Loss of toll-like receptor 5 potentiates spontaneous hepatocarcinogenesis in farnesoid X receptor-deficient mice.
Journal
Hepatology communications
ISSN: 2471-254X
Titre abrégé: Hepatol Commun
Pays: United States
ID NLM: 101695860
Informations de publication
Date de publication:
01 06 2023
01 06 2023
Historique:
received:
02
02
2023
accepted:
21
03
2023
medline:
25
5
2023
pubmed:
23
5
2023
entrez:
23
5
2023
Statut:
epublish
Résumé
HCC is the most common primary liver cancer and a leading cause of cancer-related mortality. Gut microbiota is a large collection of microbes, predominately bacteria, that harbor the gastrointestinal tract. Changes in gut microbiota that deviate from the native composition, that is, "dysbiosis," is proposed as a probable diagnostic biomarker and a risk factor for HCC. However, whether gut microbiota dysbiosis is a cause or a consequence of HCC is unknown. To better understand the role of gut microbiota in HCC, mice deficient of toll-like receptor 5 (TLR5, a receptor for bacterial flagellin) as a model of spontaneous gut microbiota dysbiosis were crossed with farnesoid X receptor knockout mice (FxrKO), a genetic model for spontaneous HCC. Male FxrKO/Tlr5KO double knockout (DKO), FxrKO, Tlr5KO, and wild-type (WT) mice were aged to the 16-month HCC time point. Compared with FxrKO mice, DKO mice had more severe hepatooncogenesis at the gross, histological, and transcript levels and this was associated with pronounced cholestatic liver injury. The bile acid dysmetabolism in FxrKO mice became more aberrant in the absence of TLR5 due in part to suppression of bile acid secretion and enhanced cholestasis. Out of the 14 enriched taxon signatures seen in the DKO gut microbiota, 50% were dominated by the Proteobacteria phylum with expansion of the gut pathobiont γ-Proteobacteria that is implicated in HCC. Collectively, introducing gut microbiota dysbiosis by TLR5 deletion exacerbated hepatocarcinogenesis in the FxrKO mouse model.
Sections du résumé
BACKGROUND
HCC is the most common primary liver cancer and a leading cause of cancer-related mortality. Gut microbiota is a large collection of microbes, predominately bacteria, that harbor the gastrointestinal tract. Changes in gut microbiota that deviate from the native composition, that is, "dysbiosis," is proposed as a probable diagnostic biomarker and a risk factor for HCC. However, whether gut microbiota dysbiosis is a cause or a consequence of HCC is unknown.
METHODS
To better understand the role of gut microbiota in HCC, mice deficient of toll-like receptor 5 (TLR5, a receptor for bacterial flagellin) as a model of spontaneous gut microbiota dysbiosis were crossed with farnesoid X receptor knockout mice (FxrKO), a genetic model for spontaneous HCC. Male FxrKO/Tlr5KO double knockout (DKO), FxrKO, Tlr5KO, and wild-type (WT) mice were aged to the 16-month HCC time point.
RESULTS
Compared with FxrKO mice, DKO mice had more severe hepatooncogenesis at the gross, histological, and transcript levels and this was associated with pronounced cholestatic liver injury. The bile acid dysmetabolism in FxrKO mice became more aberrant in the absence of TLR5 due in part to suppression of bile acid secretion and enhanced cholestasis. Out of the 14 enriched taxon signatures seen in the DKO gut microbiota, 50% were dominated by the Proteobacteria phylum with expansion of the gut pathobiont γ-Proteobacteria that is implicated in HCC.
CONCLUSIONS
Collectively, introducing gut microbiota dysbiosis by TLR5 deletion exacerbated hepatocarcinogenesis in the FxrKO mouse model.
Identifiants
pubmed: 37219858
doi: 10.1097/HC9.0000000000000166
pii: 02009842-202306010-00016
pmc: PMC10208708
pii:
doi:
Substances chimiques
Bile Acids and Salts
0
Toll-Like Receptor 5
0
Tlr5 protein, mouse
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : NCI NIH HHS
ID : F31 CA260842
Pays : United States
Informations de copyright
Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Study of Liver Diseases.
