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

TLDR

Intestinal bacterial overgrowth and TNF‑α overexpression in ob/ob mice, together with evidence that TNF‑α inhibition or intestinal decontamination improves fatty liver in animal models, implicate gut‑derived inflammation in NAFLD. The study tested whether a probiotic (VSL#3) or anti‑TNF antibodies could ameliorate NAFLD in ob/ob mice. Forty‑eight ob/ob mice on a high‑fat diet were treated for four weeks with either the diet alone, the diet plus VSL#3, or the diet plus anti‑TNF antibodies, while twelve lean littermates on the same diet served as controls. Both VSL#3 and anti‑TNF antibodies improved liver histology, lowered hepatic fatty acids and ALT, reduced JNK and NF‑κB activity, and anti‑TNF antibodies decreased hepatic TNF‑α mRNA, supporting gut‑derived inflammation as a therapeutic target in NAFLD.

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 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.