title: Randomised clinical trial: Lactobacillus GG modulates gut microbiome, metabolome and endotoxemia in patients with cirrhosis.
abstract: BACKGROUND
  Safety of individual probiotic strains approved under Investigational New Drug (IND) policies in cirrhosis with minimal hepatic encephalopathy (MHE) is not clear.
  
  
  OBJECTIVE
  The primary aim of this phase I study was to evaluate the safety, tolerability of probiotic Lactobacillus GG (LGG) compared to placebo, while secondary ones were to explore its mechanism of action using cognitive, microbiome, metabolome and endotoxin analysis in MHE patients.
  
  
  METHODS
  Cirrhotic patients with MHE patients were randomised 1:1 into LGG or placebo BID after being prescribed a standard diet and multi-vitamin regimen and were followed up for 8 weeks. Serum, urine and stool samples were collected at baseline and study end. Safety was assessed at Weeks 4 and 8. Endotoxin and systemic inflammation, microbiome using multi-tagged pyrosequencing, serum/urine metabolome were analysed between groups using correlation networks.
  
  
  RESULTS
  Thirty MHE patients (14 LGG and 16 placebo) completed the study without any differences in serious adverse events. However, self-limited diarrhoea was more frequent in LGG patients. A standard diet was maintained and LGG batches were comparable throughout. Only in the LGG-randomised group, endotoxemia and TNF-α decreased, microbiome changed (reduced Enterobacteriaceae and increased Clostridiales Incertae Sedis XIV and Lachnospiraceae relative abundance) with changes in metabolite/microbiome correlations pertaining to amino acid, vitamin and secondary BA metabolism. No change in cognition was found.
  
  
  CONCLUSIONS
  In this phase I study, Lactobacillus GG is safe and well-tolerated in cirrhosis and is associated with a reduction in endotoxemia and dysbiosis.
authors.affiliation: Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University and McGuire VAMC, Richmond, VA, USA.
authors.forename: J S
authors.initials: JS
authors.lastname: Bajaj
authors.forename: D M
authors.initials: DM
authors.lastname: Heuman
authors.forename: P B
authors.initials: PB
authors.lastname: Hylemon
authors.forename: A J
authors.initials: AJ
authors.lastname: Sanyal
authors.forename: P
authors.initials: P
authors.lastname: Puri
authors.forename: R K
authors.initials: RK
authors.lastname: Sterling
authors.forename: V
authors.initials: V
authors.lastname: Luketic
authors.forename: R T
authors.initials: RT
authors.lastname: Stravitz
authors.forename: M S
authors.initials: MS
authors.lastname: Siddiqui
authors.forename: M
authors.initials: M
authors.lastname: Fuchs
authors.forename: L R
authors.initials: LR
authors.lastname: Thacker
authors.forename: J B
authors.initials: JB
authors.lastname: Wade
authors.forename: K
authors.initials: K
authors.lastname: Daita
authors.forename: S
authors.initials: S
authors.lastname: Sistrun
authors.forename: M B
authors.initials: MB
authors.lastname: White
authors.forename: N A
authors.initials: NA
authors.lastname: Noble
authors.forename: C
authors.initials: C
authors.lastname: Thorpe
authors.forename: G
authors.initials: G
authors.lastname: Kakiyama
authors.forename: W M
authors.initials: WM
authors.lastname: Pandak
authors.forename: M
authors.initials: M
authors.lastname: Sikaroodi
authors.forename: P M
authors.initials: PM
authors.lastname: Gillevet
mesh_terms: D000368:Aged; D003967:Diarrhea / Q000453:epidemiology / Q000209:etiology; D019446:Endotoxemia / Q000628:therapy; D005260:Female; D005500:Follow-Up Studies; D041981:Gastrointestinal Tract / Q000382:microbiology; D006501:Hepatic Encephalopathy / Q000628:therapy*; D006801:Humans; D007249:Inflammation / Q000453:epidemiology; D007778:Lactobacillus; D008103:Liver Cirrhosis / Q000628:therapy*; D008297:Male; D055442:Metabolome; D064307:Microbiota; D008875:Middle Aged; D019936:Probiotics / Q000009:adverse effects / Q000627:therapeutic use*; D014409:Tumor Necrosis Factor-alpha / Q000627:therapeutic use
chemical_list: D014409:Tumor Necrosis Factor-alpha