Intestinal flora imbalance promotes alcohol-induced liver fibrosis by the TGFβ/smad signaling pathway in mice

Abstract

Intestinal flora performs a crucial role in human health and its imbalance may cause numerous pathological changes. The liver can also affect the intestinal function through bile secretion via the enterohepatic cycle. The pathophysiological association between the gut and the liver is described as the gut-liver axis. The present study investigated the role of intestinal flora in alcohol-induced liver fibrosis. A total of 36 C57 mice were randomly and equally divided into 3 different dietary regimes: Group I (alcohol injury; received alcohol); group II (alcohol injury with flora imbalance; received alcohol plus lincomycin hydrochloride) and group III (alcohol injury with corrected flora imbalance; received alcohol, lincomycin hydrochloride and extra probiotics). The present study then investigated several indicators of liver damage. Alkaline phosphatase (ALP) levels, aspartate aminotransferase (AST) levels and alanine aminotransferase (ALT) levels in mice serum were studied. Masson staining and Annexin V-fluorescein isothiocyanate/propidium iodide double staining was also performed, and the expression of mothers against decapentaplegic homolog (smad) 3 and smad4 proteins in hepatic stellate cells (HSCs) of the mice was examined using western blot analysis. The levels of serum ALP, AST and ALT were the highest in group II mice, and all 3 levels decreased in group III mice compared with those from group II. The degree of liver fibrosis was aggravated in group II mice compared with group I mice. The apoptosis of HSCs was significantly inhibited in group II mice, but was increased in group III mice. The HSCs in group II mice exhibited higher expression of smad3 and smad4, whilst group III mice (with corrected intestinal flora imbalance) exhibited downregulated expression of smad3 and smad4. The present data indicates that the intestinal flora perform a significant role in maintaining liver homeostasis. Furthermore, an imbalance of intestinal flora can exacerbate alcohol-induced liver fibrosis in mice through the transforming growth factor β/SMA/MAD homology signaling pathway, which subsequently leads to more serious liver damage.

The gut microbiota–bile acid axis: A potential therapeutic target for liver fibrosis

“…The transfer of gut microbiota metabolites, such as LPS secondary to intestinal barrier damage, to the liver results in binding to TLR4 on hepatic blastocytes and hepatic stellate cells, activating the TLR4-MyD88-NF-κB signaling pathway, upregulating levels of inflammatory factors such as TNF-α, interleukin IL-1β, and IL-6, stimulating extracellular matrix synthesis by hepatic stellate cells, and causing or exacerbating liver fibrosis ( Seki et al., 2007 ; Bastian et al., 2019 ; Chen et al., 2019a ; Giuffrè et al., 2020 ). In addition, TLR4 stimulation also promotes liver fibrosis by downregulating the expression of Bambi, an endogenous decoy receptor for the TGF-β receptor, and upregulating the TGFβ/Smad signaling pathway ( Seki and Schnabl, 2012 ; Zhang et al., 2017 ). In addition to TLR, NLR receptor-mediated innate immunity has an important role in the process of liver fibrosis.…”

The deficiency of FKBP-5 inhibited hepatocellular progression by increasing the infiltration of distinct immune cells and inhibiting obesity-associated gut microbial metabolite

“…Thus, we hypothesized that FKBP-5 deletion would suppress hepatocarcinogenesis by modulating the immune response. Previous research has suggested that an intestinal flora imbalance often plays a key role in the development of chronic liver disease and HCC (50). Additionally, research has shown that bacterial translocation caused by intestinal leakage can cause infectious complications of advanced liver disease and chronic inflammation (51).…”

Aspirin attenuates liver fibrosis by suppressing TGF‑β1/Smad signaling

“…Additionally, TGF-β1 can also activate HSCs, which further increase the synthesis and secretion of TGF-β1, thereby promoting the development of liver fibrosis ( 8 ). Furthermore, another study revealed that TGF-β1 enhanced ECM by regulating the TGF-β/Smad signaling pathway to further promote the development of fibrosis ( 6 ).…”