TAK-242 ameliorates DSS-induced colitis by regulating the gut microbiota and the JAK2/STAT3 signaling pathway

Wang, Jiajia; Zhu, Guannan; Sun, Cheng; Xiong, Ke; Yao, Tingting; Su, Yuan; Hou, Fang

doi:10.1186/s12934-020-01417-x

Cited by 46 publications

(32 citation statements)

References 56 publications

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“…In agreement with these findings, we observed that TLR4 inhibition by TAK-242 during the onset of CAC was also potent to reduce macrophage infiltration and impede tumor growth. Contrary to the results from TLR4 -/-mice, others and we found that the inhibition of TLR4 signaling by TAK-242 during DSS treatment alleviated intestinal pathology (35).…”

Section: Discussioncontrasting

confidence: 99%

“…Wang et al reported that TAK-242 application in DSS colitis interfered with the JAK2/STAT3 pathway and significantly altered the intestinal microbiota (35). Regarding microbial composition, they observed a markedly decreased abundance of Proteobacteria, Cyanobacteria and Epsilonbacteraeota, while Akkermansia were strongly expanded in TAK-242 treated DSS mice compared to DSS mice.…”

Section: Discussionmentioning

confidence: 99%

“…The overall importance of TLR4 signaling on acute colitis and CAC development has been intensely studied in murine models using TLR4 -/mice and TLR4 inhibitors, such as TAK-242 or antagonist TLR4 antibodies (15,24,35). Although complete deletion of TLR4 in TLR4 -/mice did not protect from severe DSS-induced inflammation (36), the specific lack of TLR4 signaling on colonic epithelial cells inhibited CAC development, as well as recruitment and activation of Cyclooxygenase (Cox)-2 expressing macrophages in the AOM/ DSS model (14,16).…”

Section: Discussionmentioning

confidence: 99%

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Inhibition of TLR4 Signaling Impedes Tumor Growth in Colitis-Associated Colon Cancer

et al. 2021

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Patients suffering from ulcerative colitis are at increased risk of developing colorectal cancer. Although the exact underlying mechanisms of inflammation-associated carcinogenesis remain unknown, the intestinal microbiota as well as pathogenic bacteria are discussed as contributors to inflammation and colitis-associated colon cancer (CAC). In the present study, we analyzed the impact of TLR4, the receptor for Gram-negative bacteria derived lipopolysaccharides, on intestinal inflammation and tumorigenesis in a murine model of CAC. During the inflammatory phases of CAC development, we observed a strong upregulation of Tlr4 expression in colonic tissues. Blocking of TLR4 signaling by a small-molecule-specific inhibitor during the inflammatory phases of CAC strongly diminished the development and progression of colonic tumors, which was accompanied by decreased numbers of infiltrating macrophages and reduced colonic pro-inflammatory cytokine levels compared to CAC control mice. Interestingly, inhibiting bacterial signaling by antibiotic treatment during the inflammatory phases of CAC also protected mice from severe intestinal inflammation and almost completely prevented tumor growth. Nevertheless, application of antibiotics involved rapid and severe body weight loss and might have unwanted side effects. Our results indicate that bacterial activation of TLR4 on innate immune cells in the colon triggers inflammation and promotes tumor growth. Thus, the inhibition of the TLR4 signaling during intestinal inflammation might be a novel approach to impede CAC development.

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Section: Discussioncontrasting

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Inhibition of TLR4 Signaling Impedes Tumor Growth in Colitis-Associated Colon Cancer

et al. 2021

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“…Saffron-treated mice showed depletion in the Proteobacteria phylum. Furthermore, unlike in human IBD, Cyanobacteria, which are reported to increase in DSS-induced colitis [42,43], which is in agreement with our study, were depleted by saffron as observed at the OTU-level analysis (Figure 3C,D). This reduction in colitogenic bacteria (Proteobacteria and Cyanobacteria) is likely to be sensed directly by the immune system, leading to a reduction in pro-inflammatory signals and markers.…”

Section: Discussionsupporting

confidence: 92%

Saffron Pre-Treatment Promotes Reduction in Tissue Inflammatory Profiles and Alters Microbiome Composition in Experimental Colitis Mice

