Abstract
The homeostasis of the gut microbiome is crucial for human health and for liver function. However, it has not been established whether the gut microbiome influence hepatic progenitor cells (HPCs). HPCs are capable of self‐renewal and differentiate into hepatocytes and cholangiocytes; however, HPCs are normally quiescent and are rare in adults. After sustained liver damage, a ductular reaction occurs, and the number of HPCs is substantially increased. Here, we administered five broad‐spectrum antibiotics for 14 days to deplete the gut microbiomes of male C57BL/6 mice, and we measured the plasma aminotransferases and other biochemical indices. The expression levels of two HPC markers, SRY‐related high mobility group‐box gene 9 (Sox9) and cytokeratin (CK), were also measured. The plasma aminotransferase activities were not affected, but the triglyceride, lactate dehydrogenase, low‐density lipoprotein, and high‐density lipoprotein concentrations were significantly altered; this suggests that liver function is affected by the composition of the gut microbiome. The mRNA expression of Sox9 was significantly higher in the treated mice than it was in the control mice (p < 0.0001), and a substantial expression of Sox9 and CK was observed around the bile ducts. The mRNA expression levels of proinflammatory factors (interleukin [IL]‐1β, IL‐6, tumor necrosis factor [TNF]‐α, and TNF‐like weak inducer of apoptosis [Tweak]) were also significantly higher in the antibiotic‐treated mice than the levels in the control mice. These data imply that the depletion of the gut microbiome leads to liver damage, negatively impacts the hepatic metabolism and function, and activates HPCs. However, the underlying mechanisms remain to be determined.
Highlights
The liver has numerous functions, including metabolism, bile secre‐ tion, glycogen storage, hematopoiesis, and immunity (Knell, 1980).The liver detoxifies endogenous and exogenous substances, including medicines (Brockmoller & Roots, 1994), which may be harmful
The depletion of the gut microbiome led to a reduction in liver mass, suggesting that liver function might be impaired
Lipid metabolism, choles‐ terol metabolism, glycolysis, and inflammatory status, were all substan‐ tially affected by the depletion of the gut microbiome, confirming hepatocyte dysfunction
Summary
The liver has numerous functions, including metabolism, bile secre‐ tion, glycogen storage, hematopoiesis, and immunity (Knell, 1980). The expression levels of SOX9 (p < 0.0001) and the progenitor cell marker cytokeratin (CK) (Russell et al, 2019) were significantly higher in the livers of the antibiotic‐treated mice than their expression levels in the control mice The mechanism of these effects may involve the induction of inflammation because the expression levels of proin‐ flammatory factors (IL‐1β, IL‐6, tumor necrosis factor (TNF)‐α, and TWEAK) were higher. The mRNA expression of Tweak was significantly higher in the Abx mice than it was in the control mice (Figure 4d, p < 0.0001) These data may imply that macrophages play a critical role in HPC activation by releasing inflammatory cytokines, especially IL‐6 and TWEAK. These inflammatory cytokines may be regarded as key targets for more extensive research
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