Deletion of hepatic growth hormone receptor (GHR) alters the mouse gut microbiota by affecting bile acid metabolism

ABSTRACT

Both growth hormone (GH) and gut microbiota play significant roles in diverse physiological processes, but the crosstalk between them is poorly understood. Despite the regulation of GH by gut microbiota, study on GH’s influence on gut microbiota is limited, especially on the impacts of tissue specific GH signaling and their feedback effects on the host. In this study, we profiled gut microbiota and metabolome in tissue-specific GHR knockout mice in the liver (LKO) and adipose tissue (AKO). We found that GHR disruption in the liver rather than adipose tissue affected gut microbiota. It changed the abundance of Bacteroidota and Firmicutes at phylum level as well as abundance of several genera, such as Lactobacillus, Muribaculaceae, and Parasutterella, without affecting α-diversity. Moreover, the impaired liver bile acid (BA) profile in LKO mice was strongly associated with the change of gut microbiota. The BA pools and 12-OH BAs/non-12-OH BAs ratio were increased in the LKO mice, which was due to the induction of CYP8B1 by hepatic Ghr knockout. Consequently, the impaired BA pool in cecal content interacted with gut bacteria, which in turn increased the production of bacteria derived acetic acid, propionic acid, and phenylacetic acid that were possible to participate in the impaired metabolic phenotype of the LKO mice. Collectively, our findings suggested that the liver GH signaling regulates BA metabolism by its direct regulation on CYP8B1, which is an important factor influencing gut microbiota. Our study is significant in exploring gut microbiota modification effects of tissue-specific GH signaling as well as its involvement in gut microbiota–host interaction.

KEYWORDS:

• Growth hormone
• Growth hormone receptor
• Tissue specific gene knockout
• Bile acid
• Gut microbiota
• Microbial metabolites

Acknowledgments

This work was supported by the Ministry of Science and Technology (“National Key R&D Program of China” No. 2021YFA0805100, 2021YFF0702100, and 2022YFE0132200), Shandong Provincial Natural Science Foundation (No. ZR2022MH057), and Youth Incubation Program of Shandong First Medical University & Shandong Academy of Medical Sciences (No. 202201-039). The authors thank Anhui Anke Biotechnology (Group) Co., Ltd. for kindly providing rhGH.

Disclosure statement

No potential conflict of interest was reported by the authors.

Authors’ contributions

YW, LR, and ZY designed and conducted the experiments. ZY, YW, FZ, RM, XY, KY, AM, and LR collected the samples and performed the phenotypic and biochemical parameters analyses. AM and LR performed the histological observation. ZY, LR, and YW analyzed the microbiota data. ZY and LR analyzed the metabolome data. ZY and LR drafted the manuscript. LR and YW reviewed and edited the manuscript. All the authors read and approved the final manuscript.

Data availability statement

The raw sequence data are available in the NCBI Sequence Read Archive database under accession number PRJNA913256 (http://www.ncbi.nlm.nih.gov/sra). The targeted metabolomics data are included in the supplementary files.

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/19490976.2023.2221098

Additional information

Funding

The work was supported by the Ministry of Science and Technology of the People’s Republic of China [2021YFA0805100, 2021YFF0702100, and 2022YFE0132200]; Natural Science Foundation of Shandong Province [ZR2022MH057]; Shandong First Medical University & Shandong Academy of Medical Sciences [202201-039].