Probiotic Lactobacillus GG (LGG) in Patients With Minimal Hepatic Encephalopathy

Development of complementary and alternative medicine approaches to liver disease is a
priority area at NCCAM. Minimal hepatic encephalopathy (MHE) is a significant complication
of cirrhosis which can result in poor quality of life, impaired cognition and difficulty in
driving motor vehicles with a high traffic accident risk. MHE is estimated to affect one
half of the 5.5 million cirrhotics in the U.S. Despite these negative outcomes, there is no
consensus on treatment of MHE. Currently available therapies for MHE act on intestinal flora
but are limited by adverse effects (i.e. lactulose-induced diarrhea), which negatively
impact adherence. Probiotic bacterial supplements, which also act on intestinal flora, are
an emerging therapy for MHE. Our group has performed a pilot, randomized trial which
demonstrated a significantly higher rate of MHE reversal with excellent adherence in
patients randomized to probiotic yogurt compared to no therapy. This proposal intends to
define Lactobacillus GG (LGG) as a biologically-based alternative therapy for MHE with
special focus on metabolic and stool bacteriologic changes.

The hypothesis of this Phase I proposal is: LGG will be safe and efficacious for the
treatment of minimal hepatic encephalopathy compared to placebo in a randomized,
double-blind trial.

This will be carried out with four specific aims:

Specific aim 1: To define the safety and tolerability of LGG in patients with minimal
hepatic encephalopathy against placebo in a Phase I randomized controlled trial.

Specific aim 2: To define the effect of LGG on intestinal microflora composition in
cirrhotics with minimal hepatic encephalopathy using 16s stool DNA sequencing in a
randomized, placebo-controlled trial.

Specific aim 3: To determine the effect of LGG on metabolic biomarkers and cytokines in
stool, urine and blood using nuclear magnetic resonance spectroscopy in minimal hepatic
encephalopathy.

Specific aim 4: To determine the effect of LGG on psychometric function in patients with
minimal hepatic encephalopathy.

The specific aim and sub-aims will be tested in 40 patients with non-alcoholic cirrhosis and
MHE: 20 randomized to LGG and 20 randomized to placebo to be taken BID for 8 weeks with
detailed psychometric, metabolic, anthropometric and bacteriologic evaluation. Results
generated from this study will form the basis for a RO1 proposal to develop the use of
probiotics as a biologically-based alternative treatment with long-term outcomes of
prognosis, development of overt encephalopathy and prevention of traffic accidents in
patients with MHE.

Inclusion Criteria:

- Age: 18-65 years

- Histological evidence of cirrhosis

- Maintenance of cirrhosis treatment and stability for 6 months

- Mini-mental state exam score > 25

- Presence of MHE on psychometric testing

Exclusion Criteria:

- Rx for MHE or OHE

- Antibiotics within 6 weeks

- Yogurt consumption within 2 weeks

- Neutrophil count < 500

- Inflammatory bowel disease

- History of pancreatitis

- Hepato-cellular carcinoma

- Recent (6 weeks) gastrointestinal bleed

- Recent (6 months) alcohol intake

- Psychoactive medications (including interferon/antipsychotics)

- Liver transplant