Bacteroides Fragilis Toxin Coordinates a Pro-Carcinogenic Inflammatory Cascade via Targeting of Colonic Epithelial Cells

Chung, Liam; Thiele-Orberg, Erik; Geis, Abby L.; Chan, Joshua C. C.; Fu, Kai; Shields, Christina E. DeStefano; Dejea, Christine M.; Fathi, Parinaz; Chen, Jie; Finard, Benjamin B.; Tam, Ada; McAllister, Florencia; Fan, Hongni; Wu, Xinqun; Ganguly, Sudipto; Metz, Paul; Meerbeke, Sara W. Van; Huso, David L.; Wick, Elizabeth C.; Pardoll, Drew M.; Wan, Fengyi; Wu, Shaoguang; Sears, Cynthia L.; Housseau, Franck

doi:10.2139/ssrn.3155839

Cited by 62 publications

(82 citation statements)

References 28 publications

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“…58 B. acidifaciens resembles closely another member of the same genus B. fragilis, and these bacteria have been shown in the literature to trigger a strong inflammatory cascade response, including activation of IL-17dependent pathways. 59 By decreasing the presence of these bacteria during colitis-induction, resveratrol might be able to suppress the Th17 response, which would normally lead to resident tissue destruction and microbial dysbiosis.…”

Section: Discussionmentioning

confidence: 99%

Resveratrol modulates the gut microbiota to prevent murine colitis development through induction of Tregs and suppression of Th17 cells

Alrafas

Busbee

Nagarkatti

et al. 2019

Journal of Leukocyte Biology

133

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Inflammatory diseases of the gastrointestinal tract are often associated with microbial dysbiosis. Thus, dietary interactions with intestinal microbiota, to maintain homeostasis, play a crucial role in regulation of clinical disorders such as colitis. In the current study, we investigated if resveratrol, a polyphenol found in a variety of foods and beverages, would reverse microbial dysbiosis induced during colitis. Administration of resveratrol attenuated colonic inflammation and clinical symptoms in the murine model of 2,4,6‐trinitrobenzenesulfonic acid (TNBS)‐induced colitis. Resveratrol treatment in mice with colitis led to an increase in CD4+FOXP3+ and CD4+IL‐10+ T cells, and a decrease in CD4+IFN‐γ+ and CD4+IL‐17+ T cells. 16S rRNA gene sequencing to investigate alterations in the gut microbiota revealed that TNBS caused significant dysbiosis, which was reversed following resveratrol treatment. Analysis of cecal flush revealed that TNBS administration led to an increase in species such as Bacteroides acidifaciens, but decrease in species such as Ruminococcus gnavus and Akkermansia mucinphilia, as well as a decrease in SCFA i‐butyric acid. However, resveratrol treatment restored the gut bacteria back to homeostatic levels, and increased production of i‐butyric acid. Fecal transfer experiments confirmed the protective role of resveratrol‐induced microbiota against colitis inasmuch as such recipient mice were more resistant to TNBS‐colitis and exhibited polarization toward CD4+FOXP3+ T cells and decreases in CD4+IFN‐γ+ and CD4+IL‐17+ T cells. Collectively, these data demonstrate that resveratrol‐mediated attenuation of colitis results from reversal of microbial dysbiosis induced during colitis and such microbiota protect the host from colonic inflammation by inducing Tregs while suppressing inflammatory Th1/Th17 cells.

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Section: Discussionmentioning

confidence: 99%

Resveratrol modulates the gut microbiota to prevent murine colitis development through induction of Tregs and suppression of Th17 cells

Alrafas

Busbee

Nagarkatti

et al. 2019

Journal of Leukocyte Biology

133

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“…An abundance of Bacteroides fragilis (B. fragilis) has been shown to potentiate immunotherapy in mouse sarcoma [23]. However, their presence in the microbiome has recently been associated with increased incidence of colon carcinogenesis [51]. Additionally, different species have also been shown to drive distant cancers.…”

