Parthenolide ameliorates colon inflammation through regulating Treg/Th17 balance in a gut microbiota-dependent manner

Liu, Yaojiang; Tang, Bo; Wang, Fengchao; Tang, Li; Lei, Yuanyuan; Luo, Ya; Huang, Shengjie; Ye, Min; Wu, Ling-Yi; Wang, Wei; Liu, Shuang; Yang, Shiming; Zhao, Xiao‐Fan

doi:10.7150/thno.43716

Cited by 205 publications

(125 citation statements)

References 45 publications

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“…Interestingly, we observed histological damage and tumor growth recovery during STAT6 deficiency, supporting the idea that Treg cells developed in STAT6 −/− mice are protective against colon tumorigenesis. This finding seems to be compatible with that of a recent study showing that the administration of the natural compound, Parthenolide, during experimental colitis significantly relieved colon inflammation and improved the colitis symptoms [ 40 ]. The protective effect of this molecule was associated with an increased frequency of colonic Treg cells, a downregulation of the ratio of colonic Th17 cells, together with a more abundant gut microbial diversity and flora composition [ 40 ].…”

Section: Discussionsupporting

confidence: 92%

“…This finding seems to be compatible with that of a recent study showing that the administration of the natural compound, Parthenolide, during experimental colitis significantly relieved colon inflammation and improved the colitis symptoms [ 40 ]. The protective effect of this molecule was associated with an increased frequency of colonic Treg cells, a downregulation of the ratio of colonic Th17 cells, together with a more abundant gut microbial diversity and flora composition [ 40 ]. One possible reason for the protection observed in the STAT6 −/− mice during CAC progression could be the alterations in gut microbiota.…”

Section: Discussionsupporting

confidence: 92%

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STAT6 Is Critical for the Induction of Regulatory T Cells In Vivo Controlling the Initial Steps of Colitis-Associated Cancer

Delgado‐Ramirez

Ocaña-Soriano

Ledesma-Soto

et al. 2021

IJMS

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Inflammation is the main driver of the tumor initiation and progression in colitis-associated colorectal cancer (CAC). Recent findings have indicated that the signal transducer and activator of transcription 6 (STAT6) plays a fundamental role in the early stages of CAC, and STAT6 knockout (STAT6−/−) mice are highly resistant to CAC development. Regulatory T (Treg) cells play a major role in coordinating immunomodulation in cancer; however, the role of STAT6 in the induction and function of Treg cells is poorly understood. To clarify the contribution of STAT6 to CAC, STAT6−/− and wild type (WT) mice were subjected to an AOM/DSS regimen, and the frequency of peripheral and local Treg cells was determined during the progression of CAC. When STAT6 was lacking, a remarkable reduction in tumor growth was observed, which was associated with decreased inflammation and an increased number of CD4+CD25+Foxp3+ cells in the colon, circulation, and spleen, including an over-expression of TGF-beta, IL-10, and Foxp3, compared to WT mice, during the early stages of CAC development. Conversely, WT mice showed an inverse frequency of Treg cells compared with STAT6−/− mice, which was followed by intestinal tumor formation. Increased mucosal inflammation, histological damage, and tumorigenesis were restored to levels observed in WT mice when an early inhibition/depletion of Treg cells was performed in STAT6−/− mice. Thus, with STAT6 deficiency, an increased number of Treg cells induce resistance against tumorigenesis, arresting tumor-promoting inflammation. We reported a direct role of STAT6 in the induction and function of Treg cells during CAC development and suggest that STAT6 is a potential target for the modulation of immune response in colitis and CAC.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionsupporting

confidence: 92%

STAT6 Is Critical for the Induction of Regulatory T Cells In Vivo Controlling the Initial Steps of Colitis-Associated Cancer

Delgado‐Ramirez

Ocaña-Soriano

Ledesma-Soto

et al. 2021

IJMS

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“…Multiple pro- and anti-inflammatory cytokines have been recognized to participate in CRC, peculiarly CAC development, via various mechanisms. Proinflammatory cytokines, such as TNF-α, IL-1α/β, IL-6, IL-17A, and IL-11, and their downstream transcription factors, including NF-κB and STAT3, construct an immunosuppressive stroma that addicts tumor cells; therefore, these factors are emerging as potential targets for CRC therapy 2 , 31 , 32 , 44 . In contrast, anti-inflammatory cytokines, such as IL-9, IL-23, IL-27, and especially IL-10, play the opposite role, thus retarding CRC tumorigenesis 2 , 31 , 32 .…”

