[go: up one dir, main page]
More Web Proxy on the site http://driver.im/ Skip to main content

Advertisement

Springer Nature Link
Log in

Impacts of liver macrophages, gut microbiota, and bile acid metabolism on the differences in iHFC diet-induced MASH progression between TSNO and TSOD mice

  • Original Research Paper
  • Published:
Inflammation Research Aims and scope Submit manuscript

Abstract

Background

Tsumura-Suzuki non-obese (TSNO) mice exhibit a severe form of metabolic dysfunction-associated steatohepatitis (MASH) with advanced liver fibrosis upon feeding a high-fat/cholesterol/cholate-based (iHFC) diet. Another ddY strain, Tsumura-Suzuki diabetes obese (TSOD) mice, are impaired in the progression of iHFC diet-induced MASH.

Aim

To elucidate the underlying mechanisms contributing to the differences in MASH progression between TSNO and TSOD mice.

Methods

We analyzed differences in the immune system, gut microbiota, and bile acid metabolism in TSNO and TSOD mice fed with a normal diet (ND) or an iHFC diet.

Results

TSOD mice had more anti-inflammatory macrophages in the liver than TSNO mice under ND feeding, and were impaired in the iHFC diet-induced accumulation of fibrosis-associated macrophages and formation of histological hepatic crown-like structures in the liver. The gut microbiota of TSOD mice also exhibited a distinct community composition with lower diversity and higher abundance of Akkermansia muciniphila compared with that in TSNO mice. Finally, TSOD mice had lower levels of bile acids linked to intestinal barrier disruption under iHFC feeding.

Conclusions

The dynamics of liver macrophage subsets, and the compositions of the gut microbiota and bile acids at steady state and post-onset of MASH, had major impacts on MASH development.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
£29.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price includes VAT (United Kingdom)

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7.
Fig. 8

Similar content being viewed by others

Data availability

Data will be made available upon reasonable request from interested principal investigators.

Abbreviations

7-AAD:

7-Amino-actinomycin D

ALT:

Alanine aminotransferase

BA:

Bile acid

CA:

Cholic acid

DCA:

Deoxycholic acid

hCLS:

Hepatic crown-like structure

KC:

Kupffer cell

MASH:

Metabolic dysfunction associated steatohepatitis

MASLD:

Metabolic dysfunction-associated steatotic liver disease

MCA:

Muricholic acid

ND:

Normal diet

qRT-PCR:

Quantitative real-time PCR

TCA:

Taurocholic acid

T-CHO:

Total cholesterol

TDCA:

Taurodeoxycholic acid

TG:

Triglyceride

TSNO:

Tsumura-Suzuki non-obese

TSOD:

Tsumura-Suzuki Obese Diabetes

References

  1. Rinella ME, Lazarus JV, Ratziu V, Francque SM, Sanyal AJ, Kanwal F, et al. A multi-society Delphi consensus statement on new fatty liver disease nomenclature. Hepatology. 2023;78:1966–86.

    PubMed  Google Scholar 

  2. Wree A, Broderick L, Canbay A, Hoffman HM, Feldstein AE. From NAFLD to NASH to cirrhosis-new insights into disease mechanisms. Nat Rev Gastroenterol Hepatol. 2013;10:627–36.

    CAS  PubMed  Google Scholar 

  3. Tilg H, Moschen AR. Evolution of inflammation in nonalcoholic fatty liver disease: the multiple parallel hits hypothesis. Hepatology. 2010;52:1836–46.

    CAS  PubMed  Google Scholar 

  4. Kazankov K, Jorgensen SMD, Thomsen KL, Moller HJ, Vilstrup H, George J, et al. The role of macrophages in nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. Nat Rev Gastroenterol Hepatol. 2019;16:145–59.

    CAS  PubMed  Google Scholar 

  5. Fujisaka S, Usui I, Bukhari A, Ikutani M, Oya T, Kanatani Y, et al. Regulatory mechanisms for adipose tissue M1 and M2 macrophages in diet-induced obese mice. Diabetes. 2009;58:2574–82.

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Itoh M, Kato H, Suganami T, Konuma K, Marumoto Y, Terai S, et al. Hepatic crown-like structure: a unique histological feature in non-alcoholic steatohepatitis in mice and humans. PLoS ONE. 2013;8:e82163.

