Oral-gut microbiome interactions in advanced cirrhosis: characterisation of pathogenic enterotypes and salivatypes, virulence factors and antimicrobial

IF 26.8 1区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY Journal of Hepatology Pub Date : 2024-10-22 DOI:10.1016/j.jhep.2024.09.046
Sunjae Lee, Bethlehem Arefaine, Neelu Begum, Marilena Stamouli, Elizabeth Witherden, Merianne Mohamad, Azadeh Harzandi, Ane Zamalloa, Haizhuang Cai, Roger Williams, Mike Curtis, Lindsey A. Edwards, Shilpa Chokshi, Adil Mardinoglu, Gordon Proctor, David Moyes, Mark J. McPhail, Debbie L. Shawcross, Mathias Uhlen, Saeed Shoaie, Vishal C. Patel
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Abstract

Background & Aims

Cirrhosis complications are often triggered by bacterial infections with multidrug-resistant organisms. Alterations in the gut and oral microbiome in decompensated cirrhosis (DC) influence clinical outcomes. We interrogated: (i) gut and oral microbiome community structures, (ii) virulence factors (VFs) and antimicrobial resistance genes (ARGs) and (iii) oral-gut microbial overlap in patients with differing cirrhosis severity.

Methods

15 healthy controls (HC), 26 stable cirrhosis (SC), 46 DC, 14 acute-on-chronic liver failure (ACLF) and 14 with severe infection without cirrhosis (NLS) participated. Metagenomic sequencing was undertaken on paired saliva (S) and faecal (F) samples. ‘Salivatypes’ and ‘enterotypes’ based on genera clustering were assessed against cirrhosis severity and clinical parameters. VFs and ARGs were evaluated in oral and gut niches, and distinct resistotypes identified.

Results

Salivatypes and enterotypes revealed a greater proportion of pathobionts with concomitant reduction in autochthonous genera with increasing cirrhosis severity and hyperammonaemia. Increasing overlap between oral and gut microbiome communities was observed in DC and ACLF vs SC and HCs, independent of antimicrobial, beta-blocker and acid suppressant therapies. Two distinct gut microbiome clusters [ENT2/ENT3] harboured genes encoding for the phosphoenolpyruvate:sugar phosphotransferase system (PTS) system and other VFs in DC and ACLF. Substantial ARGs (oral: 1,218 and gut: 672) were detected [575 common to both sites]. The cirrhosis resistome was distinct, with three oral and four gut resistotypes identified, respectively.

Discussion

The degree of oral-gut microbial community overlap, frequency of VFs and ARGs all increment significantly with cirrhosis severity, with progressive dominance of pathobionts and loss of commensals. Despite similar antimicrobial exposure, patients with DC and ACLF have reduced microbial richness compared to NLS, supporting the additive pathobiological effect of cirrhosis.

Impact and implications

This research underscores the crucial role of microbiome alterations in the progression of cirrhosis in an era of escalating multidrug resistant infections, highlighting the association and potential impact of increased oral-gut microbial overlap, virulence factors, and antimicrobial resistance genes on clinical outcomes. These findings are particularly significant for patients with decompensated cirrhosis and acute-on-chronic liver failure, as they reveal the intricate relationship between microbiome alterations and cirrhosis complications. This is relevant in the context of multidrug-resistant organisms and reduced oral-gut microbial diversity that exacerbate cirrhosis severity, drive hepatic decompensation and complicate treatment. For practical applications, these insights could guide for cirrhosis patients the development of targeted microbiome-based therapeutics and personalised antimicrobial regimens to mitigate infectious complications to improve their clinical outcomes.

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晚期肝硬化患者口腔-肠道微生物组的相互作用:致病性肠道菌型和唾液菌型、毒力因子和抗菌剂的特征描述
背景& 目的肝硬化并发症往往是由耐多药生物的细菌感染引发的。失代偿期肝硬化(DC)患者肠道和口腔微生物群的变化会影响临床预后。我们研究了:(i) 不同肝硬化严重程度患者的肠道和口腔微生物群落结构;(ii) 毒力因子(VFs)和抗菌药耐药基因(ARGs);(iii) 口腔-肠道微生物重叠。对成对的唾液(S)和粪便(F)样本进行了元基因组测序。根据肝硬化严重程度和临床参数评估了基于菌属聚类的 "唾液型 "和 "肠道型"。结果唾液型和肠道型显示,随着肝硬化严重程度和高氨血症程度的增加,病原菌的比例增加,自生菌属随之减少。在 DC 和 ACLF 与 SC 和 HCs 中观察到口腔和肠道微生物群落之间的重叠越来越多,这与抗菌剂、β-受体阻滞剂和抑酸剂疗法无关。在 DC 和 ACLF 中,两个不同的肠道微生物群[ENT2/ENT3]含有编码磷酸烯醇丙酮酸:糖磷酸转移酶系统(PTS)和其他 VF 的基因。检测到了大量的 ARGs(口腔:1,218 个,肠道:672 个)[575 个基因在两个部位共有]。讨论口腔-肠道微生物群落的重叠程度、VFs 和 ARGs 的频率都随着肝硬化的严重程度而显著增加,病原菌逐渐占据主导地位,共生菌逐渐减少。影响和意义这项研究强调了在多重耐药感染不断升级的时代,微生物组改变在肝硬化进展中的关键作用,突出了口腔-肠道微生物重叠、毒力因子和抗菌药耐药基因增加对临床结果的关联和潜在影响。这些发现对于失代偿期肝硬化和急性-慢性肝衰竭患者尤为重要,因为它们揭示了微生物组改变与肝硬化并发症之间错综复杂的关系。耐多药生物和口腔-肠道微生物多样性减少会加重肝硬化的严重程度,导致肝功能失代偿,并使治疗复杂化,在这种情况下,这些发现具有重要意义。在实际应用中,这些见解可以指导肝硬化患者开发基于微生物组的靶向疗法和个性化抗菌方案,以减轻感染性并发症,从而改善他们的临床疗效。
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来源期刊
Journal of Hepatology
Journal of Hepatology 医学-胃肠肝病学
CiteScore
46.10
自引率
4.30%
发文量
2325
审稿时长
30 days
期刊介绍: The Journal of Hepatology is the official publication of the European Association for the Study of the Liver (EASL). It is dedicated to presenting clinical and basic research in the field of hepatology through original papers, reviews, case reports, and letters to the Editor. The Journal is published in English and may consider supplements that pass an editorial review.
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