Human Colon Cancer–Derived <i>Clostridioides difficile</i> Strains Drive Colonic Tumorigenesis in Mice

Drewes, Julia L.; Chen, Jie; Markham, Nicholas O.; Knippel, Reece J.; Domingue, Jada C.; Tam, Ada; Chan, Joshua C. C.; Kim, Lana; McMann, Madison; Stevens, Courtney; Dejea, Christine M.; Tomkovich, Sarah; Michel, John; White, James R.; Mohammad, Fuad; Campodónico, Victoria L.; Heiser, Cody N.; Wu, Xinqun; Wu, Shaoguang; Ding, Hua; Simner, Patricia J.; Carroll, Karen C.; Shrubsole, Martha J.; Anders, Robert A.; Walk, Seth T.; Jobin, Christian; Wan, Fengyi; Coffey, Robert J.; Housseau, Franck; Lau, Ken S.; Sears, Cynthia L.

doi:10.1158/2159-8290.cd-21-1273

Cited by 47 publications

(34 citation statements)

References 46 publications

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“…The gut microbiota is closely related to CRC. In addition to Fusobacterium nucleatum , Enterotoxigenic Bacteroides fragilis , and PKS + Escherichia coli , which have been confirmed earlier [ 5 – 7 ], in recent years, various bacteria, such as Porphyromonas gingivalis , Peptostreptococcus anaerobius , and Clostridium difficile have been confirmed to be associated with CRC [ 8 – 10 ].…”

Section: Introductionmentioning

confidence: 72%

Parvimonas micra activates the Ras/ERK/c-Fos pathway by upregulating miR-218-5p to promote colorectal cancer progression

Chang

Huang

Hou

et al. 2023

J Exp Clin Cancer Res

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Background Colorectal cancer (CRC) is the third most common cancer in the world, and a strong relationship exists between CRC and gut microbiota, which affects the occurrence, development, and metastasis of cancer. Bioinformatics-based analyses revealed that the abundance of Parvimonas micra (P. micra) in the feces of patients with cancer is significantly higher than that in healthy people. Therefore, an important relationship may exist between P. micra and CRC. Methods We first confirmed that P. micra can promote the proliferation of cell lines through cell experiments and mouse models. Then we selected the signaling pathways and content of exosomes to promote the development of CRC by transcriptomics and microRNA sequencing. Finally, we confirmed that P. micra promoted CRC development through miR-218-5p/Ras/ERK/c-Fos pathway through the in vivo and in vitro experiments. Results First, it was confirmed by in vitro and in vivo experiments that P. micra can promote the development of CRC. Transcriptome analysis after the coincubation of bacteria and cells revealed that P. micra promoted cell proliferation by activating the Ras/ERK/c-Fos pathway. Furthermore, microRNA sequencing analysis of the cells and exosomes showed that miR-218-5p and protein tyrosine phosphatase receptor R (PTPRR) were the key factors involved in activating the Ras/ERK/c-Fos pathway, and the miR-218-5p inhibitor was used to confirm the role of microRNA in xenograft mice. Conclusion This experiment confirmed that P. micra promoted the development of CRC by upregulating miR-218-5p expression in cells and exosomes, inhibiting PTPRR expression, and ultimately activating the Ras/ERK/c-Fos signaling pathway.

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Section: Introductionmentioning

confidence: 72%

Parvimonas micra activates the Ras/ERK/c-Fos pathway by upregulating miR-218-5p to promote colorectal cancer progression

Chang

Huang

Hou

et al. 2023

J Exp Clin Cancer Res

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“…These data along with permeability data suggest that there is a concerted response to maintain barrier function in terms of permeability during infection that may not be present in homogenous cell culture models and explant intoxication models. Indeed, studies have reported increased crypt length and epithelial cell differentiation during infection, which may reinforce the mucosal barrier during CDI 65, 66 . Chemical inhibition of ENaC revealed that there was no difference in function during infection.…”

Section: Discussionmentioning

confidence: 98%

Toxin-mediated downregulation of absorptive ion transporters NHE3, DRA, and SGLT1 in the colon contributes to diarrhea associated withClostridioides difficileinfection

