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      Systematic review: The gut microbiota as a link between colorectal cancer and obesity

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          Summary

          Microbiome modulation is one of the novel strategies in medicine with the greatest future to improve the health of individuals and reduce the risk of different conditions, including metabolic, immune, inflammatory, and degenerative diseases, as well as cancer. Regarding the latter, many studies have reported the role of the gut microbiome in carcinogenesis, formation and progression of colorectal cancer (CRC), as well as its response to different systemic therapies. Likewise, obesity, one of the most important risk factors for CRC, is also well known for its association with gut dysbiosis. Moreover, obesity and CRC display, apart from microbial dysbiosis, chronic inflammation, which participates in their pathogenesis. Although human and murine studies demonstrate the significant impact of the microbiome in regulating energy metabolism and CRC development, little is understood about the contribution of the microbiome to the development of obesity‐associated CRC. Therefore, this systematic review explores the evidence for microbiome changes associated with these conditions and hypothesizes that this may contribute to the pathogenesis of obesity‐related CRC. Two databases were searched, and different studies on the relationship among obesity, intestinal microbiota and CRC in clinical and preclinical models were selected. Data extraction was carried out by two reviewers independently, and 101 studies were finally considered. Findings indicate the existence of a risk association between obesity and CRC derived from metabolic, immune, and microbial disorders.

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          Most cited references112

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          Adipokines in inflammation and metabolic disease.

          The worldwide epidemic of obesity has brought considerable attention to research aimed at understanding the biology of adipocytes (fat cells) and the events occurring in adipose tissue (fat) and in the bodies of obese individuals. Accumulating evidence indicates that obesity causes chronic low-grade inflammation and that this contributes to systemic metabolic dysfunction that is associated with obesity-linked disorders. Adipose tissue functions as a key endocrine organ by releasing multiple bioactive substances, known as adipose-derived secreted factors or adipokines, that have pro-inflammatory or anti-inflammatory activities. Dysregulated production or secretion of these adipokines owing to adipose tissue dysfunction can contribute to the pathogenesis of obesity-linked complications. In this Review, we focus on the role of adipokines in inflammatory responses and discuss their potential as regulators of metabolic function.
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            Fusobacterium nucleatum potentiates intestinal tumorigenesis and modulates the tumor-immune microenvironment.

            Increasing evidence links the gut microbiota with colorectal cancer. Metagenomic analyses indicate that symbiotic Fusobacterium spp. are associated with human colorectal carcinoma, but whether this is an indirect or causal link remains unclear. We find that Fusobacterium spp. are enriched in human colonic adenomas relative to surrounding tissues and in stool samples from colorectal adenoma and carcinoma patients compared to healthy subjects. Additionally, in the Apc(Min/+) mouse model of intestinal tumorigenesis, Fusobacterium nucleatum increases tumor multiplicity and selectively recruits tumor-infiltrating myeloid cells, which can promote tumor progression. Tumors from Apc(Min/+) mice exposed to F. nucleatum exhibit a proinflammatory expression signature that is shared with human fusobacteria-positive colorectal carcinomas. However, unlike other bacteria linked to colorectal carcinoma, F. nucleatum does not exacerbate colitis, enteritis, or inflammation-associated intestinal carcinogenesis. Collectively, these data suggest that, through recruitment of tumor-infiltrating immune cells, fusobacteria generate a proinflammatory microenvironment that is conducive for colorectal neoplasia progression. Copyright © 2013 Elsevier Inc. All rights reserved.
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              Gut microbiota regulates bile acid metabolism by reducing the levels of tauro-beta-muricholic acid, a naturally occurring FXR antagonist.

              Bile acids are synthesized from cholesterol in the liver and further metabolized by the gut microbiota into secondary bile acids. Bile acid synthesis is under negative feedback control through activation of the nuclear receptor farnesoid X receptor (FXR) in the ileum and liver. Here we profiled the bile acid composition throughout the enterohepatic system in germ-free (GF) and conventionally raised (CONV-R) mice. We confirmed a dramatic reduction in muricholic acid, but not cholic acid, levels in CONV-R mice. Rederivation of Fxr-deficient mice as GF demonstrated that the gut microbiota regulated expression of fibroblast growth factor 15 in the ileum and cholesterol 7α-hydroxylase (CYP7A1) in the liver by FXR-dependent mechanisms. Importantly, we identified tauro-conjugated beta- and alpha-muricholic acids as FXR antagonists. These studies suggest that the gut microbiota not only regulates secondary bile acid metabolism but also inhibits bile acid synthesis in the liver by alleviating FXR inhibition in the ileum. Copyright © 2013 Elsevier Inc. All rights reserved.
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                Author and article information

                Contributors
                merodri@ugr.es
                Journal
                Obes Rev
                Obes Rev
                10.1111/(ISSN)1467-789X
                OBR
                Obesity Reviews
                John Wiley and Sons Inc. (Hoboken )
                1467-7881
                1467-789X
                29 November 2024
                April 2025
                : 26
                : 4 ( doiID: 10.1111/obr.v26.4 )
                : e13872
                Affiliations
                [ 1 ] Department of Pharmacology, Center for Biomedical Research (CIBM) University of Granada Granada Spain
                [ 2 ] Instituto de Investigación Biosanitaria de Granada (ibs. GRANADA) Granada Spain
                [ 3 ] Instituto de Investigación Biomédica de Málaga (IBIMA) Malga Spain
                [ 4 ] Servicio de Digestivo Hospital Universitario Virgen de las Nieves Granada Spain
                Author notes
                [*] [* ] Correspondence

                María Elena Rodríguez‐Cabezas, Department of Pharmacology, Center for Biomedical Research (CIBM), University of Granada, 18071‐Granada, Spain.

                Email: merodri@ 123456ugr.es

                Author information
                https://orcid.org/0000-0001-9085-8147
                https://orcid.org/0000-0003-1927-0628
                Article
                OBR13872
                10.1111/obr.13872
                11884970
                39614602
                21aaf6ab-a32e-46bc-9750-866f20777c7e
                © 2024 The Author(s). Obesity Reviews published by John Wiley & Sons Ltd on behalf of World Obesity Federation.

                This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.

                History
                : 11 October 2024
                : 21 November 2023
                : 25 October 2024
                Page count
                Figures: 3, Tables: 2, Pages: 18, Words: 13000
                Funding
                Funded by: Junta de Andalucía , doi 10.13039/501100011011;
                Award ID: CTS164
                Funded by: Instituto de Salud Carlos III , doi 10.13039/501100004587;
                Award ID: P18‐RT‐4930
                Award ID: PI18/00826
                Award ID: PI19/01058
                Funded by: Fondo Europeo de Desarrollo Regiona , doi 10.13039/501100008530;
                Funded by: European Union , doi 10.13039/501100000780;
                Categories
                Review
                REVIEW
                Etiology and Pathophysiology
                Custom metadata
                2.0
                April 2025
                Converter:WILEY_ML3GV2_TO_JATSPMC version:6.5.4 mode:remove_FC converted:06.03.2025

                Medicine
                colitis,colorectal cancer,microbiota,obesity
                Medicine
                colitis, colorectal cancer, microbiota, obesity

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