NLRP3 activation maintains intestinal epithelial barrier and reduces liver injury in alcoholic liver disease mice

Abstract

	•Activation of the NLRP3-GSDMD pathway in the ileum of Alcoholic liver disease (ALD) mice.
	•NLRP3 activation maintains homeostasis of gut microbiota and intestinal epithelial barrier in ALD mice.
	•ALD mice infected with V. vulnificus infection exhibited no further activation of NLRP3 in the ileum, leading to increased intestinal permeability and bloodstream infections.

Keywords

alcoholic liver disease / intestinal epithelial barrier / NLRP3 inflammasome / Vibrio infection

References

[1] O’SheaRS, Dasarathy S, McCulloughAJ. Alcoholic liver disease. Hepatology. 2010; 51(1): 307-328.

[2] PenriceDD, ShahS, KezerCA, et al. Risk prediction of nosocomial and posthospital discharge infections in alcohol-associated hepatitis. Hepatol Commun. 2021; 5(12): 2096-2103.

[3] HmoudBS, PatelK, BatallerR, Singal AK. Corticosteroids and occurrence of and mortality from infections in severe alcoholic hepatitis: a meta-analysis of randomized trials. Liver Int. 2016; 36(5): 721-728.

[4] DionigiE, Garcovich M, BorzioM, et al. Bacterial infections change natural history of cirrhosis irrespective of liver disease severity. Am J Gastroenterol. 2017; 112(4): 588-596.

[5] DechetAM, YuPA, KoramN, Painter J. Nonfoodborne Vibrio infections: an important cause of morbidity and mortality in the United States, 1997–2006. Clin Infect Dis. 2008; 46(7): 970-976.

[6] HladyWG, KlontzKC. The epidemiology of Vibrio infections in Florida, 1981–1993. J Infect Dis. 1996; 173(5): 1176-1183.

[7] KoWC, ChuangYC, HuangGC, Hsu SY. Infections due to non-O1 Vibrio cholerae in southern Taiwan: predominance in cirrhotic patients. Clin Infect Dis. 1998; 27(4): 774-780.

[8] MenonMP, YuPA, IwamotoM, Painter J. Pre-existing medical conditions associated with Vibrio vulnificus septicaemia. Epidemiol Infect. 2014; 142(4): 878-881.

[9] YouJS, KimS, ParkI, Kim S. Vibrio vulnificus sepsis misdiagnosed as simple deep vein thrombosis. Am J Emerg Med. 2012; 30(9): 2098.e5-6.

[10] WarnockE, MacMath T. Primary Vibrio vulnificus septicemia. J Emerg Med. 1993; 11(2): 153-156.

[11] KikawaK, Yamasaki K, SujiuraT, et al. A successfully treated case of Vibrio vulnificus septicemia with shock. Jpn J Med. 1990; 29(3): 313-319.

[12] MaccioniL, Leclercq IA, SchnablB, StarkelP. Host factors in dysregulation of the gut barrier function during alcohol-associated liver disease. Int J Mol Sci. 2021; 22(23): 12687.

[13] GlaserT, Baiocchi L, ZhouT, et al. Pro-inflammatory signalling and gut-liver axis in non-alcoholic and alcoholic steatohepatitis: differences and similarities along the path. J Cell Mol Med. 2020; 24(11): 5955-5965.

[14] BrandlK, Schnabl B. Is intestinal inflammation linking dysbiosis to gut barrier dysfunction during liver disease? Expert Rev Gastroenterol Hepatol. 2015; 9(8): 1069-1076.

[15] YuLC, WangJT, WeiSC, Ni YH. Host-microbial interactions and regulation of intestinal epithelial barrier function: from physiology to pathology. World J Gastrointest Pathophysiol. 2012; 3(1): 27-43.

[16] GalluzziL, VitaleI, AaronsonSA, et al. Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018. Cell Death Differ. 2018; 25(3): 486-541.

[17] PlaceDE, LeeS, KannegantiTD. PANoptosis in microbial infection. Curr Opin Microbiol. 2021; 59: 42-49.

[18] PandianN, Kanneganti TD. PANoptosis: a unique innate immune inflammatory cell death modality. J Immunol. 2022; 209(9): 1625-1633.

[19] StolzerI, Schickedanz L, ChiriacMT, et al. STAT1 coordinates intestinal epithelial cell death during gastrointestinal infection upstream of Caspase-8. Mucosal Immunol. 2022; 15(1): 130-142.

[20] YuSX, ChenW, LiuZZ, et al. Non-hematopoietic MLKL protects against salmonella mucosal infection by enhancing inflammasome activation. Front Immunol. 2018; 9: 119.

[21] ZakiMH, BoydKL, VogelP, Kastan MB, LamkanfiM, KannegantiTD. The NLRP3 inflammasome protects against loss of epithelial integrity and mortality during experimental colitis. Immunity. 2010; 32(3): 379-391.

