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Preventative or adjunctive agents for the amelioration of small intestinal chemotherapy-induced mucositis are not currently available for clinical use. We have previously demonstrated that oral ingestion of Streptococcus thermophilus (TH-4) partially attenuated chemotherapy-induced mucositis in the rat. Here we assess the effects of TH-4 on small intestinal damage and tumor progression in tumor-bearing rats with experimentally-induced mucositis. Female Dark Agouti tumor-bearing (mammary adenocarcinoma) rats (n = 36; 139 ± 1 g) had small intestinal damage induced via the administration of methotrexate (MTX). Rats were administered MTX; (1.5 mg/kg intramuscular) or saline at 0 and 24 h; with daily gavage administration of TH-4 (109 cfu/mL) or skim milk from -48 to +96 h post-MTX. Rats were allocated to groups (n=9): saline control, TH-4 control, MTX control or TH-4+MTX. The non-invasive ( 13) C-sucrose breath test (SBT) was conducted prior to tumor inoculation, pre-MTX (-24 h) and prior to sacrifice (96 h) to monitor gut function. At sacrifice small intestinal segments were excised and assessed for sucrase and myeloperoxidase activity as well as histological damage. Irrespective of TH-4 treatment, MTX-treated rats had a significant decrease in bodyweight, SBT levels, sucrase and myeloperoxidase activity, and histological damage score (p < 0.05) compared to saline and TH-4 control rats. TH-4 treatment did not result in tumor progression (p > 0.05) but failed to alleviate mucositis indices. Although TH-4, at a dose of 109 cfu/mL, yielded neither protection nor amelioration of chemotherapy-induced mucositis, progression of mammary adenocarcinoma was unaffected.

Small intestinal permeability was employed to assess the efficacy of commercially available yoghurts containing probiotics in a rat model of methotrexate (MTX)-induced mucositis. Male Sprague-Dawley rats were allocated to four groups (n = 8): MTX + water, MTX + cow's milk yoghurt (CY; fermented with Lactobacillus johnsonii), MTX + sheep's milk yoghurt (SY; containing Lactobacillus bulgaricus and Streptococcus thermophilus), and saline. Treatment gavage occurred twice daily for 7 days pre-MTX and 5 days post-MTX. Intestinal permeability was assessed on days -7, -1, 2, and 5 of the trial. Intestinal sections were collected at sacrifice for histological and biochemical analyses. Histology revealed that rats receiving CY and SY did not have a significantly damaged duodenum compared to controls. However, an improved small intestinal barrier function was evident, determined by a decreased lactulose/mannitol ratio. Probiotics containing SY and CY may be useful in preventing disruption to intestinal barrier function in MTX-induced mucositis.

Background: Currently, there are no available effective preventative or adjunctive agents to alleviate symptoms of chemotherapy-induced mucositis. This is compounded by the absence of a recognized and validated noninvasive biomarker to assess gut function. This study investigated the effects of orally ingested Streptococcus thermophilus (TH-4) on chemotherapy-induced small intestinal damage in rats using the noninvasive (13)C-sucrose breath test (SBT)., Methods: Gastrointestinal damage was induced in 27 female dark agouti rats (148 +/- 1g) with MTX (1.5 mg/kg; i.m.). Rats received MTX or saline at 0 h; with daily treatment of: TH-4 at doses of 10(9) (high), 10(8) (low) cfu/mL, or skim milk (vehicle), 48 h pre and 96 h post-MTX. The noninvasive (13)C-sucrose breath test (SBT) was conducted at -24, 24 and 96 h post-MTX to monitor gut function. At sacrifice, small intestinal tissues were collected for determinations of sucrase activity, myeloperoxidase (MPO) activity and histological assessment., Results: MTX + vehicle and MTX + low TH-4-treated rats produced significantly lower SBT and sucrase activity results compared to saline controls (p < 0.001). In contrast, MTX + high TH-4 treatment showed no significant differences in the SBT compared to saline controls, and the SBT results were significantly higher compared to MTX + vehicle and MTX + low TH-4 (p < 0.05). MPO levels were significantly elevated (p < 0.05) in MTX + vehicle and MTX + low TH-4, but not following MTX + high TH-4 treatment, compared to saline controls. This was further confirmed by histological analyses., Conclusion: Oral ingestion of TH-4 at 10(9) cfu/mL is capable of partially attenuating small bowel damage in rats. The noninvasive SBT is a useful technique to longitudinally assess the efficacy of treatments or interventions for small bowel disease.