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Amuc_1100 pretreatment alleviates acute pancreatitis in a mouse model through regulating gut microbiota and inhibiting inflammatory infiltration

Acta Pharmacologica Sinica volume 45, pages 570–580 (2024)Cite this article

Abstract

Amuc_1100 is a membrane protein from Akkermansia muciniphila, which has been found to play a role in host immunological homeostasis in the gastrointestinal tract by activating TLR2 and TLR4. In this study we investigated the effects and underlying mechanisms of Amuc_1100 on acute pancreatitis (AP) induced in mice by intraperitoneal injection of caerulein and lipopolysaccharide (LPS). The mice were treated with the protein Amuc_1100 (3 μg, i.g.) for 20 days before caerulein injection. Cecal contents of the mice were collected for 16S rRNA sequencing. We found that pretreatment with Amuc_1100 significantly alleviated AP-associated pancreatic injury, reduced serum amylase and lipase. Amuc_1100 pretreatment significantly inhibited the expression of proinflammatory cytokines (TNF-α, IL-1β, IFN-γ and IL-6) in spleen and pancreas through inhibiting NF-κB signaling pathway. Moreover, Amuc_1100 pretreatment significantly decreased the inflammatory infiltration, accompanied by the reduction of Ly6C+ macrophages and neutrophils in the spleen of AP mice. Gut microbiome analysis showed that the abundance of Bacteroidetes, Proteobacteria, Desulfobacterota and Campilobacterota was decreased, while the proportion of Firmicutes and Actinobacteriota was increased in AP mice pretreated with Amuc_1100. We further demonstrated that Amuc_1100 pretreatment restored the enrichment of tryptophan metabolism, which was mediated by intestinal flora. These results provide new evidence that Amuc_1100 lessens the severity of AP through its anti-inflammatory properties with a reduction of macrophages and neutrophil infiltration, as well as its regulation of the composition of intestinal flora and tryptophan metabolism.

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Fig. 1: Amuc_1100 treatment protected against pancreatic degradation of AP mice.
Fig. 2: Supplementation with Amuc_1100 improved AP induced by caerulein and LPS.
Fig. 3: The effect of Amuc_1100 on macrophage and neutrophil infiltration in AP mice.
Fig. 4: Bacterial abundance and community composition differences across control, AP, and AP+Amuc_1100 groups.
Fig. 5: Metabolic profiling of serum in mice.
Fig. 6: AP-associated genera correlate with metabolites which differentiate mice with AP and Amuc_1100 intervention.
Fig. 7: The effect of Amuc_1100 on Trp metabolism in the serum, feces and pancreas of mice with AP.

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Acknowledgements

The authors acknowledge the science and technology experiment center in Nanjing University of Chinese Medicine for flow cytometry.

Funding

This project was financially supported by the National Natural Science Foundations of China (No. 32270192 and 82072240), the Open Funding Project of the State Key Laboratory of Bioreactor Engineering, the Open Project of the State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences (No. SIMM2205KF-15), the Open Project of Chinese Materia Medica First-Class Discipline of Nanjing University of Chinese Medicine (No. 2020YLXK008), the Natural Science Foundation of Jiangsu Province of China (BK20230064 to WL), the Fok Ying Tung Education Foundation (No. 171033 to WL), high level key discipline construction project of the National Administration of Traditional Chinese Medicine-Resource Chemistry of Chinese Medicinal Materials (No. zyyzdxk-2023083 to WL).

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  1. These authors contributed equally: Li-juan Wang, Yuan-ling Jin, Wen-long Pei

Authors and Affiliations

  1. Department of Pathogen Biology, School of Medicine and Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing, 210023, China

    Li-juan Wang, Yuan-ling Jin, Jia-cong Li, Rui-lin Zhang, Jia-ju Wang & Wei Lin

  2. Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, 211166, China

    Wen-long Pei

  3. State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai, 200237, China

    Wei Lin

  4. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China

    Wei Lin

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Contributions

WL and LJW directed the research and wrote the manuscript. LJW designed the experiments and WLP analyzed the data. YLJ carried out most of the experiments. JCL helped with raising mice. HE staining was carried out by RLZ. JJW performed some Western blot experiments.

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Correspondence to Li-juan Wang or Wei Lin.

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Wang, Lj., Jin, Yl., Pei, Wl. et al. Amuc_1100 pretreatment alleviates acute pancreatitis in a mouse model through regulating gut microbiota and inhibiting inflammatory infiltration. Acta Pharmacol Sin 45, 570–580 (2024). https://doi.org/10.1038/s41401-023-01186-4

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