    PubMed  PubMed Central  Google Scholar 

  7. Rooks MG, Garrett WS. Gut microbiota, metabolites and host immunity. Nat Rev Immunol. 2016;16:341–52.

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Li M, Wang B, Zhang M, Rantalainen M, Wang S, Zhou H, et al. Symbiotic gut microbes modulate human metabolic phenotypes. Proc Natl Acad Sci U S A. 2008;105:2117–22.

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Ley RE, Turnbaugh PJ, Klein S, Gordon JI. Microbial ecology: human gut microbes associated with obesity. Nature. 2006;444:1022–3.

    CAS  PubMed  Google Scholar 

  10. Mouzaki M, Comelli EM, Arendt BM, Bonengel J, Fung SK, Fischer SE, et al. Intestinal microbiota in patients with nonalcoholic fatty liver disease. Hepatology. 2013;58:120–7.

    CAS  PubMed  Google Scholar 

  11. Zhu L, Baker SS, Gill C, Liu W, Alkhouri R, Baker RD, et al. Characterization of gut microbiomes in nonalcoholic steatohepatitis (NASH) patients: a connection between endogenous alcohol and NASH. Hepatology. 2013;57:601–9.

    CAS  PubMed  Google Scholar 

  12. De Minicis S, Rychlicki C, Agostinelli L, Saccomanno S, Candelaresi C, Trozzi L, et al. Dysbiosis contributes to fibrogenesis in the course of chronic liver injury in mice. Hepatology. 2014;59:1738–49.

    PubMed  Google Scholar 

  13. Setchell KD, Lawson AM, Tanida N, Sjovall J. General methods for the analysis of metabolic profiles of bile acids and related compounds in feces. J Lipid Res. 1983;24:1085–100.

    CAS  PubMed  Google Scholar 

  14. Hegyi P, Maleth J, Walters JR, Hofmann AF, Keely SJ. Guts and gall: bile acids in regulation of intestinal epithelial function in health and disease. Physiol Rev. 2018;98:1983–2023.

    CAS  PubMed  Google Scholar 

  15. Rohr MW, Narasimhulu CA, Rudeski-Rohr TA, Parthasarathy S. Negative effects of a high-fat diet on intestinal permeability: a review. Adv Nutr. 2020;11:77–91.

    PubMed  Google Scholar 

  16. 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.

    CAS  PubMed  Google Scholar 

  17. Takahashi Y, Fukusato T. Histopathology of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis. World J Gastroenterol. 2014;20:15539–48.

    PubMed  PubMed Central  Google Scholar 

  18. Ichimura-Shimizu M, Omagari K, Yamashita M, Tsuneyama K. Development of a novel mouse model of diet-induced nonalcoholic steatohepatitis-related progressive bridging fibrosis. Biosci Biotechnol Biochem. 2021;85:941–7.

    PubMed  Google Scholar 

  19. Miura T, Suzuki W, Ishihara E, Arai I, Ishida H, Seino Y, et al. Impairment of insulin-stimulated GLUT4 translocation in skeletal muscle and adipose tissue in the Tsumura Suzuki obese diabetic mouse: a new genetic animal model of type 2 diabetes. Eur J Endocrinol. 2001;145:785–90.

    CAS  PubMed  Google Scholar 

  20. Takahashi A, Tabuchi M, Suzuki W, Iizuka S, Nagata M, Ikeya Y, et al. Insulin resistance and low sympathetic nerve activity in the Tsumura Suzuki obese diabetic mouse: a new model of spontaneous type 2 diabetes mellitus and obesity. Metabolism. 2006;55:1664–9.

    CAS  PubMed  Google Scholar 

  21. Nishida T, Tsuneyama K, Fujimoto M, Nomoto K, Hayashi S, Miwa S, et al. Spontaneous onset of nonalcoholic steatohepatitis and hepatocellular carcinoma in a mouse model of metabolic syndrome. Lab Invest. 2013;93:230–41.

    CAS  PubMed  Google Scholar 

  22. Tada Y, Kasai K, Makiuchi N, Igarashi N, Kani K, Takano S, et al. Roles of macrophages in advanced liver fibrosis, identified using a newly established mouse model of diet-induced non-alcoholic steatohepatitis. Int J Mol Sci. 2022;23:13251.

