SCID/NOD mice model for 5-FU induced intestinal mucositis: Safety and effects of probiotics as therapy

Abstract

For chemotherapy patients, intestinal mucositis is a frequent complication. Previously, we evaluated the beneficial effect of oral probiotics in 5-Fluorouracil (5-FU) induced mucositis in BALB/c mice. Here, we used SCID/NOD mice instead to simulate the immunodeficiency of chemotherapy patients: first, to evaluate the safety of probiotic supplementation and second, to determine the probiotic effect in response to 5-FU intestinal mucositis. Thirty-six SCID/NOD mice were injected with saline (three control groups) or 5-FU (three experimental groups) intraperitoneally daily for five days. Mice were given either oral saline daily, probiotic suspension of Lactobacillus casei variety rhamnosus (Lcr35, Antibiophilus™, France) or Lactobacillus acidophilus and Bifidobacterium bifidum (LaBi, Infloran™, Italy). Blood, liver, spleen, and lymph node tissue samples were evaluated for probiotic translocation via culture and Q-PCR. Weight change, diarrhea score, jejunal villus height (VH) and crypt depth (CD), and serum cytokine levels of TNF-α, IFNγ, IL-1β, IL-6, IL-4, IL-10, IL-13, and IL-17 were also assessed. No weight loss was found in the SCID control group. Mean weight loss of 10.63±0.87% was noted by day five in 5-FU group without probiotics but it was only 6.2±0.43% if mice were given Lcr35 (p<0.01) and 7.1±1.80% (p<0.01) if they were given LaBi. Diarrhea score of 5-FU group without probiotics was 2.0±0.0 by day five, which dropped to 1.33±0.17 (p<0.05) and 1.42±0.24 (p<0.05) with Lcr35 and LaBi, respectively. Average VH significantly decreased and CD significantly increased in SCID mice given 5-FU. With probiotics, average CD improved (p<0.05) while VH lengthened as well. Besides IL-13, all cytokine levels increased in 5-FU SCID mice. Both Lcr35 and LaBi significantly inhibited serum cytokines (p<0.05). No probiotic strains were detected in blood cultures of any mice. Using SCID/NOD mice as a novel model for 5-FU induced intestinal mucositis, we find that probiotics Lcr35 and LaBi do not lead to bacteremia, can improve diarrhea and body weight, can restore jejunal crypt depth, and significantly inhibit cytokines TNF-α, IL-1β, IFNγ, IL-6, IL-4, IL-10, and IL-17.