Amelioration of Chemotherapy-Induced Intestinal Mucositis by Orally Administered Probiotics in a Mouse Model

Abstract

Background and AimsIntestinal mucositis is a frequently encountered side effect in oncology patients undergoing chemotherapy. No well-established or up to date therapeutic strategies are available. To study a novel way to alleviate mucositis, we investigate the effects and safety of probiotic supplementation in ameliorating 5-FU-induced intestinal mucositis in a mouse model.MethodsSeventy-two mice were injected saline or 5-Fluorouracil (5-FU) intraperitoneally daily. Mice were either orally administrated daily saline, probiotic suspension of Lactobacillus casei variety rhamnosus (Lcr35) or Lactobacillus acidophilus and Bifidobacterium bifidum (LaBi). Diarrhea score, pro-inflammatory cytokines serum levels, intestinal villus height and crypt depth and total RNA from tissue were assessed. Samples of blood, liver and spleen tissues were assessed for translocation.ResultsMarked diarrhea developed in the 5-FU groups but was attenuated after oral Lcr35 and LaBi administrations. Diarrhea scores decreased significantly from 2.64 to 1.45 and 0.80, respectively (P<0.001). Those mice in 5-FU groups had significantly higher proinflammatory cytokine levels (TNF-α: 234.80 vs. 29.10, P<0.001, IL-6: 25.13 vs. 7.43, P<0.001, IFN-γ: 22.07 vs. 17.06, P = 0.137). A repairing of damage in jejunal villi was observed following probiotics administration. We also found TNF-α, IL-1β and IL-6 mRNA expressions were up-regulated in intestinal mucositis tissues following 5-FU treatment (TNF-α: 4.35 vs. 1.18, IL-1β: 2.29 vs. 1.07, IL-6: 1.49 vs. 1.02) and that probiotics treatment suppressed this up-regulation (P<0.05). No bacterial translocation was found in this study.ConclusionsIn conclusion, our results show that oral administration of probiotics Lcr35 and LaBi can ameliorate chemotherapy-induced intestinal mucositis in a mouse model. This suggests probiotics may serve as an alternative therapeutic strategy for the prevention or management of chemotherapy-induced mucositis in the future.

Apoptosis, Dysbiosis and Expression of Inflammatory Cytokines are Sequential Events in the Development of 5‐Fluorouracil‐Induced Intestinal Mucositis in Mice

“…The microbiota was also recently implicated in the development of chemotherapy‐associated intestinal mucositis . For example, several studies demonstrated that probiotics attenuate 5‐FU‐induced intestinal mucositis by stabilizing intestinal microbiota . Similarly, we found that co‐administration of ampicillin, a broad‐spectrum antibiotic, and aztreonam, an antibiotic against Gram‐negative bacteria, significantly reduced the severity of intestinal mucositis, diminished myeloperoxidase activity and suppressed the late burst of inflammatory cytokines.…”

Modulations of probiotics on gut microbiota in a 5‐fluorouracil‐induced mouse model of mucositis

“…Our previous research successfully demonstrated that Lactobacillus were associated with the maintenance of the tight junction integrity and appearance . These results shed light on the potential of probiotics to restore the dysbiosis of 5‐FU‐induced intestinal mucositis both in BALB/c and SCID/NOD mice models: repairing the jejunum, ameliorating diarrhea, and halting bodyweight loss . The exact mechanisms by which probiotics exert their beneficial effects remain unclear.…”

“…In a study including 150 colorectal cancer patients treated with 5‐FU, Lactobacillus rhamnosus supplementation could decrease the incidence of severe diarrhea and the need for chemotherapy dose reduction as compared with placebo . Besides, in our previous mouse model studies, we successfully demonstrated that oral administration of probiotics Lactobacillus casei variety rhamnosus and Lactobacillus acidophilus and Bifidobacterium bifidum could ameliorate the chemotherapy‐induced intestinal mucositis …”

“…Recent studies had shown probiotics could modulate intestinal barrier function and improve chemotherapy‐induced mucositis in the animal model . Our previous researches demonstrated the effects of probiotic supplementation in ameliorating 5‐FU‐induced intestinal mucositis in an experimental mouse model . A better understanding of the pathogenesis of chemotherapy‐induced mucositis is mandatory to develop optimal preventive and curative measures for patient care.…”

A review of complementary therapies for chemotherapy induced gastrointestinal mucositis

“…Pre-treatment EcN and LGG (Lactobacillus rhamnosus) supernatants lowered caspase activity, inhibited enterocyte apoptosis and loss of intestinal barrier function induced by 5-FU treatment of IEC-6 cells (82). Oral administration of probiotics Lactobacillus casei variety rhamnosus (Lcr35) or Lactobacillus acidophilus and Bifidobacterium bifidum (LaBi) appeard to ameliorate the intestinal mucositis severity by inhibition the expressions of proinflammatory cytokines (83). Various microorganisms used as probiotics for treatment of chemotherapy induced GIM are summarized in Table 2.…”