Références
Singal AG, Lampertico P, Nahon P. Epidemiology and surveillance for hepatocellular carcinoma: new trends. J Hepatol. 2020;72:250–61.
Buzzetti E, Pinzani M, Tsochatzis EA. The multiple-hit pathogenesis of non-alcoholic fatty liver disease (NAFLD). Metabolism. 2016;65:1038–48.
Tang M, Zhao Y, Zhao J, Wei S, Liu M, Zheng N, et al. Liver cancer heterogeneity modeled by in situ genome editing of hepatocytes. Sci Adv. 2022;8:eabn5683.
Lai ECH, Yee Lau W. Hepatocellular carcinoma presenting with obstructive jaundice. ANZ J Surg. 2006;76:631–66.
Vinayagamoorthy V, Srivastava A, Sarma MS. Newer variants of progressive familial intrahepatic cholestasis. World J Hepatol. 2021;13:2024–38.
Colosimo S, Tomlinson JW. Bile acids as drivers and biomarkers of hepatocellular carcinoma. World J Hepatol. 2022;14:1730–8.
Kim I, Ahn SH, Inagaki T, Choi M, Ito S, Guo GL, et al. Differential regulation of bile acid homeostasis by the farnesoid X receptor in liver and intestine. J Lipid Res. 2007;48:2664–72.
Kim I, Morimura K, Shah Y, Yang Q, Ward JM, Gonzalez FJ. Spontaneous hepatocarcinogenesis in farnesoid X receptor-null mice. Carcinogenesis. 2007;28:940–6.
Sinal CJ, Tohkin M, Miyata M, Ward JM, Lambert G, Gonzalez FJ. Targeted disruption of the nuclear receptor FXR/BAR impairs bile acid and lipid homeostasis. Cell. 2000;102:731–44.
Yang F, Huang X, Yi T, Yen Y, Moore DD, Huang W. Spontaneous development of liver tumors in the absence of the bile acid receptor farnesoid X receptor. Cancer Res. 2007;67:863–7.
Su H, Ma C, Liu J, Li N, Gao M, Huang A, et al. Downregulation of nuclear receptor FXR is associated with multiple malignant clinicopathological characteristics in human hepatocellular carcinoma. Am J Physiol Gastrointest Liver Physiol. 2012;303:G1245–253.
Liu N, Meng Z, Lou G, Zhou W, Wang X, Zhang Y, et al. Hepatocarcinogenesis in FXR-/- mice mimics human HCC progression that operates through HNF1alpha regulation of FXR expression. Mol Endocrinol. 2012;26:775–85.
Petersen C, Round JL. Defining dysbiosis and its influence on host immunity and disease. Cell Microbiol. 2014;16:1024–33.
Liu Q, Li F, Zhuang Y, Xu J, Wang J, Mao X, et al. Alteration in gut microbiota associated with hepatitis B and non-hepatitis virus related hepatocellular carcinoma. Gut Pathog. 2019;11:1.
Kang Y, Cai Y, Yang Y. The gut microbiome and hepatocellular carcinoma: implications for early diagnostic biomarkers and novel therapies. Liver Cancer. 2022;11:113–25.
Komiyama S, Yamada T, Takemura N, Kokudo N, Hase K, Kawamura YI. Profiling of tumour-associated microbiota in human hepatocellular carcinoma. Sci Rep. 2021;11:10589.
Nejman D, Livyatan I, Fuks G, Gavert N, Zwang Y, Geller LT, et al. The human tumor microbiome is composed of tumor type-specific intracellular bacteria. Science. 2020;368:973–80.
Huang JH, Wang J, Chai XQ, Li ZC, Jiang YH, Li J, et al. The intratumoral bacterial metataxonomic signature of hepatocellular carcinoma. Microbiol Spectr. 2022;10:e0098322.
