Haematococcus pluvialis peptides ameliorated cyclophosphamide‐induced immunodeficiency in mice by regulating intestinal barrier function

BACKGROUND: Immunodeficiency is a pathological state characterized by impaired functional integrity of the immune system, which contributes to the development of various diseases. Natural bioactive peptides are a promising option for improving immune function. RESULTS: This study examined the therapeutic effects and underlying mechanisms of Haematococcus pluvialis peptides (HPP) against CTX-induced immunodeficiency in mice. The results demonstrated that HPP increased bodyweight, immune organ indices, and blood cell count - white blood cells (WBC), red blood cells (RBC), platelets (PLT), hemoglobin (HGB), lymphocytes (Lym), and granulocytes (Gran), as well as serum cytokine levels (interferon-gamma (IFN-γ), interleukin-2 (IL-2), and immunoglobulin A (IgA) - in immunodeficient mice. Haematococcus pluvialis peptides improved the villus length and crypt depth of the small intestine and increased intestinal levels of superoxide dismutase (SOD), glutathione peroxidase (GSH-PX), and secretory immunoglobulin A (SIgA). Colonic levels of tight junction proteins - zonula occludens-1 (ZO-1) and occludin - were up-regulated. Fecal microbiota analysis suggested that HPP promoted the enrichment of beneficial bacterial genera (Ligilactobacillus, norank_f_Muribaculaceae, Alistipes) and suppressed pathogenic bacteria (Escherichia-Shigella and Klebsiella). Gut microbial metabolites analysis showed that HPP altered various fecal metabolites involved in lipids and lipid-like molecules, organoheterocyclic compounds, phenylpropanoids and polyketides, as well as organic acids and their derivatives. Fecal microbiota transplantation (FMT) experiments also validated the decisive role of gut microbiota in the immunomodulatory function of HPP. CONCLUSION: These results offer novel insights into the protective efficacy and underlying mechanisms of HPP for alleviating immunodeficiency, establishing a robust theoretical basis for its application as a promising immunomodulatory agent. © 2026 Society of Chemical Industry.