Abstract
Lipopolysaccharide (LPS) has essential role in the pathogenesis of D-galactosamine-sensitized animal models and alcoholic liver diseases of humans, by stimulating release of pro-inflammatory mediators that cause hepatic damage and intestinal barrier impairment. Oral pretreatment of probiotics has been shown to attenuate LPS-induced hepatic injury, but it is unclear whether the effect is direct or due to improvement in the intestinal barrier. The present study tested the hypothesis that pretreatment with probiotics enables the liver to withstand directly LPS-induced hepatic injury and inflammation. In a mouse model of LPS-induced hepatic injury, the levels of hepatic tumor necrosis factor-alpha (TNF-α) and serum alanine aminotransferase (ALT) of mice with depleted intestinal commensal bacteria were not significantly different from that of the control models. Pre-feeding mice for 10 days with Lactobacillus fermentum ZYL0401 (LF41), significantly alleviated LPS-induced hepatic TNF-α expression and liver damage. After LF41 pretreatment, mice had dramatically more L.fermentum-specific DNA in the ileum, significantly higher levels of ileal cyclooxygenase (COX)-2 and interleukin 10 (IL-10) and hepatic prostaglandin E2 (PGE2). However, hepatic COX-1, COX-2, and IL-10 protein levels were not changed after the pretreatment. There were also higher hepatic IL-10 protein levels after LPS challenge in LF41-pretreaed mice than in the control mice. Attenuation of hepatic TNF-α was mediated via the PGE2/E prostanoid 4 (EP4) pathway, and serum ALT levels were attenuated in an IL-10-dependent manner. A COX-2 blockade abolished the increase in hepatic PGE2 and IL-10 associated with LF41. In LF41-pretreated mice, a blockade of IL-10 caused COX-2-dependent promotion of hepatic PGE2, without affecting hepatic COX-2levels. In LF41-pretreated mice, COX2 prevented enhancing TNF-α expression in both hepatic mononuclear cells and the ileum, and averted TNF-α-mediated increase in intestinal permeability. Together, we demonstrated that LF41 pre-feeding enabled the liver to alleviate LPS-induced hepatic TNF-α expression and injury via a PGE2-EP4- and IL-10-dependent mechanism.
Highlights
Lipopolysaccharides (LPS), produced by Gram-negative bacteria, enter the systemic circulation and activate the innate immune system
Mice with an antibiotic formula pretreated to deplete intestinal commensal bacteria (S1 Fig) displayed no change in hepatic Tnf mRNA and serum ALT levels in this liver damage model compared with mice without receiving the antibiotics treatment (Fig 1A)
We found that oral pretreatment of mice for 10 consecutive days with high-dose Lactobacillus fermentum ZYL0401 (LF41) (H-LF41), but not low-dose LF41 (L-LF41) or high dose of Lactobacillus rhamnosus GG (LGG) or Bifidobacterium catenulatum ZYB0401 (BC41), resulted in attenuation of LPS-induced hepatic Tnf mRNA levels and serum ALT activity
Summary
Lipopolysaccharides (LPS), produced by Gram-negative bacteria, enter the systemic circulation and activate the innate immune system. Pretreatment with VSL#3 was associated with lower levels of hepatic pro-inflammatory cytokines induced by GalN/LPS, and less liver damage and dysfunction of the gut barrier [12]. Pretreatment withVSL#3 may promote the entrance of gut-derived factor(s) into the liver, to up-regulate hepatic peroxisome proliferator-activated receptor gamma, a nuclear receptor whose antagonism to LPS-induced inflammation is well known [12,13,14]. It has been shown in a murine alcoholic liver disease model that oral administration of supernatant derived from Lactobacillus rhamnosus GG (LGG) correlates with attenuation of the hepatic inflammation and injury and intestinal barrier dysfunction [15]. The preventive effect against hepatic TNF-α expression was mediated via the PGE2/E prostanoid 4 (EP4) pathway, and serum ALT levels was suppressed in an IL10-dependent manner
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