduce the numbers of ETEC able to colonize the ileum, thereby rendering it unable to cause diarrhea.;In a longer duration study that lasted 4 weeks, a more natural seeder pig challenge model was utilized, and ColE1 addition was also efficacious. This study utilized a post weaning diet containing thought to be protective against PWD such as spray dried plasma and whey protein for the first two weeks. To this diet, 20 mg/kg ColE1 was added. Exposure to the seeder animal without dietary ColE1 supplementation resulted in similar rates of PWD as those achieved by direct oral challenge in the previous study. Much lower rates of diarrhea were noted in the ColE1 fed group (18%) as compared to the control animals (80%) between days 4 and 10 after exposure to the sick animal. Body weight gains were significantly higher in the ColE1 fed pigs as a result, compared to those without the dietary addition at weeks 1 and 2. In a group of pigs not exposed to ETEC challenge, no body weight differences were noted when ColE1 was added to the diet. Semi quantitative real time PCR analysis of ileum mucosa showed higher levels of TNFalpha in the challenged, non-treated animals than those with the ColE1 addition and both diets in the non-challenged room 4 weeks after exposure to the seeder animal. Levels of COX-2 and PGHS, enzymes responsible for maintenance of immune function and barrier function in the intestine, were higher in the ColE1 fed, challenged animals than any other group.;Overall, the addition of the ColE1 purified from a Colicin E1 producing E. coli culture reduced the incidence and severity of PWD in both an oral challenge model and a seeder pig challenge model. The expense required to purify the ColE1 used in this study makes it cost prohibitive for use as an additive in swine feed at this time. For this reason, we have utilized recombinant yeast technology to express the ColE1. This method requires no purification cost because intracellular expression of the ColE1 enables the yeast cell to be directly fed to the pigs.