Vijay-Kumar M, Sanders CJ, Taylor RT, Kumar A, Aitken JD, Sitaraman SV, et al. Deletion of TLR5 results in spontaneous colitis in mice. J Clin Invest. 2007;117:3909–21.
Kilkenny C, Browne WJ, Cuthill IC, Emerson M, Altman DG. Improving bioscience research reporting: the ARRIVE guidelines for reporting animal research. PLoS Biol. 2010;8:e1000412.
Gewirtz AT, Simon PO Jr, Schmitt CK, Taylor LJ, Hagedorn CH, O’Brien AD, et al. Salmonella typhimurium translocates flagellin across intestinal epithelia, inducing a proinflammatory response. J Clin Invest. 2001;107:99–109.
Bolyen E, Rideout JR, Dillon MR, Bokulich NA, Abnet CC, Al-Ghalith GA, et al. Reproducible, interactive, scalable and extensible microbiome data science using QIIME 2. Nat Biotechnol. 2019;37:852–7.
Segata N, Izard J, Waldron L, Gevers D, Miropolsky L, Garrett WS, et al. Metagenomic biomarker discovery and explanation. Genome Biol. 2011;12:R60.
Nadkarni MA, Martin FE, Jacques NA, Hunter N. Determination of bacterial load by real-time PCR using a broad-range (universal) probe and primers set. Microbiology (Reading). 2002;148(Pt 1):257–66.
Singh V, Yeoh BS, Chassaing B, Xiao X, Saha P, Aguilera Olvera R, et al. Dysregulated microbial fermentation of soluble fiber induces cholestatic liver cancer. Cell. 2018;175:679–94 e22.
Vijay-Kumar M, Aitken JD, Carvalho FA, Cullender TC, Mwangi S, Srinivasan S, et al. Metabolic syndrome and altered gut microbiota in mice lacking Toll-like receptor 5. Science. 2010;328:228–31.
Gomez-Ospina N, Potter CJ, Xiao R, Manickam K, Kim MS, Kim KH, et al. Mutations in the nuclear bile acid receptor FXR cause progressive familial intrahepatic cholestasis. Nat Commun. 2016;7:10713.
Vitale G, Mattiaccio A, Conti A, Turco L, Seri M, Piscaglia F, et al. Genetics in familial intrahepatic cholestasis: clinical patterns and development of liver and biliary cancers: a review of the literature. Cancers (Basel). 2022;14. doi:10.3390/cancers14143421
doi: 10.3390/cancers14143421
Li T, Apte U. Bile acid metabolism and signaling in cholestasis, inflammation, and cancer. Adv Pharmacol. 2015;74:263–302.
Schneider KM, Candels LS, Hov JR, Myllys M, Hassan R, Schneider CV, et al. Gut microbiota depletion exacerbates cholestatic liver injury via loss of FXR signalling. Nat Metab. 2021;3:1228–41.
Kong B, Wang L, Chiang JYL, Zhang Y, Klaassen CD, Guo GL. Mechanism of tissue-specific farnesoid X receptor in suppressing the expression of genes in bile-acid synthesis in mice. Hepatology. 2012;56:1034–43.
Takahashi S, Tanaka N, Fukami T, Xie C, Yagai T, Kim D, et al. Role of farnesoid X eceptor and bile acids in hepatic tumor development. Hepatol Commun. 2018;2:1567–82.
Yu J, Lo JL, Huang L, Zhao A, Metzger E, Adams A, et al. Lithocholic acid decreases expression of bile salt export pump through farnesoid X receptor antagonist activity. J Biol Chem. 2002;277:31441–7.
Singh V, Yeoh BS, Abokor AA, Golonka RM, Tian Y, Patterson AD, et al. Vancomycin prevents fermentable fiber-induced liver cancer in mice with dysbiotic gut microbiota. Gut Microbes. 2020;11:1077–91.
Arai N, Miura K, Aizawa K, Sekiya M, Nagayama M, Sakamoto H, et al. Probiotics suppress nonalcoholic steatohepatitis and carcinogenesis progression in hepatocyte-specific PTEN knockout mice. Sci Rep. 2022;12:16206.