Section: Discussionmentioning

confidence: 99%

C5aR1 is a master regulator in Colorectal Tumorigenesis via Immune modulation

Ding¹,

Li²,

Li³

et al. 2020

Theranostics

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Numerous factors have been claimed to play important roles in colorectal cancer (CRC) tumorigenesis, including myeloid-derived suppressor cells (MDSCs) and other immune cells, cytokines, and chemokines; however, the precise mechanisms of colorectal tumorigenesis remain elusive, and there is a lack of effective preventive treatments. Here, we investigated the role of complement system, a key regulator of immune surveillance and homeostasis, in colorectal tumorigenesis. Methods: The prototypical CRC model was induced by combined administration of azoxymethane (AOM)/ dextran sulfate sodium (DSS) in Wild-type (WT), C3 -, C5 -, C5ar1 -, and C5ar2 -deficient mice. Using flow cytometry, immunohistochemical staining and multiplex bead assay, we profiled the immune cells, cytokines and chemokines. Bone marrow transplantation was employed to determine the contribution of immune cells in colorectal tumorigenesis. Further, we used C5aR1 antagonist PMX205 to investigate the protective role in colorectal tumorigenesis. Results: Complement was extensively activated in inflamed tissues of AOM/DSS-induced murine CRC model, leading to multifaceted consequences. The deficiency of complement C5 or especially C5ar1 , but not C3 almost completely prevented CRC tumorigenesis. C5a/C5aR1 signaling recruited MDSCs into the inflamed colorectum to impair CD8 + T cells, and modulated the production of critical cytokines and chemokines, thus initiating CRC. Moreover, the C5aR1 antagonist PMX205 strongly impeded colorectal tumorigenesis. Bone marrow transplantation further revealed that C5aR1 expression by immune cells was critical for colorectal tumorigenesis. Conclusion: Our study identifies C5a/C5aR1 signaling as a vital immunomodulatory program in CRC tumorigenesis and suggests a feasible preventive strategy.

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“…2.9. Gut Microbiota and IBD: Dysbiosis Is a Typical Feature in IBD Statistical data analysis has shown that the effects of diet on IBD vary from person to person, mainly because of the diversity of gut microflora [69][70][71][72]. Our intestines are home to a wide variety of microorganisms, some still unknown.…”

Section: Dietary Nutrients and Microbiotamentioning

confidence: 99%

Dietary Regulation of the Crosstalk between Gut Microbiome and Immune Response in Inflammatory Bowel Disease

Yao

Fan

et al. 2021

Foods

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Inflammatory bowel disease (IBD), a chronic, recurring inflammatory response, is a growing global public health issue. It results from the aberrant crosstalk among environmental factors, gut microbiota, the immune system, and host genetics, with microbiota serving as the core of communication for differently-sourced signals. In the susceptible host, dysbiosis, characterized by the bloom of facultative anaerobic bacteria and the decline of community diversity and balance, can trigger an aberrant immune response that leads to reduced tolerance against commensal microbiota. In IBD, such dysbiosis has been profoundly proven in animal models, as well as clinic data analysis; however, it has not yet been conclusively ascertained whether dysbiosis actually promotes the disease or is simply a consequence of the inflammatory disorder. Better insight into the complex network of interactions between food, the intestinal microbiome, and host immune response will, therefore, contribute significantly to the diagnosis, treatment, and management of IBD. In this article, we review the ways in which the mutualistic circle of dietary nutrients, gut microbiota, and the immune system becomes anomalous during the IBD process, and discuss the roles of bacterial factors in shaping the intestinal inflammatory barrier and adjusting immune capacity.

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Parthenolide ameliorates colon inflammation through regulating Treg/Th17 balance in a gut microbiota-dependent manner

Cited by 205 publications

References 45 publications

STAT6 Is Critical for the Induction of Regulatory T Cells In Vivo Controlling the Initial Steps of Colitis-Associated Cancer

STAT6 Is Critical for the Induction of Regulatory T Cells In Vivo Controlling the Initial Steps of Colitis-Associated Cancer

C5aR1 is a master regulator in Colorectal Tumorigenesis via Immune modulation

Dietary Regulation of the Crosstalk between Gut Microbiome and Immune Response in Inflammatory Bowel Disease

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