BACKGROUND: Cirrhosis and alcohol can independently affect the gut-liver axis with systemic inflammation. However, their concurrent impact in humans is unclear. METHODS: Our aim was to determine the effect of continued alcohol misuse on the gut-liver axis in cirrhotic patients. Age- and MELD-balanced cirrhotic patients who were currently drinking (Alc) or abstinent (NAlc) and healthy controls underwent serum and stool collection. A subset underwent upper endoscopy and colonoscopy for biopsies and duodenal fluid collection. The groups were compared regarding (i) inflammation/intestinal barrier: systemic tumor necrosis factor levels, intestinal inflammatory cytokine (duodenum, ileum, sigmoid), and ileal antimicrobial peptide expression; (ii) microbiota composition: 16SrRNA sequencing of duodenal, ileal, and colonic mucosal and fecal microbiota; and (iii) microbial functionality: duodenal fluid and fecal bile acid (BA) profile (conjugation and dehydroxylation status), intestinal BA transporter (ASBT, FXR, FGF-19, SHP) expression, and stool metabolomics using gas chromatography/mass spectrometry. RESULTS: Alc patients demonstrated a significant duodenal, ileal, and colonic mucosal and fecal dysbiosis, compared to NAlc and controls with lower autochthonous bacterial taxa. BA profile skewed toward a potentially toxic profile (higher secondary and glycine-conjugated BAs) in duodenal fluid and stool in Alc patients. Duodenal fluid demonstrated conjugated secondary BAs only in the Alc group. There was a greater expression of all ileal BA transporters in Alc patients. This group also showed higher endotoxemia, systemic and ileal inflammatory expression, and lower amino acid and bioenergetic-associated metabolites, without change in antimicrobial peptide expression. CONCLUSIONS: Despite cirrhosis, continued alcohol misuse predisposes patients to widespread dysbiosis with alterations in microbial functionality such as a toxic BA profile, which can lead to intestinal and systemic inflammation.
BACKGROUND:Cirrhosis and alcohol can independently affect the gut-liver axis with systemic inflammation. However, their concurrent impact in humans is unclear. METHODS: Our aim was to determine the effect of continued alcohol misuse on the gut-liver axis in cirrhotic patients. Age- and MELD-balanced cirrhoticpatients who were currently drinking (Alc) or abstinent (NAlc) and healthy controls underwent serum and stool collection. A subset underwent upper endoscopy and colonoscopy for biopsies and duodenal fluid collection. The groups were compared regarding (i) inflammation/intestinal barrier: systemic tumor necrosis factor levels, intestinal inflammatory cytokine (duodenum, ileum, sigmoid), and ileal antimicrobial peptide expression; (ii) microbiota composition: 16SrRNA sequencing of duodenal, ileal, and colonic mucosal and fecal microbiota; and (iii) microbial functionality: duodenal fluid and fecal bile acid (BA) profile (conjugation and dehydroxylation status), intestinal BA transporter (ASBT, FXR, FGF-19, SHP) expression, and stool metabolomics using gas chromatography/mass spectrometry. RESULTS:Alcpatients demonstrated a significant duodenal, ileal, and colonic mucosal and fecal dysbiosis, compared to NAlc and controls with lower autochthonous bacterial taxa. BA profile skewed toward a potentially toxic profile (higher secondary and glycine-conjugated BAs) in duodenal fluid and stool in Alcpatients. Duodenal fluid demonstrated conjugated secondary BAs only in the Alc group. There was a greater expression of all ileal BA transporters in Alcpatients. This group also showed higher endotoxemia, systemic and ileal inflammatory expression, and lower amino acid and bioenergetic-associated metabolites, without change in antimicrobial peptide expression. CONCLUSIONS: Despite cirrhosis, continued alcohol misuse predisposes patients to widespread dysbiosis with alterations in microbial functionality such as a toxic BA profile, which can lead to intestinal and systemic inflammation.
Authors: Katharina Brandl; Phillipp Hartmann; Lily J Jih; Donald P Pizzo; Josepmaria Argemi; Meritxell Ventura-Cots; Sally Coulter; Christopher Liddle; Lei Ling; Stephen J Rossi; Alex M DePaoli; Rohit Loomba; Wajahat Z Mehal; Derrick E Fouts; Michael R Lucey; Francisco Bosques-Padilla; Philippe Mathurin; Alexander Louvet; Guadalupe Garcia-Tsao; Elizabeth C Verna; Juan G Abraldes; Robert S Brown; Victor Vargas; Jose Altamirano; Juan Caballería; Debbie Shawcross; Peter Stärkel; Samuel B Ho; Ramon Bataller; Bernd Schnabl Journal: J Hepatol Date: 2018-04-12 Impact factor: 25.083
Authors: Phillipp Hartmann; Katrin Hochrath; Angela Horvath; Peng Chen; Caroline T Seebauer; Cristina Llorente; Lirui Wang; Yazen Alnouti; Derrick E Fouts; Peter Stärkel; Rohit Loomba; Sally Coulter; Christopher Liddle; Ruth T Yu; Lei Ling; Stephen J Rossi; Alex M DePaoli; Michael Downes; Ronald M Evans; David A Brenner; Bernd Schnabl Journal: Hepatology Date: 2018-04-16 Impact factor: 17.425
Authors: Matias A Avila; Jean-François Dufour; Alexander L Gerbes; Fabien Zoulim; Ramon Bataller; Patrizia Burra; Helena Cortez-Pinto; Bin Gao; Ian Gilmore; Philippe Mathurin; Christophe Moreno; Vladimir Poznyak; Bernd Schnabl; Gyongyi Szabo; Maja Thiele; Mark R Thursz Journal: Gut Date: 2019-12-26 Impact factor: 23.059
Authors: Dennis R Warner; Jeffrey B Warner; Josiah E Hardesty; Ying L Song; Taylor N King; Jing X Kang; Chih-Yu Chen; Shanfu Xie; Fang Yuan; Md Aminul Islam Prodhan; Xipeng Ma; Xiang Zhang; Eric C Rouchka; Krishna Rao Maddipati; Joan Whitlock; Eric C Li; Gary P Wang; Craig J McClain; Irina A Kirpich Journal: J Lipid Res Date: 2019-10-04 Impact factor: 5.922