[22] PatnaikSK, Mohanty S, MishraD, et al. A prospective study on the clinical significance of infections in a hospital setting among the cirrhotic patients and their outcomes. Cureus. 2023; 15(4): e37912.

[23] ParkJK, LeeCH, KimIH, et al. Clinical characteristics and prognostic impact of bacterial infection in hospitalized patients with alcoholic liver disease. J Korean Med Sci. 2015; 30(5): 598-605.

[24] AppenrodtB, Grünhage F, GentemannMG, ThyssenL, Sauerbruch T, LammertF. Nucleotide-binding oligomerization domain containing 2 (NOD2) variants are genetic risk factors for death and spontaneous bacterial peritonitis in liver cirrhosis. Hepatology. 2010; 51(4): 1327-1333.

[25] ChuH, DuanY, LangS, et al. The Candida albicans exotoxin Candidalysin promotes alcohol-associated liver disease. J Hepatol. 2020; 72(3): 391-400.

[26] DuanY, Llorente C, LangS, et al. Bacteriophage targeting of gut bacterium attenuates alcoholic liver disease. Nature. 2019; 575(7783): 505-511.

[27] BertolaA, Mathews S, KiSH, WangH, GaoB. Mouse model of chronic and binge ethanol feeding (the NIAAA model). Nat Protoc. 2013; 8(3): 627-637.

[28] DroliaR, Tenguria S, DurkesAC, TurnerJR, BhuniaAK. Listeria adhesion protein induces intestinal epithelial barrier dysfunction for bacterial translocation. Cell Host Microbe. 2018; 23(4): 470-484.

[29] HammerAM, MorrisNL, EarleyZM, Choudhry MA. The first line of defense: the effects of alcohol on post-burn intestinal barrier, immune cells, and microbiome. Alcohol Res: Curr Rev. 2015; 37(2): 209-222.

[30] ChenY, YangF, LuH, et al. Characterization of fecal microbial communities in patients with liver cirrhosis. Hepatology. 2011; 54(2): 562-572.

[31] HerpS, Durai Raj AC, Salvado SilvaM, WoelfelS, Stecher B. The human symbiont Mucispirillum schaedleri: causality in health and disease. Med Microbiol Immunol (Berl). 2021; 210(4): 173-179.

[32] DubinkinaVB, TyakhtAV, OdintsovaVY, et al. Links of gut microbiota composition with alcohol dependence syndrome and alcoholic liver disease. Microbiome. 2017; 5(1): 141.

[33] GaoB, AhmadMF, NagyLE, Tsukamoto H. Inflammatory pathways in alcoholic steatohepatitis. J Hepatol. 2019; 70(2): 249-259.

[34] ChoYE, SongBJ. Pomegranate prevents binge alcohol-induced gut leakiness and hepatic inflammation by suppressing oxidative and nitrative stress. Redox Biol. 2018; 18: 266-278.

[35] ChopykDM, Grakoui A. Contribution of the intestinal microbiome and gut barrier to hepatic disorders. Gastroenterology. 2020; 159(3): 849-863.

[36] StärkelP, Leclercq S, de TimaryP, SchnablB. Intestinal dysbiosis and permeability: the yin and yang in alcohol dependence and alcoholic liver disease. Clin Sci (Lond). 2018; 132(2): 199-212.

[37] FukuiH. Leaky gut and gut-liver axis in liver cirrhosis: clinical studies update. Gut Liver. 2021; 15(5): 666-676.

[38] LiD, HeQ, YangH, et al. Daily dose of bovine lactoferrin prevents ethanol-induced liver injury and death in male mice by regulating hepatic alcohol metabolism and modulating gut microbiota. Mol Nutr Food Res. 2021; 65(18): e2100253.

[39] Van der MerweS, Chokshi S, BernsmeierC, AlbillosA. The multifactorial mechanisms of bacterial infection in decompensated cirrhosis. J Hepatol. 2021; 75(1): S82-s100.

[40] PetrasekJ, BalaS, CsakT, et al. IL-1 receptor antagonist ameliorates inflammasome-dependent alcoholic steatohepatitis in mice. J Clin Invest. 2012; 122(10): 3476-3489.

[41] KhanovaE, WuR, WangW, et al. Pyroptosis by caspase11/4-gasdermin-D pathway in alcoholic hepatitis in mice and patients. Hepatology. 2018; 67(5): 1737-1753.

[42] VoicanCS, Njiké-Nakseu M, BoujedidiH, et al. Alcohol withdrawal alleviates adipose tissue inflammation in patients with alcoholic liver disease. Liver Int. 2015; 35(3): 967-978.

[43] CuiK, YanG, XuC, et al. Invariant NKT cells promote alcohol-induced steatohepatitis through interleukin-1beta in mice. J Hepatol. 2015; 62(6): 1311-1318.