et al. 2021

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Inflammatory bowel disease (IBD) is a chronic inflammatory condition of the gastrointestinal tract with an incompletely understood pathogenesis. Long-standing colitis is associated with increased risk of colon cancer. Despite the availability of various anti-inflammatory and immunomodulatory drugs, many patients fail to respond to pharmacologic therapy and some experience drug-induced adverse events. Dietary supplements, particularly saffron (Crocus sativus), have recently gained an appreciable attention in alleviating some symptoms of digestive diseases. In our study, we investigated whether saffron may have a prophylactic effect in a murine colitis model. Saffron pre-treatment improved the gross and histopathological characteristics of the colonic mucosa in murine experimental colitis. Treatment with saffron showed a significant amelioration of colitis when compared to the vehicle-treated mice group. Saffron treatment significantly decreased secretion of serotonin and pro-inflammatory cytokines, such as TNF-α, IL-1β, and IL-6, in the colon tissues by suppressing the nuclear translocation of NF-κB. The gut microbiome analysis revealed distinct clusters in the saffron-treated and untreated mice in dextran sulfate sodium (DSS)-induced colitis by visualization of the Bray–Curtis diversity by principal coordinates analysis (PCoA). Furthermore, we observed that, at the operational taxonomic unit (OTU) level, Cyanobacteria were depleted, while short-chain fatty acids (SCFAs), such as isobutyric acid, acetic acid, and propionic acid, were increased in saffron-treated mice. Our data suggest that pre-treatment with saffron inhibits DSS-induced pro-inflammatory cytokine secretion, modulates gut microbiota composition, prevents the depletion of SCFAs, and reduces the susceptibility to colitis.

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“…In a previous study [ 44 ] estimates of alpha diversity were based on an evenly rarefied OTU abundance matrix and included observed richness, observed species, and the Shannon, Simpson, ACE, and Chao1 indexes using the R package vegan. The significance of differences in measured alpha-diversity metrics across samples was tested using a nonparametric Kruskal–Wallis rank sum test and the Benjamini–Hochberg correction.…”

Section: Methodsmentioning

confidence: 99%

Long-term efficacy and safety of monotherapy with a single fresh fecal microbiota transplant for recurrent active ulcerative colitis: a prospective randomized pilot study

Hou

Lian

et al. 2021

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Background To assess the long-term safety and efficacy of monotherapy with a single fresh fecal microbiota transplant (FMT) for recurrent ulcerative colitis (UC). Results Twenty-six eligible patients were enrolled, and 6 patients were excluded. Ultimately, 20 patients were randomized to the FMT group (n = 10) and the control group (n = 10); 80% were females (F/M = 16/4), the mean age was 48 ± 14 years, and the mean duration was 6.4 ± 8.2 years. The mean length of post-FMT follow-up was 19.1 ± 10.1 months (6–38). No statistically significant differences in baseline demographic or clinical characteristics were found between the groups. Ninety percent of patients in the FMT group and 50% of patients in the control group met the primary endpoint at week 8. The Mayo score was significantly decreased compared with that of the control group (n = 10) when reassessed at week 4 (P = 0.001) and week 8 (P = 0.019) after FMT; there was no significant difference 6 months after treatment. The median remission time was 24 months (95% CI 68.26–131.7%) in both the FMT (range 6–38 months) and control groups (range 7–35 months), with no significant difference (P = 0.895). Participants tolerated FMT treatment, and no adverse events occurred during long-term follow-up, with one treatment-related significant adverse event (EBV infection) occurring within 2 weeks after FMT. Stool microbiota composition analysis indicated improved gut microbiota diversity after FMT, with expansion of stool-donor taxa. Bacteroidetes, Firmicutes and Proteobacteria were the dominant bacterial phyla of the gut microbiota in active UC patients. The relative abundance of Bacteroidetes decreased and that of Proteobacteria increased significantly in active UC patients compared with donors, while Firmicutes showed no significant changes. A single fresh FMT could effectively reconstruct the gut microbiota composition in patients with active UC and maintain stability, with increased Bacteroidetes and decreased Proteobacteria abundance. FMT significantly reduced the relative abundance of Escherichia and increased the relative abundance of Prevotella at the genus level. Pyruvate metabolism, glyoxylate and dicarboxylate metabolism, and pantothenate and CoA biosynthesis showed significant differences after transplantation. Conclusions Monotherapy with a single fresh FMT is an effective and safe strategy to induce long-term remission without drugs in patients with active UC and may be an alternative induction therapy for recurrent UC or even primary UC.

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TAK-242 ameliorates DSS-induced colitis by regulating the gut microbiota and the JAK2/STAT3 signaling pathway

Cited by 46 publications

References 56 publications

Inhibition of TLR4 Signaling Impedes Tumor Growth in Colitis-Associated Colon Cancer

Inhibition of TLR4 Signaling Impedes Tumor Growth in Colitis-Associated Colon Cancer

Saffron Pre-Treatment Promotes Reduction in Tissue Inflammatory Profiles and Alters Microbiome Composition in Experimental Colitis Mice

Long-term efficacy and safety of monotherapy with a single fresh fecal microbiota transplant for recurrent active ulcerative colitis: a prospective randomized pilot study

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