Randomised clinical trial: Lactobacillus GG modulates gut microbiome, metabolome and endotoxemia in patients with cirrhosis

Abstract

Summary Background Safety of individual probiotic strains approved under Investigational New Drug (IND) policies in cirrhosis with minimal hepatic encephalopathy (MHE) is not clear. Aim 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 randomized 1:1 into LGG or placebo BID after being prescribed a standard diet and multi-vitamin regimen and were followed 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 analyzed between groups using correlation networks. Results 30 MHE patients (14 LGG and 16 placebo) completed the study without any differences in serious adverse events. However, self-limited diarrhea was more frequent in LGG patients. A standard diet was maintained and LGG batches were comparable throughout. Only in the LGG-randomized 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, LGG is safe and well-tolerated in cirrhosis and is associated with a reduction in endotoxemia and dysbiosis.

The role of microbiota in hepatic encephalopathy

“…Being a safety study, this was not powered to detect cognitive changes, which were not observed between groups. Similar to the rifaximin MHE trial, however, there were significant changes in functionality related to pathways of amino-acid, vitamin, and bile acid metabolism in the LGG compared to the placebo group 43 ). Therefore in addition to just the microbiota composition, functional alterations of microbiota are important to analyze.…”

Gleaning Insights from Fecal Microbiota Transplantation and Probiotic Studies for the Rational Design of Combination Microbial Therapies

“…Probiotic administration has been shown to limit dysbiosis in many disease states, including colitis models, and to restore a normal microbiota composition more quickly than with placebo (289)(290)(291). Patients with minimal hepatic encephalopathy secondary to cirrhosis who were treated with LGG showed significantly increased prevalences of Lachnospiraceae and Clostridia cluster XIV and decreased prevalences of Enterobacteriaceae and Porphyromonadaceae relative to placebo-treated controls (292).…”

“…It is thus of particular interest that probiotics such as LGG and S. boulardii have been found in some animal models to decrease the levels of Enterobacteriaceae and Porphyromonadaceae, which are increased in active UC (292). The ability of these and other probiotics to speed the restoration of the microbiota following antibiotic treatment and to promote the activity of butyrate-producing bacteria may also help prevent insults that lead to active UC.…”

Clinical science workshop: targeting the gut-liver-brain axis

“…Although no proven statistical benefit over lactulose, probiotics had a better tolerated side-effect profile (Bajaj et al 2014a). Meta-analyses of the use of probiotics with the aim of favorably altering enteric flora towards reducing bacterial ammonia production have however shown conflicting results; one indicated an improvement in covert HE and secondary prevention of overt HE (Xu et al 2014), however another has shown no statistically significant benefit on clinical (McGee et al 2011).…”