Target-modified low-molecular-weight pectin restores intestinal immune homeostasis in cyclophosphamide-induced immunocompromised mice

The targeted-modified low-molecular-weight pectin (LMP), a natural polysaccharide derived from citrus fruits, represents a promising food-derived immunomodulatory agent. This study assessed the efficacy of targeted-modified LMP at oral doses of 50, 100, and 150 mg/kg/day for 7 days in mice with cyclophosphamide-induced immunosuppression. We demonstrated that targeted-modified LMP promotes multifaceted immune recovery primarily by regulating the crosstalk between gut microbiota and immune system. Treatment restored systemic humoral immunity in a dose-dependent manner, with serum IgA, IgG, and IgE levels reaching 105.2%, 70.2%, and 77.2% of normal levels, respectively, in the high-dose group. The immunomodulatory effects were initiated by structural remodeling of intestinal microbiota, featuring elevated levels of beneficial bacterial families, restoration of the Firmicutes/Bacteroidota ratio, and enhanced production of short-chain fatty acids—with the high-dose group showing marked increases of 178.9% in acetic acid, 408.9% in propionic acid, and 197.1% in butyric acid. These microbial metabolites subsequently upregulated their corresponding receptors (GPR41/43), leading to activation of the MAPK and NF-κB signaling pathways. This molecular cascade ultimately improved gut barrier integrity, demonstrated by upregulated expression of tight junction proteins and mucin (ZO-1, Claudin-1, and MUC2 restored to 52.3–68.0% and 62.5% of normal levels, respectively), along with ameliorated colon histology. Our findings delineate a clear pathway by which targeted-modified LMP restores immune homeostasis, providing a mechanistic rationale for its development as a dietary intervention against immunosuppression.