Peritore-Galve

Kaji

Smith

et al. 2022

Preprint

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Background & Aim:Clostridioides difficileinfection (CDI) is the leading cause of hospital-acquired diarrhea and pseudomembranous colitis. Two protein toxins, TcdA and TcdB, produced byC. difficileare the major determinants of disease. However, the physiological cause of diarrhea associated with CDI is not well understood. We investigated the effects of CDI on paracellular permeability and apical ion transporters.Methods: We studied intestinal permeability and apical membrane transporters in female C57BL/6J mice. Üssing chambers were used to measure regional differences in paracellular permeability and ion transporter function in intestinal mucosa. Intestinal tissues were collected from mice and analyzed by immunofluorescence microscopy and RNA-sequencing.Results: CDI increased intestinal permeability through the size-selective leak pathway in vivo, but permeability was not increased at the sites of pathological damage. Chloride secretion was reduced in the cecum during infection by decreased CaCC function. Infected mice had decreased SGLT1 (also called SLC5A1) activity in the cecum and colon along with diminished apical abundance and an increase in luminal glucose. SGLT1 and DRA (also called SLC26A3) expression was ablated by either TcdA or TcdB, but NHE3 (also called SLC9A3) was decreased in a TcdB-dependent manner. Finally, expression of these three ion transporters was drastically reduced at the transcriptional level.Conclusions: CDI increases intestinal permeability and decreases apical abundance of NHE3, SGLT1, and DRA. This combination may cause a dysfunction in water and solute absorption in the lower gastrointestinal tract, leading to osmotic diarrhea. These findings may open novel pathways for attenuating CDI-associated diarrhea.

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“…For example, metagenomics is combined with metabolomics ( Oh et al, 2020 ). Meta-analysis attempts to systematically merge data across multiple studies and transform it into metadata that can be analyzed simultaneously ( Armour et al, 2019 ; Wang et al, 2021 ; Drewes et al, 2022 ), which reduce study bias, increase statistical power and improve overall biological understanding of a study effect. As for data mining, machine learning has been applied to find biomarkers and carry out classification or prediction tasks, such as diagnosis, disease course, and disease severity ( Marcos-Zambrano et al, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

The gut microbiome in human health and disease—Where are we and where are we going? A bibliometric analysis

Huang

Liu

et al. 2022

Front. Microbiol.

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BackgroundThere are trillions of microbiota in our intestinal tract, and they play a significant role in health and disease via interacting with the host in metabolic, immune, neural, and endocrine pathways. Over the past decades, numerous studies have been published in the field of gut microbiome and disease. Although there are narrative reviews of gut microbiome and certain diseases, the whole field is lack of systematic and quantitative analysis. Therefore, we outline research status of the gut microbiome and disease, and present insights into developments and characteristics of this field to provide a holistic grasp and future research directions.MethodsAn advanced search was carried out in the Web of Science Core Collection (WoSCC), basing on the term “gut microbiome” and its synonyms. The current status and developing trends of this scientific domain were evaluated by bibliometric methodology. CiteSpace was used to perform collaboration network analysis, co-citation analysis and citation burst detection.ResultsA total of 29,870 articles and 13,311 reviews were retrieved from the database, which involve 42,900 keywords, 176 countries/regions, 19,065 institutions, 147,225 authors and 4,251 journals. The gut microbiome and disease research is active and has received increasing attention. Co-cited reference analysis revealed the landmark articles in the field. The United States had the largest number of publications and close cooperation with other countries. The current research mainly focuses on gastrointestinal diseases, such as inflammatory bowel disease (IBD), ulcerative colitis (UC) and Crohn’s disease (CD), while extra-intestinal diseases are also rising, such as obesity, diabetes, cardiovascular disease, Alzheimer’s disease, Parkinson’s disease. Omics technologies, fecal microbiota transplantation (FMT) and metabolites linked to mechanism would be more concerned in the future.ConclusionThe gut microbiome and disease has been a booming field of research, and the trend is expected to continue. Overall, this research field shows a multitude of challenges and great opportunities.

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Human Colon Cancer–Derived Clostridioides difficile Strains Drive Colonic Tumorigenesis in Mice

Cited by 47 publications

References 46 publications

Parvimonas micra activates the Ras/ERK/c-Fos pathway by upregulating miR-218-5p to promote colorectal cancer progression

Parvimonas micra activates the Ras/ERK/c-Fos pathway by upregulating miR-218-5p to promote colorectal cancer progression

Toxin-mediated downregulation of absorptive ion transporters NHE3, DRA, and SGLT1 in the colon contributes to diarrhea associated withClostridioides difficileinfection

The gut microbiome in human health and disease—Where are we and where are we going? A bibliometric analysis

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