Probiotics and antibodies to TNF inhibit inflammatory activity and improve nonalcoholic fatty liver disease.
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.
Li
Zhiping
Z
The Johns Hopkins University, Baltimore, MD 21205, USA.
Yang
Shiqi
S
Lin
Huizhi
H
Huang
Jiawen
J
Watkins
Paul A
PA
Moser
Ann B
AB
Desimone
Claudio
C
Song
Xiao-yu
XY
Diehl
Anna Mae
AM
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D000906:Antibodies / Q000494:pharmacology*; D004247:DNA / Q000378:metabolism; D004041:Dietary Fats / Q000008:administration & dosage; D005227:Fatty Acids / Q000378:metabolism; D005234:Fatty Liver / Q000378:metabolism / Q000473:pathology*; D006505:Hepatitis / Q000517:prevention & control*; D007333:Insulin Resistance / Q000502:physiology; D007473:Ion Channels; D048031:JNK Mitogen-Activated Protein Kinases; D008099:Liver / Q000378:metabolism; D008297:Male; D026901:Membrane Transport Proteins; D051379:Mice; D008810:Mice, Inbred C57BL / Q000235:genetics; D024101:Mitochondrial Proteins; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors; D016328:NF-kappa B / Q000378:metabolism; D009765:Obesity / Q000235:genetics; D010084:Oxidation-Reduction; D019936:Probiotics / Q000494:pharmacology*; D011506:Proteins / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000276:immunology*; D000071246:Uncoupling Protein 2
D000906:Antibodies; D004041:Dietary Fats; D005227:Fatty Acids; D007473:Ion Channels; D026901:Membrane Transport Proteins; D024101:Mitochondrial Proteins; D016328:NF-kappa B; D011506:Proteins; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; C000604390:Ucp2 protein, mouse; D000071246:Uncoupling Protein 2; D004247:DNA; D000410:Alanine Transaminase; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases