Inflammatory bowel disease (IBD) is characterized by chronic, relapsing inflammation for which there is no known cure and limited treatment and preventative options. Plant products in many nutritional supplements have been shown by multiple groups to be protective in IBD. We have identified polysaccharides from Acai berries (Acai PS) and polyphenols from apple peels (APP) that specifically stimulate γδ T cells, as well as NK cell and monocyte populations. The effects are similar in some respects to responses induced by patterns derived from the microbiota. Mice fed Acai PS, but not APP, had increased IL-12 expression in spleens, MLN and serum compared to water fed mice and displayed no adverse inflammatory effects in response to the fed supplements. Ingestion of both APP and Acai PS protected from dextran sulfate sodium (DSS)-induced colitis. Acai PS-, but not APP- fed mice with colitis had increased expression of NKG2A, an NK cell receptor implicated in protection from DSS-induced colitis. Acai PS also protected against Salmonella Typhimurium-induced enterocolitis. Novel oral innate agonists Acai PS and APP protect against colitis, but perhaps through distinct mechanisms. Augmented immune signaling is likely to contribute to maintenance of the epithelial barrier and underlying immunity. Considering the paucity of therapeutic and prophylactic options, these plant derived agonists may represent novel therapeutic options for patients with IBD.