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

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

doi:10.1016/j.jhep.2024.09.046

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

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 ShoaieVishal C Patel

Research output: Contribution to journal › Article › peer-review

7 Citations (Scopus)

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: Fifteen healthy controls (HCs), as well as 26 patients with stable cirrhosis (SC), 46 with DC, 14 with acute-on-chronic liver failure (ACLF) and 14 with severe infection without cirrhosis participated. Metagenomic sequencing was undertaken on paired saliva and faecal 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 gastric acid-suppressing therapies. Two distinct gut microbiome clusters harboured genes encoding for the PTS (phosphoenolpyruvate:sugar phosphotransferase 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 increase 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 patients with severe infection without cirrhosis, 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 the development of targeted microbiome-based therapeutics and personalised antimicrobial regimens for patients with cirrhosis to mitigate infectious complications and improve clinical outcomes.

Original language	English
Journal	Journal of Hepatology
DOIs	https://doi.org/10.1016/j.jhep.2024.09.046
Publication status	E-pub ahead of print - 22 Oct 2024

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10.1016/j.jhep.2024.09.046

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Lee, S., Arefaine, B., Begum, N., Stamouli, M., Witherden, E., Mohamad, M., Harzandi, A., Zamalloa, A., Cai, H., Williams, R., Curtis, M., Edwards, L. A., Chokshi, S., Mardinoglu, A., Proctor, G., Moyes, D., McPhail, M. J., Shawcross, D. L., Uhlen, M., ... Patel, V. C. (2024). Oral-gut microbiome interactions in advanced cirrhosis: characterisation of pathogenic enterotypes and salivatypes, virulence factors and antimicrobial resistance. Journal of Hepatology. Advance online publication. https://doi.org/10.1016/j.jhep.2024.09.046

@article{dda172213e2d479fafec72ca50b7a734,

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

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: Fifteen healthy controls (HCs), as well as 26 patients with stable cirrhosis (SC), 46 with DC, 14 with acute-on-chronic liver failure (ACLF) and 14 with severe infection without cirrhosis participated. Metagenomic sequencing was undertaken on paired saliva and faecal samples. {\textquoteleft}Salivatypes{\textquoteright} and {\textquoteleft}enterotypes{\textquoteright} 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 gastric acid-suppressing therapies. Two distinct gut microbiome clusters harboured genes encoding for the PTS (phosphoenolpyruvate:sugar phosphotransferase 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 increase 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 patients with severe infection without cirrhosis, 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 the development of targeted microbiome-based therapeutics and personalised antimicrobial regimens for patients with cirrhosis to mitigate infectious complications and improve clinical outcomes.",

author = "Sunjae Lee and Bethlehem Arefaine and Neelu Begum and Marilena Stamouli and Elizabeth Witherden and Merianne Mohamad and Azadeh Harzandi and Ane Zamalloa and Haizhuang Cai and Roger Williams and Mike Curtis and Edwards, {Lindsey A} and Shilpa Chokshi and Adil Mardinoglu and Gordon Proctor and David Moyes and McPhail, {Mark J} and Shawcross, {Debbie L} and Mathias Uhlen and Saeed Shoaie and Patel, {Vishal C}",

year = "2024",

month = oct,

day = "22",

doi = "10.1016/j.jhep.2024.09.046",

language = "English",

journal = "Journal of Hepatology",

issn = "0168-8278",

publisher = "Elsevier",

}

Lee, S , Arefaine, B , Begum, N, Stamouli, M, Witherden, E, Mohamad, M, Harzandi, A, Zamalloa, A, Cai, H, Williams, R, Curtis, M, Edwards, LA, Chokshi, S, Mardinoglu, A , Proctor, G , Moyes, D , McPhail, MJ , Shawcross, DL, Uhlen, M, Shoaie, S & Patel, VC 2024, 'Oral-gut microbiome interactions in advanced cirrhosis: characterisation of pathogenic enterotypes and salivatypes, virulence factors and antimicrobial resistance', Journal of Hepatology. https://doi.org/10.1016/j.jhep.2024.09.046

TY - JOUR

T1 - Oral-gut microbiome interactions in advanced cirrhosis

T2 - characterisation of pathogenic enterotypes and salivatypes, virulence factors and antimicrobial resistance

AU - Lee, Sunjae

AU - Arefaine, Bethlehem

AU - Begum, Neelu

AU - Stamouli, Marilena

AU - Witherden, Elizabeth

AU - Mohamad, Merianne

AU - Harzandi, Azadeh

AU - Zamalloa, Ane

AU - Cai, Haizhuang

AU - Williams, Roger

AU - Curtis, Mike

AU - Edwards, Lindsey A

AU - Chokshi, Shilpa

AU - Mardinoglu, Adil

AU - Proctor, Gordon

AU - Moyes, David

AU - McPhail, Mark J

AU - Shawcross, Debbie L

AU - Uhlen, Mathias

AU - Shoaie, Saeed

AU - Patel, Vishal C

PY - 2024/10/22

Y1 - 2024/10/22

N2 - 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: Fifteen healthy controls (HCs), as well as 26 patients with stable cirrhosis (SC), 46 with DC, 14 with acute-on-chronic liver failure (ACLF) and 14 with severe infection without cirrhosis participated. Metagenomic sequencing was undertaken on paired saliva and faecal 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 gastric acid-suppressing therapies. Two distinct gut microbiome clusters harboured genes encoding for the PTS (phosphoenolpyruvate:sugar phosphotransferase 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 increase 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 patients with severe infection without cirrhosis, 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 the development of targeted microbiome-based therapeutics and personalised antimicrobial regimens for patients with cirrhosis to mitigate infectious complications and improve clinical outcomes.

AB - 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: Fifteen healthy controls (HCs), as well as 26 patients with stable cirrhosis (SC), 46 with DC, 14 with acute-on-chronic liver failure (ACLF) and 14 with severe infection without cirrhosis participated. Metagenomic sequencing was undertaken on paired saliva and faecal 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 gastric acid-suppressing therapies. Two distinct gut microbiome clusters harboured genes encoding for the PTS (phosphoenolpyruvate:sugar phosphotransferase 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 increase 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 patients with severe infection without cirrhosis, 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 the development of targeted microbiome-based therapeutics and personalised antimicrobial regimens for patients with cirrhosis to mitigate infectious complications and improve clinical outcomes.

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U2 - 10.1016/j.jhep.2024.09.046

DO - 10.1016/j.jhep.2024.09.046

M3 - Article

C2 - 39447963

SN - 0168-8278

JO - Journal of Hepatology

JF - Journal of Hepatology

ER -

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

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