Because of the metabolic and antibacterial actions of short-chain fatty acids (SCFA), their roles in modifying the clinicopathologic features of shigellosis were evaluated in a rabbit model of shigellosis. Acute colitis was induced in adult rabbits by intracolonic administration of Shigella flexneri 2a. After 24 h, rabbits were given 6-h colonic infusions of SCFA (acetate, propionate, n-butyrate; 60:30:40 mM) or SCFA-free solution (control); groups of rabbits were killed in batches of 2 or 3 animals at 24, 48, 72, and 96 h after treatment, for histologic and bacteriologic assessment. SCFA significantly reduced fecal blood and mucus and improved clinical symptoms. Histologically, SCFA significantly (P<.01) reduced mucosal congestion, cellular infiltration, and necrotic changes. SCFA also significantly (P<.05) reduced the number of shigellae in the colon. No such improvements occurred in the control group. SCFA may be useful agents in improving clinicopathologic features of shigellosis and should be clinically evaluated.