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

Zhiping Li, Shiqi Yang, Huizhi Lin, Jiawen Huang, Paul A. Watkins, Ann B. Moser, Claudio DeSimone, Xiao Yu Song, Anna Mae Diehl

Research output: Contribution to journalArticlepeer-review

Abstract

Ob/ob mice, a model for nonalcoholic fatty liver disease (NAFLD), develop intestinal bacterial overgrowth and overexpress tumor necrosis factor α (TNF-α). In animal models for alcoholic fatty liver disease (AFLD), decontaminating the or intestine or inhibiting TNF-α 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-α 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-α 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 κB (NF-κB), the target of IKKβ, another TNF-regulated enzyme that causes insulin resistance. Consistent with treatment-related improvements in hepatic insulin resistance, fatty acid β-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.

Original languageEnglish (US)
Pages (from-to)343-350
Number of pages8
JournalHepatology
Volume37
Issue number2
DOIs
StatePublished - Feb 1 2003

ASJC Scopus subject areas

  • Hepatology

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