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Schneider CA, Rasband WS, Eliceiri KW. NIH Image to ImageJ: 25 years of image analysis. Nat Methods. 2012;9:671–5.

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Kleiner DE, Brunt EM, Van Natta M, Behling C, Contos MJ, Cummings OW, et al. Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology. 2005;41:1313–21.

    PubMed  Google Scholar 

  25. Tolivia J, Navarro A, del Valle E, Perez C, Ordonez C, Martinez E. Application of photoshop and scion image analysis to quantification of signals in histochemistry, immunocytochemistry and hybridocytochemistry. Anal Quant Cytol Histol. 2006;28:43–53.

    PubMed  Google Scholar 

  26. Ishibashi R, Furusawa Y, Honda H, Watanabe Y, Fujisaka S, Nishikawa M, et al. Isoliquiritigenin attenuates adipose tissue inflammation and metabolic syndrome by modifying gut bacteria composition in mice. Mol Nutr Food Res. 2022;66:e2101119.

    PubMed  Google Scholar 

  27. Chudan S, Ishibashi R, Nishikawa M, Tabuchi Y, Nagai Y, Ikushiro S, et al. Effect of soluble oat fiber on intestinal microenvironment and TNBS-induced colitis. Food Funct. 2023;14:2188–99.

    CAS  PubMed  Google Scholar 

  28. Watanabe S, Chen Z, Fujita K, Nishikawa M, Ueda H, Iguchi Y, et al. Hyodeoxycholic Acid (HDCA) Prevents Development of Dextran Sulfate Sodium (DSS)-induced colitis in mice: possible role of synergism between DSS and HDCA in increasing fecal bile acid levels. Biol Pharm Bull. 2022;45:1503–9.

    CAS  PubMed  Google Scholar 

  29. Kasai K, Igarashi N, Tada Y, Kani K, Takano S, Yanagibashi T, et al. Impact of vancomycin treatment and gut microbiota on bile acid metabolism and the development of non-alcoholic steatohepatitis in mice. Int J Mol Sci. 2023;24:4050.

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Nishitsuji K, Watanabe S, Xiao J, Nagatomo R, Ogawa H, Tsunematsu T, et al. Effect of coffee or coffee components on gut microbiome and short-chain fatty acids in a mouse model of metabolic syndrome. Sci Rep. 2018;8:16173.

    PubMed  PubMed Central  Google Scholar 

  31. Nishitsuji K, Xiao J, Nagatomo R, Umemoto H, Morimoto Y, Akatsu H, et al. Analysis of the gut microbiome and plasma short-chain fatty acid profiles in a spontaneous mouse model of metabolic syndrome. Sci Rep. 2017;7:15876.

    PubMed  PubMed Central  Google Scholar 

  32. Zheng X, Huang F, Zhao A, Lei S, Zhang Y, Xie G, et al. Bile acid is a significant host factor shaping the gut microbiome of diet-induced obese mice. BMC Biol. 2017;15:120.

    PubMed  PubMed Central  Google Scholar 

  33. Islam KB, Fukiya S, Hagio M, Fujii N, Ishizuka S, Ooka T, et al. Bile acid is a host factor that regulates the composition of the cecal microbiota in rats. Gastroenterology. 2011;141:1773–81.

    CAS  PubMed  Google Scholar 

  34. Han Y, Ling Q, Wu L, Wang X, Wang Z, Chen J, et al. Akkermansia muciniphila inhibits nonalcoholic steatohepatitis by orchestrating TLR2-activated gammadeltaT17 cell and macrophage polarization. Gut Microbes. 2023;15:2221485.

    PubMed  PubMed Central  Google Scholar 

  35. Li T, Lin X, Shen B, Zhang W, Liu Y, Liu H, et al. Akkermansia muciniphila suppressing nonalcoholic steatohepatitis associated tumorigenesis through CXCR6(+) natural killer T cells. Front Immunol. 2022;13:1047570.

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Thomas C, Pellicciari R, Pruzanski M, Auwerx J, Schoonjans K. Targeting bile-acid signalling for metabolic diseases. Nat Rev Drug Discov. 2008;7:678–93.

