Milk diets influence doxorubicin-induced intestinal toxicity in piglets

Abstract

Chemotherapy-induced gastrointestinal (GI) toxicity is a common adverse effect of cancer treatment. We used preweaned piglets as models to test our hypothesis that the immunomodulatory and GI trophic effects of bovine colostrum would reduce the severity of GI complications associated with doxorubicin (DOX) treatment. Five-day-old pigs were administered DOX (1 × 100 mg/m(2)) or an equivalent volume of saline (SAL) and either fed formula (DOX-Form, n = 9, or SAL-Form, n = 7) or bovine colostrum (DOX-Colos, n = 9, or SAL-Colos, n = 7). Pigs were euthanized 5 days after initiation of chemotherapy to assess markers of small intestinal function and inflammation. All DOX-treated animals developed diarrhea, growth deficits, and leukopenia. However, the intestines of DOX-Colos pigs had lower intestinal permeability, longer intestinal villi with higher activities of brush border enzymes, and lower tissue IL-8 levels compared with DOX-Form (all P < 0.05). DOX-Form pigs, but not DOX-Colos pigs, had significantly higher plasma C-reactive protein, compared with SAL-Form. Plasma citrulline was not affected by DOX treatment or diet. Thus a single dose of DOX induces intestinal toxicity in preweaned pigs and may lead to a systemic inflammatory response. The toxicity is affected by type of enteral nutrition with more pronounced GI toxicity when formula is fed compared with bovine colostrum. The results indicate that bovine colostrum may be a beneficial supplementary diet for children subjected to chemotherapy and subsequent intestinal toxicity.

Bovine Colostrum Against Chemotherapy‐Induced Gastrointestinal Toxicity in Children With Acute Lymphoblastic Leukemia: A Randomized, Double‐Blind, Placebo‐Controlled Trial

“…Most of the proposed beneficial compounds in milk are present in higher concentration in colostrum, compared with mature milk, and whole bovine colostrum has been suggested as a possible intervention against chemotherapy‐induced mucositis . In piglets, data from our group suggest that colostrum has gut‐protective effects, relative to formula, in relation to chemotherapy . However, beneficial effects of increasing colostrum doses could not be clearly demonstrated in chemotherapy‐treated pigs fed a normal milk diet, indicating that both dosing regime and the control diet may be important.…”

“…However, beneficial effects of increasing colostrum doses could not be clearly demonstrated in chemotherapy‐treated pigs fed a normal milk diet, indicating that both dosing regime and the control diet may be important. Preclinical studies have suggested effects of bovine colostrum in terms of preserved intestinal barrier function, better nutrient absorption and reduced intestinal inflammation . Corresponding surrogate markers of clinical manifest gastrointestinal toxicity were not assessed in the current clinical trial, and previous results from animal models did not translate into actual clinical benefits on IM and infectious or inflammatory outcomes in this study.…”

“…Preclinical studies have suggested effects of bovine colostrum in terms of preserved intestinal barrier function, better nutrient absorption and reduced intestinal inflammation. 26,27 Corresponding surrogate markers of clinical manifest gastrointestinal toxicity were not assessed in the current clinical trial, and previous results from animal models did not translate into actual clinical benefits on IM and infectious or inflammatory outcomes in this study.…”

“…21,22,37 In piglets, data from our group suggest that colostrum has gut-protective effects, relative to formula, in relation to chemotherapy. 26,27 However, beneficial effects of increasing colostrum doses could not be clearly demonstrated in chemotherapy-treated pigs fed a normal milk diet, 38 indicating that both dosing regime and the control diet may be important. Preclinical studies have suggested effects of bovine colostrum in terms of preserved intestinal barrier function, better nutrient absorption and reduced intestinal inflammation.…”

“…Whereas some effects may be species specific, other may be shared across species . Preclinical studies in piglets indicate that exclusive feeding with intact bovine colostrum benefits gut responses after chemotherapy when compared with formula milk . In these preclinical models, bovine colostrum reduced gut toxicity by preserving intestinal function in terms of preserved nutrient absorption capacity, greater brush border enzyme activity, and preserved intestinal barrier function as well as reducing tissue inflammatory cytokine concentrations.…”