Probiotics and antibodies to TNF inhibit inflammatory activity and improve nonalcoholic fatty liver disease.

Published

Journal Article

Ob/ob mice, a model for nonalcoholic fatty liver disease (NAFLD), develop intestinal bacterial overgrowth and overexpress tumor necrosis factor alpha (TNF-alpha). In animal models for alcoholic fatty liver disease (AFLD), decontaminating the intestine or inhibiting TNF-alpha improves AFLD. Because AFLD and NAFLD may have a similar pathogenesis, treatment with a probiotic (to modify the intestinal flora) or anti-TNF antibodies (to inhibit TNF-alpha activity) may improve NAFLD in ob/ob mice. To evaluate this hypothesis, 48 ob/ob mice were given either a high-fat diet alone (ob/ob controls) or the same diet + VSL#3 probiotic or anti-TNF antibodies for 4 weeks. Twelve lean littermates fed a high-fat diet served as controls. Treatment with VSL#3 or anti-TNF antibodies improved liver histology, reduced hepatic total fatty acid content, and decreased serum alanine aminotransferase (ALT) levels. These benefits were associated with decreased hepatic expression of TNF-alpha messenger RNA (mRNA) in mice treated with anti-TNF antibodies but not in mice treated with VSL#3. Nevertheless, both treatments reduced activity of Jun N-terminal kinase (JNK), a TNF-regulated kinase that promotes insulin resistance, and decreased the DNA binding activity of nuclear factor kappaB (NF-kappaB), the target of IKKbeta, another TNF-regulated enzyme that causes insulin resistance. Consistent with treatment-related improvements in hepatic insulin resistance, fatty acid beta-oxidation and uncoupling protein (UCP)-2 expression decreased after treatment with VSL#3 or anti-TNF antibodies. In conclusion, these results support the concept that intestinal bacteria induce endogenous signals that play a pathogenic role in hepatic insulin resistance and NAFLD and suggest novel therapies for these common conditions.

Full Text

Duke Authors

Cited Authors

  • Li, Z; Yang, S; Lin, H; Huang, J; Watkins, PA; Moser, AB; Desimone, C; Song, X-Y; Diehl, AM

Published Date

  • February 2003

Published In

Volume / Issue

  • 37 / 2

Start / End Page

  • 343 - 350

PubMed ID

  • 12540784

Pubmed Central ID

  • 12540784

International Standard Serial Number (ISSN)

  • 0270-9139

Digital Object Identifier (DOI)

  • 10.1053/jhep.2003.50048

Language

  • eng

Conference Location

  • United States