Research ArticleFunctional analysis of the relationship between intestinal microbiota and the expression of hepatic genes and pathways during the course of liver regeneration
Introduction
Commensal bacteria are implicated in digestive tract health and disease. It is known that intestinal microbiota plays a role in regulating host cell proliferation and tissue repair [1], [2]. For example, germ-free mice have reduced intestinal epithelial cell turnover due to reduced proliferation, apoptosis, and crypt-to-tip cellular migration [3]. Germ-free mice also exhibit increased cancer incidence compared to conventional mice [4]. In addition, increased bacterial load and dysbiosis are found in colonic biopsies of patients with colorectal adenoma or cancer [5]. Moreover, Gram-negative bacteria-generated lipopolysaccharide (LPS) stimulates liver regeneration and tissue repair through Toll-like receptor 4 (TLR4) signaling [6]. Gut microbiota also affects metabolic phenotype of the mammalian host and participates in microbial-host co-metabolism [7]. Alterations in gut bacterial communities are associated with metabolic disorders [8], metabolic syndrome [9], obesity [10], [11], [12], and non-alcoholic steatohepatitis [13]. There is an intrinsic link between proliferation and metabolism. Cell proliferation elevates metabolic demands to generate the energy and precursors for biosynthesis of macromolecules, and yet metabolic disorder dampens proliferation. Thus, through the gut-liver axis, intestinal microbiota, which is implicated in both proliferation and metabolism, may significantly regulate liver regeneration.
The liver is a major organ for host metabolism that can remarkably regenerate itself in response to partial resection or injury [14]. Liver regeneration requires activation of an array of genes and networks of signal transducers. Bile acids (BAs) have been identified as key metabolic signals during liver regeneration, and BA levels are tightly regulated by both host and microbiota [15]. There exists a “gut-liver axis” that facilitates bidirectional communication between intestinal microbes and BAs [1]. In one direction, the gut microbiota plays a pivotal role in regulating BA homeostasis. On the other end, BAs influence the gut microbiota profile. Although the bidirectional relationship of BAs and microbiota in the gut-liver axis has been investigated in humans and mice, whether it is linked to the regenerative process after liver resection remains largely unclear [16].
Previous studies have demonstrated the significance of BAs and its receptor farnesoid X receptor (FXR) in regulating liver regeneration [15]. However, the interplay between BAs, gut microbiota, and hepatic gene profiles during liver regeneration has not been defined. This is the first study to demonstrate the dynamic shift of hepatic transcripts and pathways in relation to gut microbiota as well as BA profiles in partial hepatectomy (PHx)-induced liver regeneration.
Section snippets
Animal experiments and sample collection
See Supplementary material and methods for sources of materials and methodological details.
Statistical analysis
Data are given as mean ± SD. Statistical analysis was performed using Student’s t test or one-way analysis of variance. Significance was defined by p <0.05.
PHx-induced liver regeneration
After 2/3 liver resection, liver mass was restored to its original size at 7 to 9 days, consistent with previously reported findings (Supplementary Fig. 1A) [17], [18], [19]. Ki67 immunostaining of liver sections revealed that cell proliferation started 1 day after PHx, peaked on day 2, and ceased on day 9 (Supplementary Fig.1B, C).
Alteration in microbial communities during liver regeneration
To characterize changes in the intestinal microbiota associated with regeneration, we constructed and sequenced 16S rRNA amplicon libraries from cecal contents. Mice
Discussion
The presented data, for the first time, analyzed changes in intestinal commensal microbiota occurring in mice whose livers are undergoing regeneration. Functional analysis demonstrated specific and unique functions of gut microbiota at each stage of liver regeneration. Accordingly, hepatic gene profiling also revealed unique expression patterns that can be associated with specific biological pathways involved in the regenerative process. Moreover, based on these unique functions of microbiota
Financial support
This study is supported by grants funded by National Institutes of Health CA53596, DK092100, and U01CA179582.
Conflict of interest
The authors who have taken part in this study declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.
Acknowledgement
The authors thank Thinh Chau and Lisa Teixeira for editing the manuscript. This study is supported by grants funded by National Institutes of Health CA53596, DK092100, and U01CA179582.
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2023, Science and SportsCitation Excerpt :In contrast, although the abundance of Peptostreptococcaceae was also decreased, the relative abundance of Lachnospiraceae displayed significantly higher abundance in group Hydro than in group Ctrl. Lachnospiraceae has the function of converting lactic acid to butyric acid [45], and its abundance is closely related to liver metabolism and immune function [46]. Butyric acid, as a short chain fatty acid, can provide energy for intestinal epithelial cells and regulate host cell response, and plays an important role in human colon [47].