Irinotecan Injures Tight Junction and Causes Bacterial Translocation in Rat

Nakao, Toshihiro; Kurita, Nobuhiro; Komatsu, Masato; Yoshikawa, Kozo; Iwata, Takashi; Utusnomiya, Toru; Shimada, Mitsuo

doi:10.1016/j.jss.2010.10.003

Cited by 55 publications

(49 citation statements)

References 16 publications

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“…Most recently, a preclinical study conducted by Nakao et al (2012) investigated tight junction proteins in tumor-naïve rats and found tight junction changes were associated with gut barrier dysfunction. Specifically, a significant decrease in both occludin and claudin-1 mRNA expression was identified; 28 however given their small sample size (n = 10) and single time-point evaluation, these conclusions should be interpreted with caution. In contrast, several other preclinical studies found no change in occludin and ZO-1 mRNA expression following administration of methotrexate (MTX), but demonstrated decreased claudin-1 mRNA expression.…”

Section: Discussionmentioning

confidence: 89%

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Irinotecan disrupts tight junction proteins within the gut

Wardill

Bowen

Al‐Dasooqi

et al. 2013

Cancer Biology & Therapy

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Section: Discussionmentioning

confidence: 89%

“…This phenomenon was recently reported, with bacteria found in the basolateral compartment and mesenteric lymph nodes of chemotherapy-treated rats. 28 It is therefore hypothesized that bacteria-and proinflammatory cytokine-mediated tight junction disruption are pivotal in the development of gut toxicity.…”

Section: Introductionmentioning

confidence: 99%

Irinotecan disrupts tight junction proteins within the gut

Wardill

Bowen

Al‐Dasooqi

et al. 2013

Cancer Biology & Therapy

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“…Despite these findings, the molecular characteristics of tight junctions have been largely ignored clinically, assessed only in in vivo studies. These studies consistently show decreased expression, redistribution and phosphorylation of claudin-1, occludin and ZO-1 (7,(17)(18)(19), however few report these changes in combination with robust permeability data.…”

Section: Introductionmentioning

confidence: 97%

“…The current understanding of the molecular mechanisms that drive gut toxicity has not yet lead to any advances in its treatment and thus, a better understanding of the underlying biology is required. Recent research has outlined emerging evidence implicating intestinal barrier injury and tight junction disruption in the development of gut toxicity (6,7), however few studies have investigated their regulation and involvement in diarrhea.…”

Section: Introductionmentioning

confidence: 99%

“…In vivo studies have shown increased intestinal permeability, caused by irinotecan treatment, permits endotoxin and bacterial translocation, thus increasing the risk of secondary infection (7). In patients with ulcerative colitis, loss of intestinal barrier function and tight junction integrity has been shown to contribute to diarrhea development via passive back-flow of anions and water into the lumen (21).…”

Section: Introductionmentioning

confidence: 99%

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TLR4-Dependent Claudin-1 Internalization and Secretagogue-Mediated Chloride Secretion Regulate Irinotecan-Induced Diarrhea

Wardill

Bowen

Sebille

et al. 2016

Molecular Cancer Therapeutics

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We have previously shown increased intestinal permeability, to 4-kDa FITC-dextran, in BALB/c mice treated with irinotecan. Importantly, genetic deletion of Toll-like receptor 4 (TLR4; Tlr4−/−) protected against loss of barrier function, indicating that TLR4 is critical in tight junction regulation. The current study aimed (i) to determine the molecular characteristics of intestinal tight junctions in wild-type and Tlr4−/− BALB/c mice and (ii) to characterize the secretory profile of the distal colon. Forty-two female wild-type and 42 Tlr4−/− BALB/c mice weighing between 18 and 25 g received a single 270 mg/kg [intraperitoneal (i.p.)] dose of irinotecan hydrochloride or vehicle control and were killed at 6, 24, 48, 72, and 96 hours. The secretory profile of the distal colon, following carbachol and forksolin, was assessed using Ussing chambers at all time points. Tight junction integrity was assessed at 24 hours, when peak intestinal permeability and diarrhea were reported, using immunofluorescence, Western blotting, and RT-PCR. Irinotecan caused internalization of claudin-1 with focal lesions of ZO-1 and occludin proteolysis in the ileum and colon of wild-type mice. Tlr4−/− mice maintained phenotypically normal tight junctions. Baseline conductance, a measure of paracellular permeability, was increased in irinotecan-treated wild-type mice at 24 hours (53.19 ± 6.46 S/cm2; P = 0.0008). No change was seen in Tlr4−/− mice. Increased carbachol-induced chloride secretion was seen in irinotecan-treated wild-type and Tlr4−/− mice at 24 hours (wild-type: 100.35 ± 18.37 μA/cm2; P = 0.022; Tlr4−/−: 102.72 ± 18.80 μA/cm2; P = 0.023). Results suggest that TLR4-dependent claudin-1 internalization and secondary anion secretion contribute to irinotecan-induced diarrhea. Mol Cancer Ther; 15(11); 2767–79. ©2016 AACR.

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Effect of TU‐100 on Peyer's patches in a bacterial translocation rat model

Takasu

Miyazaki

Yoshikawa

et al. 2021

Annals of Gastroent Surgery

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Background Daikenchuto (TU‐100), a Japanese herbal medicine, is widely used for various gastrointestinal diseases. We have previously reported that TU‐100 suppresses CPT‐11‐induced bacterial translocation (BT) by maintaining the diversity of the microbiome. In this study we show that TU‐100 modulates the immune response during BT by inducing PD‐1 expression in Peyer's patches. Methods Eighteen male Wistar rats were divided into four groups: a control group; a control + TU‐100 group, given TU‐100 1000 mg/kg orally for 5 d; a BT group, given CPT‐11 250 mg/kg intra‐peritoneal for 2 d; and a TU‐100 group, given TU‐100 1000 mg/kg orally for 5 d with CPT‐11 250 mg/kg intra‐peritoneal on days 4 and 5. Results The size of Peyer's patch was significantly bigger in the BT group compared to the control group (9.0 × 104 µm2 vs 29.4 × 104 µm2, P < .05), but improved in the TU‐100 group (15.4 × 104 µm2, P < .005). TU‐100 significantly induced PD‐1 expression in Peyer's patch compared to the control group and the BT group (control vs BT vs TU‐100 = 4.3 ± 4.9 vs 5.1 ± 10.3 vs 17.9 ± 17.8). The CD4+ cells were increased in the BT group (P < .05) compared to the control group but decreased in the TU‐100 group. The Foxp3+ cells were increased in the BT group compared to the control group (P < .05), and further increased in the TU‐100 group compared to the BT group. CPT‐11 significantly increased TLR4, NF‐κβ, TNF‐α mRNA expressions in the BT group. TU‐100 cotreatment significantly reversed these mRNA expressions. Conclusion TU‐100 may have a protective effect against BT through PD‐1 expression in Peyer's patch.

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Irinotecan Injures Tight Junction and Causes Bacterial Translocation in Rat

Cited by 55 publications

References 16 publications

Irinotecan disrupts tight junction proteins within the gut

Irinotecan disrupts tight junction proteins within the gut

TLR4-Dependent Claudin-1 Internalization and Secretagogue-Mediated Chloride Secretion Regulate Irinotecan-Induced Diarrhea

Effect of TU‐100 on Peyer's patches in a bacterial translocation rat model

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