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We hypothesized that AHCC; (Amino UP Chemical Co., Ltd., Sapporo, Japan), a mushroom mycelium extract obtained from liquid culture of Lentinula edodes, restores immune function in LPS-induced inflammation in the gut, especially when the nitric oxide signaling pathway is impaired. This is the first inter-disciplinary proposal to identify molecular mechanisms involved in LPS-induced immune dysfunction in the gut in conscious animals treated or non-treated with AHCC, a promoter of immune support. Specifically, we have tested the effects of AHCC on LPS-induced deleterious effects on blood pressure and gut injury in conscious rats. The time course of biological markers of innate/acquired immune responses, and inflammation/oxidative stress is fully described in the present manuscript. Rats were randomly assigned into 3 groups (N = 6 per group). Group 1 received 10% of AHCC in drinking water for 5 days; Group 2 received lipopolysaccharide (LPS; Escherichia coli 0111:B4 purchased from Sigma) only at 20 mg/kg IV; Group 3 received combined treatments (AHCC + LPS). LPS was administered at 20 mg/kg IV, 5 days following AHCC treatment. We have demonstrated that AHCC decreased the LPS-deleterious effects of blood pressure and also decreased inflammatory markers e.g., cytokines, nitric oxide and edema formation. Finally, AHCC diminished lymphocyte infiltration, restoring gut architecture. Because AHCC was administered prior to LPS, our results indicate the potential impact of AHCC's prophylactic effects on LPS inflammation. Consequently, additional experiments are warrant to assess its therapeutic effects in sepsis-induced inflammation.LPS-induced hypotension and sustained loss of blood flow into the splanchnic bed lead to gut mucosa atrophyThe prebiotic, AHCC, is widely used in Chinese medicine for its anti-inflammatory and immuno-protective propertiesAHCC modulated LPS effects of blood pressure, inflammatory markers, lymphocyte infiltration and restored gut architectureAHCC is a novel therapeutic agent for treatment of hypotensive states commonly seen in acute inflammation patients.