Abstract: Objective: To investigate the immunomodulatory effects of yeast protein in cyclophosphamide (CTX)-induced immunosuppressed mice and to explore its potential mechanism from the perspective of the gut-immune axis. Methods: BALB/c mice were randomly divided into five groups with 6 mice in each group: normal control, immunosuppression model, positive drug, low-dose yeast protein, and high-dose yeast protein. All groups, except the normal control, were injected intraperitoneally with CTX to induce immunosuppression and were administered with corresponding drugs by gavage for 14 consecutive days. During the experiment, body mass, immune organ indices, serum cytokine levels, immune cell activity, T cell subset ratio, intestinal tissue morphology, fecal short-chain fatty acids (SCFAs) contents, the expression of intestinal barrier and aryl hydrocarbon receptor (AhR) axis-related genes, and the diversity and abundance of the intestinal microbiota were detected and analyzed. Results: Yeast protein significantly increased organ indices in the model group, regulated the expression of tumor necrosis factor‑α (TNF‑α), interleukin (IL)‑4, IL‑10 and interferon‑γ (IFN‑γ), enhanced natural killer (NK) cell activity and humoral immunity, restored delayed-type hypersensitivity (DTH), alleviated the imbalance of CD3 +CD4 +/CD3 +CD8 + T lymphocyte subsets, and ameliorated pathological damage in the spleen and ileum. It also elevated fecal SCFA contents and upregulated the transcription levels of intestinal barrier genes (ZO-1, Mucin-2, and Claudin-3) and key genes in the AhR pathway (AhR, CYP1A1, ERK, and STAT3). Furthermore, yeast protein effectively improved intestinal microbiota dysbiosis caused by CTX, and increased the diversity and abundance of the intestinal microbiota. Conclusion: Yeast protein ameliorates CTX-induced immunosuppression in mice via the gut-immune axis through multiple targets including immune cells, intestinal barrier and intestinal microecology and therefore can be used as a candidate ingredient for novel natural immunomodulators.

Key words: yeast protein; immunomodulation; cyclophosphamide; gut-immune axis