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. 2018 Jul:33:122-133.
doi: 10.1016/j.ebiom.2018.06.029. Epub 2018 Jul 2.

V体育2025版 - Induction and Amelioration of Methotrexate-Induced Gastrointestinal Toxicity are Related to Immune Response and Gut Microbiota

Bailing Zhou  1 , Xuyang Xia  2 , Peiqi Wang  3 , Shuang Chen  1 , Chaoheng Yu  1 , Rong Huang  1 , Rui Zhang  1 , Yantai Wang  1 , Lian Lu  1 , Fengjiao Yuan  1 , Yaomei Tian  1 , Yingzi Fan  1 , Xueyan Zhang  1 , Yang Shu  2 , Shouyue Zhang  2 , Ding Bai  3 , Lei Wu  1 , Heng Xu  4 , Li Yang  5
Affiliations

Induction and Amelioration of Methotrexate-Induced Gastrointestinal Toxicity are Related to Immune Response and Gut Microbiota

Bailing Zhou et al. EBioMedicine. 2018 Jul.

Abstract

As a widely used anticancer and immunosuppressive agent, methotrexate (MTX) can induce multiple adverse drug reactions (ADRs), such as gastrointestinal toxicity, the mechanisms are poorly understood. Gut microbiota has been widely reported to be associated with the onset of multiple diseases as well as treatment outcomes of different drugs. In this study, mucosal injury was observed in MTX-treated mice, leading to significant changes in macrophages (i. e. , M1/M2 ratio, P < 0. 05) but not in dendritic cells. Moreover, the population, diversity and principal components of the gut microbiota in mice were dramatically altered after MTX treatment in a time-dependent manner, and Bacteroidales exhibited the most distinct variation among all the taxa (P < 0. 05). Bacteroides fragilis was significantly decreased with MTX treatment (P < 0. 01) and tended to decrease proportionately with increasing macrophage density. Gavage of mice with B. fragilis ameliorated MTX-induced inflammatory reactions and modulate macrophage polarization. In conclusion, our results delineate a strong impact of the gut microbiota on MTX-induced intestinal mucositis and provide a potential method for the prevention of such ADRs. VSports手机版.

Keywords: Gastrointestinal toxicity; Gut microbiota; Methotrexate; Mononuclear phagocyte. V体育安卓版.

