The circulating microbiome signature and inferred functional metagenomics in alcoholic hepatitis

Puneet Puri, Suthat Liangpunsakul, Jeffrey E. Christensen, Vijay H. Shah, Patrick S. Kamath, Gregory J. Gores, Susan Walker, Megan Comerford, Barry Katz, Andrew Borst, Andy Yu, Divya P. Kumar, Faridoddin Mirshahi, Svetlana Radaeva, Naga Chalasani, David Crabb, Arun J. Sanyal

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Abstract

Intestinal dysbiosis is implicated in alcoholic hepatitis (AH). However, changes in the circulating microbiome, its association with the presence and severity of AH, and its functional relevance in AH is unknown. Qualitative and quantitative assessment of changes in the circulating microbiome were performed by sequencing bacterial DNA in subjects with moderate AH (MAH) (n = 18) or severe AH (SAH) (n = 19). These data were compared with heavy drinking controls (HDCs) without obvious liver disease (n = 19) and non-alcohol-consuming controls (NACs, n = 20). The data were related to endotoxin levels and markers of monocyte activation. Linear discriminant analysis effect size (LEfSe) analysis, inferred metagenomics, and predictive functional analysis using PICRUSt were performed. There was a significant increase in 16S copies/ng DNA both in MAH (P < 0.01) and SAH (P < 0.001) subjects. Compared with NACs, the relative abundance of phylum Bacteroidetes was significantly decreased in HDCs, MAH, and SAH (P < 0.001). In contrast, all alcohol-consuming groups had enrichment with Fusobacteria; this was greatest for HDCs and decreased progressively in MAH and SAH. Subjects with SAH had significantly higher endotoxemia (P = 0.01). Compared with alcohol-consuming groups, predictive functional metagenomics indicated an enrichment of bacteria with genes related to methanogenesis and denitrification. Furthermore, both HDCs and SAH showed activation of a type III secretion system that has been linked to gram-negative bacterial virulence. Metagenomics in SAH versus NACs predicted increased isoprenoid synthesis via mevalonate and anthranilate degradation, known modulators of gram-positive bacterial growth and biofilm production, respectively. Conclusion: Heavy alcohol consumption appears to be the primary driver of changes in the circulating microbiome associated with a shift in its inferred metabolic functions.

Original languageEnglish (US)
JournalHepatology
DOIs
StateAccepted/In press - Jan 1 2018

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Alcoholic Hepatitis
Metagenomics
Microbiota
Drinking
Fusobacteria
Alcohols
Dysbiosis
Bacteroidetes
Denitrification
Bacterial DNA
Mevalonic Acid
Endotoxemia
Terpenes
Discriminant Analysis
Biofilms
Endotoxins
Alcohol Drinking
Virulence
Liver Diseases
Monocytes

ASJC Scopus subject areas

  • Hepatology

Cite this

Puri, P., Liangpunsakul, S., Christensen, J. E., Shah, V. H., Kamath, P. S., Gores, G. J., ... Sanyal, A. J. (Accepted/In press). The circulating microbiome signature and inferred functional metagenomics in alcoholic hepatitis. Hepatology. https://doi.org/10.1002/hep.29623

The circulating microbiome signature and inferred functional metagenomics in alcoholic hepatitis. / Puri, Puneet; Liangpunsakul, Suthat; Christensen, Jeffrey E.; Shah, Vijay H.; Kamath, Patrick S.; Gores, Gregory J.; Walker, Susan; Comerford, Megan; Katz, Barry; Borst, Andrew; Yu, Andy; Kumar, Divya P.; Mirshahi, Faridoddin; Radaeva, Svetlana; Chalasani, Naga; Crabb, David; Sanyal, Arun J.

In: Hepatology, 01.01.2018.

Research output: Contribution to journalArticle

Puri, P, Liangpunsakul, S, Christensen, JE, Shah, VH, Kamath, PS, Gores, GJ, Walker, S, Comerford, M, Katz, B, Borst, A, Yu, A, Kumar, DP, Mirshahi, F, Radaeva, S, Chalasani, N, Crabb, D & Sanyal, AJ 2018, 'The circulating microbiome signature and inferred functional metagenomics in alcoholic hepatitis', Hepatology. https://doi.org/10.1002/hep.29623
Puri, Puneet ; Liangpunsakul, Suthat ; Christensen, Jeffrey E. ; Shah, Vijay H. ; Kamath, Patrick S. ; Gores, Gregory J. ; Walker, Susan ; Comerford, Megan ; Katz, Barry ; Borst, Andrew ; Yu, Andy ; Kumar, Divya P. ; Mirshahi, Faridoddin ; Radaeva, Svetlana ; Chalasani, Naga ; Crabb, David ; Sanyal, Arun J. / The circulating microbiome signature and inferred functional metagenomics in alcoholic hepatitis. In: Hepatology. 2018.
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abstract = "Intestinal dysbiosis is implicated in alcoholic hepatitis (AH). However, changes in the circulating microbiome, its association with the presence and severity of AH, and its functional relevance in AH is unknown. Qualitative and quantitative assessment of changes in the circulating microbiome were performed by sequencing bacterial DNA in subjects with moderate AH (MAH) (n = 18) or severe AH (SAH) (n = 19). These data were compared with heavy drinking controls (HDCs) without obvious liver disease (n = 19) and non-alcohol-consuming controls (NACs, n = 20). The data were related to endotoxin levels and markers of monocyte activation. Linear discriminant analysis effect size (LEfSe) analysis, inferred metagenomics, and predictive functional analysis using PICRUSt were performed. There was a significant increase in 16S copies/ng DNA both in MAH (P < 0.01) and SAH (P < 0.001) subjects. Compared with NACs, the relative abundance of phylum Bacteroidetes was significantly decreased in HDCs, MAH, and SAH (P < 0.001). In contrast, all alcohol-consuming groups had enrichment with Fusobacteria; this was greatest for HDCs and decreased progressively in MAH and SAH. Subjects with SAH had significantly higher endotoxemia (P = 0.01). Compared with alcohol-consuming groups, predictive functional metagenomics indicated an enrichment of bacteria with genes related to methanogenesis and denitrification. Furthermore, both HDCs and SAH showed activation of a type III secretion system that has been linked to gram-negative bacterial virulence. Metagenomics in SAH versus NACs predicted increased isoprenoid synthesis via mevalonate and anthranilate degradation, known modulators of gram-positive bacterial growth and biofilm production, respectively. Conclusion: Heavy alcohol consumption appears to be the primary driver of changes in the circulating microbiome associated with a shift in its inferred metabolic functions.",
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AU - Puri, Puneet