Section: Discussionmentioning

confidence: 99%

Perturbation of the gut microbiota by antibiotics results in accelerated breast tumour growth and metabolic dysregulation

Kirkup

McKee

Makin

et al. 2019

Preprint

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Background: Breast cancer is the second most prevalent cancer worldwide with around 1.7 million new cases diagnosed every year. Whilst prognosis is generally favourable in early stages, this worsens significantly in advanced disease. Therefore, it is pertinent to focus on mitigating factors that may slow growth or progression. Recently, the gut microbiome has been implicated in a wide-range of roles in tumour biology. Through modulation of immunity, the gut microbiota can improve the efficacy of several immunotherapies. However, despite the prevalence of breast cancer, there is still a lack of microbiota studies in this field, including exploring the influence of external microbiome-modulating factors such as antibiotics. We describe herein how disruption of the gut microbiota via antibiotics may be detrimental to patient outcomes through acceleration of tumour growth. Results:Supplementing animals with a cocktail of antibiotics leads to gut microbiota alterations and is accompanied by significant acceleration of tumour growth. Surprisingly, and distinct from previous microbiome-tumour studies, the mechanism driving these effects do not appear to be due to gross immunological changes. Analysis of intratumoural immune cell populations and cytokine production are not affected by antibiotic administration. Through global tumour transcriptomics, we have uncovered dysregulated gene expression networks relating to protein and lipid metabolism that are correlated with accelerated tumour growth.Fecal metabolomics revealed a reduction of the microbial-derived short-chain fatty acid butyrate that may contribute to accelerated tumour growth. Finally, through use of a routinely administered antibiotic in breast cancer patients, Cephalexin, we have shown that tumour growth is also significantly affected. Metataxanomic sequencing and analysis highlighted significant antibiotic-associated reductions in the butyrate producing genera Odoribacter and Anaeotruncus, and increased abundance of Bacteroides. Conclusions:Our data indicate that perturbation of the microbiota by antibiotics may have negative impacts on breast cancer patient outcomes. This is of importance as antibiotics are regularly prescribed to breast cancer patients undergoing mastectomy or breast reconstruction. We have also shown that the metabolic impact of disruption to the microbiome should be considered alongside the potent immunological effects. We believe our work lays the foundation for improving the use of antibiotics in patients, and with further investigation could potentially inform clinical practice.

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“…STAT3 activation is required for Th17 cell development and, consistent with this, ETBF induces a rapid mucosal Th17 inflammatory response within 1 week of colonization. 79 Colon tumors induced by ETBF also have a marked increase in STAT3 activation. IL-17 is produced by a subpopulation of Th17 cells.…”

Section: Bacteroides Fragilismentioning

confidence: 99%

The role of microbiota in the development of colorectal cancer

Dai

Zhang

et al. 2019

Intl Journal of Cancer

104

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Colorectal cancer is the third largest cancer in worldwide and has been proven to be closely related to the intestinal microbiota. Many reports and clinical studies have shown that intestinal microbial behavior may lead to pathological changes in the host intestines. The changes can be divided into epigenetic changes and carcinogenic changes at the gene level, which ultimately promote the production and development of colorectal cancer. This article reviews the pathways of microbial signaling in the intestinal epithelial barrier, the role of microbiota in inflammatory colorectal tumors, and typical microbial carcinogenesis. Finally, by gaining a deeper understanding of the intestinal microbiota, we hope to achieve the goal of treating colorectal cancer using current microbiota technologies, such as fecal microbiological transplantation.

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Bacteroides Fragilis Toxin Coordinates a Pro-Carcinogenic Inflammatory Cascade via Targeting of Colonic Epithelial Cells

Cited by 62 publications

References 28 publications

Resveratrol modulates the gut microbiota to prevent murine colitis development through induction of Tregs and suppression of Th17 cells

Resveratrol modulates the gut microbiota to prevent murine colitis development through induction of Tregs and suppression of Th17 cells

Perturbation of the gut microbiota by antibiotics results in accelerated breast tumour growth and metabolic dysregulation

The role of microbiota in the development of colorectal cancer

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