    CAS  PubMed  Google Scholar 

  37. Makiuchi N, Takano S, Tada Y, Kasai K, Igarashi N, Kani K, et al. Dynamics of liver macrophage subsets in a novel mouse model of non-alcoholic steatohepatitis using C57BL/6 mice. Biomedicines. 2023;11:2659.

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Cahova M, Palenickova E, Dankova H, Sticova E, Burian M, Drahota Z, et al. Metformin prevents ischemia reperfusion-induced oxidative stress in the fatty liver by attenuation of reactive oxygen species formation. Am J Physiol Gastrointest Liver Physiol. 2015;309:G100–11.

    CAS  PubMed  Google Scholar 

  39. Jindal A, Bruzzi S, Sutti S, Locatelli I, Bozzola C, Paternostro C, et al. Fat-laden macrophages modulate lobular inflammation in nonalcoholic steatohepatitis (NASH). Exp Mol Pathol. 2015;99:155–62.

    CAS  PubMed  Google Scholar 

  40. McMahan RH, Wang XX, Cheng LL, Krisko T, Smith M, El Kasmi K, et al. Bile acid receptor activation modulates hepatic monocyte activity and improves nonalcoholic fatty liver disease. J Biol Chem. 2013;288:11761–70.

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Reid DT, Reyes JL, McDonald BA, Vo T, Reimer RA, Eksteen B. Kupffer cells undergo fundamental changes during the development of experimental NASH and are critical in initiating liver damage and inflammation. PLoS ONE. 2016;11:e0159524.

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Han Y, Li L, Wang B. Role of Akkermansia muciniphila in the development of nonalcoholic fatty liver disease: current knowledge and perspectives. Front Med. 2022;16:667–85.

    PubMed  Google Scholar 

  43. Zhai Q, Feng S, Arjan N, Chen W. A next generation probiotic, Akkermansia muciniphila. Crit Rev Food Sci Nutr. 2019;59:3227–36.

    CAS  PubMed  Google Scholar 

  44. Plovier H, Everard A, Druart C, Depommier C, Van Hul M, Geurts L, et al. A purified membrane protein from Akkermansia muciniphila or the pasteurized bacterium improves metabolism in obese and diabetic mice. Nat Med. 2017;23:107–13.

    CAS  PubMed  Google Scholar 

  45. Ashrafian F, Shahriary A, Behrouzi A, Moradi HR, Keshavarz AziziRaftar S, Lari A, et al. Akkermansia muciniphila-derived extracellular vesicles as a mucosal delivery vector for amelioration of obesity in mice. Front Microbiol. 2019;10:2155.

    PubMed  PubMed Central  Google Scholar 

  46. Ottman N, Davids M, Suarez-Diez M, Boeren S, Schaap PJ, dos Santos VAPM, et al. Genome-scale model and omics analysis of metabolic capacities of reveal a preferential mucin-degrading lifestyle. Appl Environ Microb. 2017;83:e10147.

    Google Scholar 

  47. Liu R, Hong J, Xu X, Feng Q, Zhang D, Gu Y, et al. Gut microbiome and serum metabolome alterations in obesity and after weight-loss intervention. Nat Med. 2017;23:859–68.

    CAS  PubMed  Google Scholar 

  48. Ottman N, Reunanen J, Meijerink M, Pietila TE, Kainulainen V, Klievink J, et al. Pili-like proteins of Akkermansia muciniphila modulate host immune responses and gut barrier function. PLoS ONE. 2017;12:e0173004.

    PubMed  PubMed Central  Google Scholar 

  49. Chelakkot C, Choi Y, Kim DK, Park HT, Ghim J, Kwon Y, et al. Akkermansia muciniphila-derived extracellular vesicles influence gut permeability through the regulation of tight junctions. Exp Mol Med. 2018;50:e450.

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Li T, Jahan A, Chiang JY. Bile acids and cytokines inhibit the human cholesterol 7 alpha-hydroxylase gene via the JNK/c-jun pathway in human liver cells. Hepatology. 2006;43:1202–10.