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Figures

Fig. 1
Fig. 1
MTX induces inflammatory responses in intestinal tissues. (a) Representative hematoxylin-eosin (HE) staining of the jejunum and colon in control and MTX-treated mice on day 14. (b) Representative immunofluorescence staining of the monocyte surface marker (CD11b) in the jejunum and colon of Balb/c mice treated with or without MTX on day 14. Nuclei were counterstained with DAPI (blue); magnification 200×.
Fig. 2
Fig. 2
MTX induces alterations in intestinal cytokines. (a-d) Real-time PCR analyses of expression of cytokines (a) IFN-γ, (B) IL-1β, (c) TNF-α, and (d) IL-6 in the mouse jejunum after treatment with or without MTX (n = 3/group). (e-h) Expression levels of cytokines (e) IFN-γ, (f) IL-1β, (g) TNF-α, and (h) IL-6 in the mouse colon (n = 3/group). Shown are the means ± SEM; *P < 0.05 and **P < 0.01 versus PBS treatment (normal).
Fig. 3
Fig. 3
MTX induces changes in macrophage subsets in the mesenteric lymph nodes (MLNs) and spleens. (a, b) MTX-associated changes in (a) CD11b+F4/80+ M1 macrophages and (b) CD11b+CD206+ M2 macrophages in MLNs on day 7 and day 14. (c, d) MTX-associated changes in (c) CD11b+F4/80+ M1 macrophages and (d) CD11b+CD206+ M2 macrophages in the spleens on day 7 and day 14. (e) M1/M2 ratio in the MLNs on day 7 and day 14. (f) M1/M2 ratio in the spleens on day 7 and day 14. (A-F, n = 3/group) Shown are the means ±SEM; *P < 0.05 and **P < 0.01 versus PBS treatment.
Fig. 4
Fig. 4
MTX induces changes in intestinal microbial components. (a) Alpha diversity and (b) principal component analysis (PCA) of the gut microbiota in MTX-treated and PBS-treated mice on day 0, day 7, and day 14. Shown are the means ± SEM; ns, not significant; *adjusted P < 0.05 versus day 0.
Fig. 5
Fig. 5
MTX induces alterations in various microbial taxa over time. (a) Heatmap of OTUs of intestinal microbiota in the MTX-treated mice (n = 7). (b, c) Examples of OTUs for which the abundance (b) decreased or (c) increased after MTX treatment. (d) Linear discriminant analysis (LDA) effect size (LEfSe) of the differentially abundant microbial taxa on day 0, day 7, and day 14 in the MTX-treated mice. Only taxa meeting an LDA significant threshold of >3.6 are shown. (e) Changes in Bacteroidales in mice treated with or without MTX. Shown are the means ±SEM; ns, not significant; * adjusted P < 0.05 and ** adjusted P < 0.01 versus day 0.
Fig. 6
Fig. 6
Trend towards a decrease in Bacteroidales in feces post MTX treatment. Real-time PCR analyses of feces DNA targeting (a) B. thetaiotamicron, (b) B. fragilis, and (c) B. uniforms in the MTX-treated PBS-treated mice. Ns, not significant; *P < 0.05, **P < 0.01 and ***P < 0.001 versus day 0.
Fig. 7
Fig. 7
B. fragilis protects from MTX-induced inflammatory responses. (a-d) Effects of B. fragilis and MTX on the expression of cytokines (a) IFN-γ, (b) IL-1β, (c) TNF-α, and (d) IL-6 in Caco2 cells and IEC6 cells. *P < 0.05 and **P < 0.01 versus the MTX group.
Fig. 8
Fig. 8
B. fragilis ameliorates MTX-induced macrophage alterations. (a) M1 macrophages and (b) M2 macrophages in the MLNs. (c) M1 macrophages and (d) M2 macrophages in the spleen. (A-D, n = 3/group). *P < 0.05 and **P < 0.01 versus blank control. #P < 0.05, ##P < 0.01 and ###P < 0.001 versus metronidazole + MTX.
Supplementary Fig. 1
Supplementary Fig. 1
Thickness of muscularis mucosae (n = 3). *P < 0.05 and **P < 0.01 versus PBS.
Supplementary Fig. 2
Supplementary Fig. 2
MTX induces changes in dendritic cells (DCs) in the mesenteric lymph nodes (MLNs) but not in the spleen.
Supplementary Fig. 3
Supplementary Fig. 3
Observed species, ACE and Shannon diversity analysis.
Supplementary Fig. 4
Supplementary Fig. 4
Weighted UniFrac analysis.
Supplementary Fig. 5
Supplementary Fig. 5
LefSe analysis for MTX-treated mice versus PBS-treated mice.
Supplementary Fig. 6
Supplementary Fig. 6
RAW264.7 macrophages inhibit B. fragilis proliferation.
Supplementary Fig. 7
Supplementary Fig. 7
MTX inhibits the proliferation of Caco2 cells and IEC6 cells.
Supplementary Fig. 8
Supplementary Fig. 8
Oral gavage with B. fragilis increases intestinal B. fragilis content.
Supplementary Fig. 9
Supplementary Fig. 9
B. fragilis protects from MTX-associated tissue injury. (a) Hematoxylin-eosin (HE) staining of the jejunum and colon in control and MTX-treated mice. (b) Thickness of muscularis mucosae (n = 3). *P < 0.05 and **P < 0.01 versus PBS. #P < 0.05, ##P < 0.01 versus MTX.
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