[44] HelsleyRN, MiyataT, KadamA, et al. Gut microbial trimethylamine is elevated in alcohol-associated hepatitis and contributes to ethanol-induced liver injury in mice. eLife. 2022; 11: e76554.

[45] AddoloratoG, Ponziani FR, DionisiT, et al. Gut microbiota compositional and functional fingerprint in patients with alcohol use disorder and alcohol-associated liver disease. Liver Int. 2020; 40(4): 878-888.

[46] LlopisM, Cassard AM, WrzosekL, et al. Intestinal microbiota contributes to individual susceptibility to alcoholic liver disease. Gut. 2016; 65(5): 830-839.

[47] BajajJS, HeumanDM, HylemonPB, et al. The cirrhosis dysbiosis ratio defines changes in the gut microbiome associated with cirrhosis and its complications. J Hepatol. 2014; 60(5): 940-947.

[48] BajajJS, HeumanDM, HylemonPB, et al. Altered profile of human gut microbiome is associated with cirrhosis and its complications. J Hepatol. 2014; 60(5): 940-947.

[49] XingC, WangM, AjibadeAA, et al. Microbiota regulate innate immune signaling and protective immunity against cancer. Cell Host Microbe. 2021; 29(6): 959-974.

[50] ParkerBJ, Wearsch PA, VelooACM, Rodriguez-PalaciosA. The genus Alistipes: gut bacteria with emerging implications to inflammation, cancer, and mental health. Front Immunol. 2020; 11: 906.

[51] ShiY, ZouY, XiongY, et al. Host Gasdermin D restrains systemic endotoxemia by capturing Proteobacteria in the colon of high-fat diet-feeding mice. Gut Microbes. 2021; 13(1): 1946369.

[52] RauchI, DeetsKA, JiDX, et al. NAIP-NLRC4 inflammasomes coordinate intestinal epithelial cell expulsion with eicosanoid and il-18 release via activation of caspase-1 and -8. Immunity. 2017; 46(4): 649-659.

[53] SellinME, Müller AA, FelmyB, et al. Epithelium-intrinsic NAIP/NLRC4 inflammasome drives infected enterocyte expulsion to restrict Salmonella replication in the intestinal mucosa. Cell Host Microbe. 2014; 16(2): 237-248.

[54] ZhangJ, YuQ, JiangD, et al. Epithelial Gasdermin D shapes the host-microbial interface by driving mucus layer formation. Sci Immunol. 2022; 7(68): eabk2092.

[55] GülE, Fattinger SA, SellinME, HardtW-D. Epithelial inflammasomes, gasdermins, and mucosal inflammation—Lessons from Salmonella and Shigella infected mice. Semin Immunol. 2023; 70: 101812.

[56] QinZ, ZhouF, ZhangL. Novel pyroptosis-independent functions of gasdermins. Signal Transduct Target Ther. 2022; 7(1): 127.

[57] Henao-MejiaJ, ElinavE, JinC, et al. Inflammasome-mediated dysbiosis regulates progression of NAFLD and obesity. Nature. 2012; 482(7384): 179-185.

[58] DeSantisDA, KoCW, LiuY, et al. Alcohol-induced liver injury is modulated by Nlrp3 and Nlrc4 inflammasomes in mice. Mediat Inflamm. 2013; 2013: 751374.

[59] BrossMH, SochK, MoralesR, Mitchell RB. Vibrio vulnificus infection: diagnosis and treatment. Am Fam Physician. 2007; 76(4): 539-544.

[60] RivaA, Chokshi S. Immune checkpoint receptors: homeostatic regulators of immunity. Hepatol Int. 2018; 12(3): 223-236.

[61] DhandaAD, Collins PL. Immune dysfunction in acute alcoholic hepatitis. World J Gastroenterol. 2015; 21(42): 11904-11913.

[62] FengZH, LiSQ, ZhangJX, et al. Analysis of gene expression profiles, cytokines, and bacterial loads relevant to alcoholic liver disease mice infected with V. vulnificus. Front Immunol. 2021; 12: 695491.

[63] LiB, LeiSS. Alcohol induces more severe fatty liver disease by influencing cholesterol metabolism. Evid Based Complement Alternat Med. 2019; 2019: 7095684.

[64] TaminiauB, KorsakN, LemaireC, Delcenserie V, DaubeG. Validation of real-time PCR for detection of six major pathogens in seafood products. Food Control. 2014; 44: 130-137.

[65] ZhongW, WeiX, HaoL, et al. Paneth cell dysfunction mediates alcohol-related steatohepatitis through promoting bacterial translocation in mice: role of zinc deficiency. Hepatology. 2020; 71(5): 1575-1591.

[66] ZhaoY, ChenF, WuW, et al. GPR43 mediates microbiota metabolite SCFA regulation of antimicrobial peptide expression in intestinal epithelial cells via activation of mTOR and STAT3. Muc Immunol. 2018; 11(3): 752-762.

RIGHTS & PERMISSIONS

2024 The Author(s). Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.