    CAS  PubMed  Google Scholar 

  51. Fujita K, Iguchi Y, Une M, Watanabe S. Ursodeoxycholic acid suppresses lipogenesis in mouse liver: possible role of the decrease in beta-muricholic acid, a Farnesoid x receptor antagonist. Lipids. 2017;52:335–44.

    CAS  PubMed  Google Scholar 

  52. Zeng H, Safratowich BD, Cheng WH, Larson KJ, Briske-Anderson M. Deoxycholic acid modulates cell-junction gene expression and increases intestinal barrier dysfunction. Molecules. 2022;27:723.

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Liu H, Kohmoto O, Sakaguchi A, Hori S, Tochigi M, Tada K, et al. Taurocholic acid, a primary 12alpha-hydroxylated bile acid, induces leakiness in the distal small intestine in rats. Food Chem Toxicol. 2022;165:113136.

    CAS  PubMed  Google Scholar 

  54. Stenman LK, Holma R, Eggert A, Korpela R. A novel mechanism for gut barrier dysfunction by dietary fat: epithelial disruption by hydrophobic bile acids. Am J Physiol Gastrointest Liver Physiol. 2013;304:G227–34.

    CAS  PubMed  Google Scholar 

  55. Pols TW, Nomura M, Harach T, Lo Sasso G, Oosterveer MH, Thomas C, et al. TGR5 activation inhibits atherosclerosis by reducing macrophage inflammation and lipid loading. Cell Metab. 2011;14:747–57.

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Keitel V, Donner M, Winandy S, Kubitz R, Haussinger D. Expression and function of the bile acid receptor TGR5 in Kupffer cells. Biochem Biophys Res Commun. 2008;372:78–84.

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank Ms. Kaori Ito at Toyama Prefectural University for her secretarial and technical support. We also thank Michelle Kahmeyer-Gabbe, PhD, from Edanz (https://jp.edanz.com/ac) for editing a draft of this manuscript.

Funding

This research received financial support from the Japan Society for the Promotion of Science (JSPS) through the JSPS KAKENHI (JP22K07005) and the Toyama Pharmaceutical Valley Development Consortium.

Author information

Authors and Affiliations

  1. Department of Pharmaceutical Engineering, Faculty of Engineering, Toyama Prefectural University, 5180 Kurokawa, Imizu, Toyama, 939-0398, Japan

    Naoya Igarashi, Kaichi Kasai, Yuki Tada, Koudai Kani, Miyuna Kato, Shun Takano, Kana Goto, Yudai Matsuura, Yukihiro Furusawa & Yoshinori Nagai

  2. Department of Pathology and Laboratory Medicine, Tokushima University Graduate School of Biomedical Sciences, 3-8-15 Kuramoto-cho, Tokushima, 770-8503, Japan

    Mayuko Ichimura-Shimizu & Koichi Tsuneyama

  3. Institute of Natural Medicine, University of Toyama, 2630 Sugitani, Toyama, 930-0194, Japan

    Shiro Watanabe

Authors
  1. Naoya Igarashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kaichi Kasai
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yuki Tada
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Koudai Kani
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Miyuna Kato
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Shun Takano
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Kana Goto
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Yudai Matsuura
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Mayuko Ichimura-Shimizu
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Shiro Watanabe
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Koichi Tsuneyama
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Yukihiro Furusawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Yoshinori Nagai
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Conceptualization, YN; Methodology, YN, MI-S, SW, KT, and YF; Investigation NI, KKasai, YT, KKani, MK, ST, KG, YM, MI-S, SW, KT, and YF; Writing—original draft preparation, YN; Writing—review and editing, YN; Supervision, KT and YN; Project administration, YN; Funding acquisition, YN. All the authors have read and agreed to the published version of the manuscript.

Corresponding author

Correspondence to Yoshinori Nagai.

Ethics declarations

Conflict of interest

The authors declare no conflict interest.

Additional information

Responsible Editor: John Di Battista.

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 1708 KB)

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Igarashi, N., Kasai, K., Tada, Y. et al. Impacts of liver macrophages, gut microbiota, and bile acid metabolism on the differences in iHFC diet-induced MASH progression between TSNO and TSOD mice. Inflamm. Res. 73, 1081–1098 (2024). https://doi.org/10.1007/s00011-024-01884-7

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00011-024-01884-7

Keywords

Search

Navigation