Innate immune reactivity of the ileum-liver axis in nonalcoholic steatohepatitis

Over-proliferation and bacterial translocation of Gram-negative bacilli within the intestinal flora, and increased portal venous levels of endotoxins, are involved in nonalcoholic steatohepatitis (NASH).

To evaluate the innate immune response in the small intestine and liver using the rat NASH model.

We produced the NASH model by administering a choline-deficient amino acid-defined diet to F344 rats. We analyzed the serum and liver tissue to assess the effects of innate immune reactivity in this NASH model.

Significant increases were detected in serum ALT levels and in the portal venous serum and whole-liver levels of TNF-α and IFN-γ in the NASH group. Strong Sirius red staining and TNF-α immune staining were seen in the NASH group, and real-time PCR revealed significantly increased expression of TNF-α and TLR4 mRNA in the NASH group. Higher TNF-α levels were detected in the Kupffer cells isolated culture supernatant in the NASH group than in the control group. Immune staining of the ileal tissue specimens resulted in greater staining of TNF-α, TLR4, and macrophage/dendritic cells, mainly in the submucosa, in the NASH group than in the control group.

In the small intestine and liver of the rat NASH model, the possibility that enhancement of the innate immune response, mediated by the TLR4 signal, led to increased production of TNF-α was suggested. This interaction between the small intestine and liver may be involved in the onset and progression of NASH.