Gut-microbiota prompt activation of natural killer cell on alcoholic liver disease

Abstract

The liver is rich in innate immune cells, such as natural killer (NK) cells, natural killer T cells, and Kupffer cells associated with the gut microbiome. These immune cells are dysfunctional owing to alcohol consumption. However, there is insufficient data on the association between immune cells and gut microbiome in alcoholic liver disease (ALD). Therefore, the purpose of this study was to evaluate the effects of probiotic strains on NK cells in ALD patients. In total, 125 human blood samples [control ( n = 22), alcoholic hepatitis ( n = 43), and alcoholic cirrhosis ( n = 60]) were collected for flow cytometric analysis. C57BL/6J mice were divided into four groups (normal, EtOH-fed, and 2 EtOH+strain groups [ Phocaeicola dorei and Lactobacillus helveticus ]). Lymphocytes isolated from mouse livers were analyzed using flow cytometry. The frequency of NK cells increased in patients with alcoholic hepatitis and decreased in patients with alcoholic cirrhosis. The expression of NKp46, an NK cell-activating receptor, was decreased in patients with alcoholic hepatitis and increased in patients with alcoholic cirrhosis compared to that in the control group. The number of cytotoxic CD56dimCD16 + NK cells was significantly reduced in patients with alcoholic cirrhosis. We tested the effect of oral administration P. dorei and L. helveticus in EtOH-fed mice. P. dorei and L. helveticus improved liver inflammation and intestinal barrier damage caused by EtOH supply and increased NK cell activity. Therefore, these observations suggest that the gut microbiome may ameliorate ALD by regulating immune cells.

Updated Insights into Probiotics and Hepatobiliary Diseases

“…The frequency of NKp46, an NK cell-activating receptor in NK cells, exhibited a negative association with the Maddrey discriminant function (MDF) score (r = −0.4285, p = 0.0073), a prognostic index for alcoholic hepatitis, and the frequency of NK cells were decreased in alcoholic cirrhosis. To confirm the effects of probiotics on ALD via the modulation of immune cells, EtOH-fed mice were treated with the probiotics Phocaeicola dorei and Lactobacillus helveticus ; the probiotics ameliorated the ALD with a reduction in liver inflammation, improvement in the intestinal barrier integrality, and an increase in NK cell activity [ 34 ].…”

Inflammation in Steatotic Liver Diseases: Pathogenesis and Therapeutic Targets

“…Furthermore, probiotic strains can reverse alcohol-induced defects in the gut barrier and suppress NK cell function, which holds potential significance in treating ALD. 44 NKT cells, characterized by the expression of NK cell surface receptors and unique TCRs, also play a vital role in ALD pathogenesis. NKT cells are divided into two subsets according to differences in T cell receptor (TCR) characteristics.…”

Inflammation in Alcohol-Associated Hepatitis: Pathogenesis and Therapeutic Targets

“… 76 , 77 Moreover, NKT cells in severe AH patients have significantly altered cytokines production, such as IL-22 is significantly decreased. 78 The frequency of NK cells is increased in AH patients; however, the NK cell activating receptor NKp46 is significantly decreased, 79 but how NK cells contribute to the AH development and progression remains unclear.…”