Chemotherapy-induced mucositis (CIM) is a debilitating side effect impacting as many as 90% of patients with cancer undergoing treatment. Patients receiving 5-fluorouracil (5FU), a first-line chemotherapeutic in colorectal cancer, experience significant gastrointestinal distress that perpetuates poor patient quality of life and reduces treatment tolerance, efficacy, and survival. Natural compounds have shown promise in improving CIM through their pleiotropic actions, including immune and mucosal regulation. We examined whether panaxynol, a bioactive compound isolated from American ginseng, can alleviate murine CIM symptomology and severity. Intestinal mucositis was induced in C57BL/6J male and female mice by 5 consecutive intraperitoneal injections of 5FU (35 mg/kg/day); PBS was used as the control. Vehicle or panaxynol (2.5 mg/kg/day) was administered via oral gavage every other day, starting on day -1, for a total of four treatments. Panaxynol significantly improved overall mucositis symptomology, attenuated 5FU-induced cytopenia and anemia, ameliorated the 5FU-induced loss of goblet cells per crypt, suppressed proinflammatory immune cells in the colonic lamina propria, and altered microbial diversity and taxonomy. Sex differences were observed, with panaxynol exerting a stronger effect in males, significantly reducing the relative percentage of colonic macrophages and neutrophils. Panaxynol treatment was associated with sex-dependent alterations in gut microbial community structure and modulation of specific taxa, including Dubosiella and Bifidobacterium, alongside male-specific increases in Romboutsia and Alistipes; Akkermansia abundance was primarily influenced by 5FU treatment. These preclinical findings support the potential of panaxynol as a therapeutic candidate for the treatment of CIM and highlight the importance of considering sex as a biological variable.NEW & NOTEWORTHY This study identifies panaxynol, a bioactive compound from American ginseng, as a novel therapeutic candidate for chemotherapy-induced intestinal mucositis. In a murine 5-fluorouracil model, panaxynol attenuated mucosal injury, reduced cytopenia, suppressed proinflammatory immune cells, and altered gut microbial community structure. Importantly, panaxynol exhibited sex-dependent effects, with stronger immunological and microbial modulation in males. These findings highlight panaxynol's pleiotropic protective actions and underscore the importance of sex as a biological variable in mucositis therapeutics.
Keywords: american ginseng; chemotherapy; immune profile; macrophages; microbiome.