AU - Liangpunsakul, Suthat

AU - Christensen, Jeffrey E.

AU - Shah, Vijay H.

AU - Kamath, Patrick S.

AU - Gores, Gregory J.

AU - Walker, Susan

AU - Comerford, Megan

AU - Katz, Barry

AU - Borst, Andrew

AU - Yu, Andy

AU - Kumar, Divya P.

AU - Mirshahi, Faridoddin

AU - Radaeva, Svetlana

AU - Chalasani, Naga

AU - Crabb, David

AU - Sanyal, Arun J.

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N2 - Intestinal dysbiosis is implicated in alcoholic hepatitis (AH). However, changes in the circulating microbiome, its association with the presence and severity of AH, and its functional relevance in AH is unknown. Qualitative and quantitative assessment of changes in the circulating microbiome were performed by sequencing bacterial DNA in subjects with moderate AH (MAH) (n = 18) or severe AH (SAH) (n = 19). These data were compared with heavy drinking controls (HDCs) without obvious liver disease (n = 19) and non-alcohol-consuming controls (NACs, n = 20). The data were related to endotoxin levels and markers of monocyte activation. Linear discriminant analysis effect size (LEfSe) analysis, inferred metagenomics, and predictive functional analysis using PICRUSt were performed. There was a significant increase in 16S copies/ng DNA both in MAH (P < 0.01) and SAH (P < 0.001) subjects. Compared with NACs, the relative abundance of phylum Bacteroidetes was significantly decreased in HDCs, MAH, and SAH (P < 0.001). In contrast, all alcohol-consuming groups had enrichment with Fusobacteria; this was greatest for HDCs and decreased progressively in MAH and SAH. Subjects with SAH had significantly higher endotoxemia (P = 0.01). Compared with alcohol-consuming groups, predictive functional metagenomics indicated an enrichment of bacteria with genes related to methanogenesis and denitrification. Furthermore, both HDCs and SAH showed activation of a type III secretion system that has been linked to gram-negative bacterial virulence. Metagenomics in SAH versus NACs predicted increased isoprenoid synthesis via mevalonate and anthranilate degradation, known modulators of gram-positive bacterial growth and biofilm production, respectively. Conclusion: Heavy alcohol consumption appears to be the primary driver of changes in the circulating microbiome associated with a shift in its inferred metabolic functions.

AB - Intestinal dysbiosis is implicated in alcoholic hepatitis (AH). However, changes in the circulating microbiome, its association with the presence and severity of AH, and its functional relevance in AH is unknown. Qualitative and quantitative assessment of changes in the circulating microbiome were performed by sequencing bacterial DNA in subjects with moderate AH (MAH) (n = 18) or severe AH (SAH) (n = 19). These data were compared with heavy drinking controls (HDCs) without obvious liver disease (n = 19) and non-alcohol-consuming controls (NACs, n = 20). The data were related to endotoxin levels and markers of monocyte activation. Linear discriminant analysis effect size (LEfSe) analysis, inferred metagenomics, and predictive functional analysis using PICRUSt were performed. There was a significant increase in 16S copies/ng DNA both in MAH (P < 0.01) and SAH (P < 0.001) subjects. Compared with NACs, the relative abundance of phylum Bacteroidetes was significantly decreased in HDCs, MAH, and SAH (P < 0.001). In contrast, all alcohol-consuming groups had enrichment with Fusobacteria; this was greatest for HDCs and decreased progressively in MAH and SAH. Subjects with SAH had significantly higher endotoxemia (P = 0.01). Compared with alcohol-consuming groups, predictive functional metagenomics indicated an enrichment of bacteria with genes related to methanogenesis and denitrification. Furthermore, both HDCs and SAH showed activation of a type III secretion system that has been linked to gram-negative bacterial virulence. Metagenomics in SAH versus NACs predicted increased isoprenoid synthesis via mevalonate and anthranilate degradation, known modulators of gram-positive bacterial growth and biofilm production, respectively. Conclusion: Heavy alcohol consumption appears to be the primary driver of changes in the circulating microbiome associated with a shift in its inferred metabolic functions.

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