Li J, Sung CYJ, Lee N, Ni Y, Pihlajamäki J, Panagiotou G, et al. Probiotics modulated gut microbiota suppresses hepatocellular carcinoma growth in mice. Proc Natl Acad Sci USA. 2016;113:E1306–15.
Yamada S, Takashina Y, Watanabe M, Nagamine R, Saito Y, Kamada N, et al. Bile acid metabolism regulated by the gut microbiota promotes non-alcoholic steatohepatitis-associated hepatocellular carcinoma in mice. Oncotarget. 2018;9:9925–39.
Brackett CM, Kojouharov B, Veith J, Greene KF, Burdelya LG, Gollnick SO, et al. Toll-like receptor-5 agonist, entolimod, suppresses metastasis and induces immunity by stimulating an NK-dendritic-CD8 + T-cell axis. Proc Natl Acad Sci USA. 2016;113:E874–83.
Haderski GJ, Kandar BM, Brackett CM, Toshkov IM, Johnson CP, Paszkiewicz GM, et al. TLR5 agonist entolimod reduces the adverse toxicity of TNF while preserving its antitumor effects. PLoS One. 2020;15:e0227940.
Carvalho FA, Koren O, Goodrich JK, Johansson MEV, Nalbantoglu I, Aitken JD, et al. Transient inability to manage proteobacteria promotes chronic gut inflammation in TLR5-deficient mice. Cell Host Microbe. 2012;12:139–52.
Ridlon JM, Kang DJ, Hylemon PB, Bajaj JS. Bile acids and the gut microbiome. Curr Opin Gastroenterol. 2014;30:332–8.
Dapito DH, Mencin A, Gwak GY, Pradere JP, Jang MK, Mederacke I, et al. Promotion of hepatocellular carcinoma by the intestinal microbiota and TLR4. Cancer Cell. 2012;21:504–16.
Loo TM, Kamachi F, Watanabe Y, Yoshimoto S, Kanda H, Arai Y, et al. Gut microbiota promotes obesity-associated liver cancer through PGE(2)-mediated suppression of antitumor immunity. Cancer Discov. 2017;7:522–38.
Yoshimoto S, Loo TM, Atarashi K, Kanda H, Sato S, Oyadomari S, et al. Obesity-induced gut microbial metabolite promotes liver cancer through senescence secretome. Nature. 2013;499:97–101.
Shiau DJ, Kuo WT, Davuluri GVN, Shieh CC, Tsai PJ, Chen CC, et al. Hepatocellular carcinoma-derived high mobility group box 1 triggers M2 macrophage polarization via a TLR2/NOX2/autophagy axis. Sci Rep. 2020;10:13582.
Li S, Li F, Xu L, Liu X, Zhu X, Gao W, et al. TLR2 agonist promotes myeloid-derived suppressor cell polarization via Runx1 in hepatocellular carcinoma. Int Immunopharmacol. 2022;111:109168.
Liu Y, Zhang X, Chen S, Wang J, Yu S, Li Y, et al. Gut-derived lipopolysaccharide promotes alcoholic hepatosteatosis and subsequent hepatocellular carcinoma by stimulating neutrophil extracellular traps through toll-like receptor 4. Clin Mol Hepatol. 2022;28:522–39.
Zhou S, Du R, Wang Z, Shen W, Gao R, Jiang S, et al. TLR4 increases the stemness and is highly expressed in relapsed human hepatocellular carcinoma. Cancer Med. 2019;8:2325–2337.
Nischalke HD, Fischer J, Klüners A, Matz‐Soja M, Krämer B, Langhans B, et al. A genetic variant in toll-like receptor 5 is linked to chemokine levels and hepatocellular carcinoma in steatohepatitis. Liver Int. 2021;41:2139–48.
Chassaing B, Ley RE, Gewirtz AT. Intestinal epithelial cell toll-like receptor 5 regulates the intestinal microbiota to prevent low-grade inflammation and metabolic syndrome in mice. Gastroenterology. 2014;147:1363–77. e17.