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 journalArticle

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

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Probiotics
Tumor Necrosis Factor-alpha
Alcoholic Fatty Liver
Anti-Idiotypic Antibodies
Alcoholic Liver Diseases
Insulin Resistance
Antibodies
Liver
High Fat Diet
Phosphotransferases
Fatty Acids
Therapeutics
Alanine Transaminase
Intestines
Non-alcoholic Fatty Liver Disease
Histology
Animal Models
Diet
Bacteria
Messenger RNA

ASJC Scopus subject areas

  • Hepatology

Cite this

Probiotics and antibodies to TNF inhibit inflammatory activity and improve nonalcoholic fatty liver disease. / Li, Zhiping; Yang, Shiqi; Lin, Huizhi; Huang, Jiawen; Watkins, Paul A; Moser, Ann B.; DeSimone, Claudio; Song, Xiao Yu; Diehl, Anna Mae.

In: Hepatology, Vol. 37, No. 2, 01.02.2003, p. 343-350.

Research output: Contribution to journalArticle

Li, Zhiping ; Yang, Shiqi ; Lin, Huizhi ; Huang, Jiawen ; Watkins, Paul A ; Moser, Ann B. ; DeSimone, Claudio ; Song, Xiao Yu ; Diehl, Anna Mae. / Probiotics and antibodies to TNF inhibit inflammatory activity and improve nonalcoholic fatty liver disease. In: Hepatology. 2003 ; Vol. 37, No. 2. pp. 343-350.
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