Oral microbiota : aspects on pathogenesis of liver and pancreas diseases

Oral microbiome is regarded as a complex ecological community consisting of different bacteria, archaea, and viruses, dedicated to not only the health of the oral cavity but also to the whole system. Altered oral microbiome is associated with many systemic inflammation and diseases, especially in the gastrointestinal system, including oral infection, pancreas diseases, and liver dysfunction. This thesis focused primarily on the role of the oral microbiome in different diseases in the gastrointestinal system to investigate the cross-talk between the host immune system and the oral microbial community.

In paper I, a cohort study was performed to investigate the interaction between humoral immunity to pancreas-associated oral microbes and Intraductal papillary mucinous neoplasms (IPMNs), a cystic precursor to pancreatic cancer (PC). Our findings indicated that humoral reactivity against pancreas-associated oral microbes, Fusobacterium Nucleatum (F. Nucleatum) could reflect IPMN severity, and validate the possible binding sites of this oral pathogen, which are beneficial for biomarker development to identify the phase of IPMN and spot the potential risk in the progression to PC.

In paper II, we studied the Mucosal-associated invariant T (MAIT) cells, one of the subsets of innate-like T cells, in a classic oral infectious disease - apical periodontitis (AP) and the involvement of MAIT cells in the local defense at the oral tissue barrier. The novel and optimized methods described the presence of MAIT cells at the site of AP lesion in the oral cavity where the translocation of oral microbiota could take place, and bacteria relative abundance was observed to be negatively correlated with MAIT cell T cell receptor (TCR) transcript expressions in AP, which deepen the understanding the immune sensing of polymicrobial-related oral diseases.

In paper III, we described the oral dysbiosis observed in alcoholic liver disease (ALD) patients with liver injury and established an animal model of ALD to investigate the role and mechanism of Porphyromonas gingivalis (P. gingivalis), a keystone pathogen for periodontitis, in the advancement of this diseases. P. gingivalis was observed to aggravate the hepatic steatosis and inflammation cell infiltration in vivo and demonstrated to induce the ferroptosis in human fetal hepatocyte line in vitro. Our findings showed that P. gingivalis was a promoter that could aggravate the pathogenesis of ALD via ferroptosis, suggesting that periodontal disease treatment and oral microbial control in ALD patients accompanied by ferroptosis inhibition may be a potential treatment in the future.

In paper IV, we investigated the oral bacterial community in patients diagnosed with chronic hepatitis B (CHB), focusing on those with well-controlled liver function who were not receiving antiviral treatment. We characterized their oral microbiota composition and assessed their oral health status. Our findings underscore the importance of the oral microbiome in the context of viral hepatitis, suggesting that maintaining oral health could serve as a beneficial adjunctive strategy in managing liver diseases.

List of scientific papers

I. Hassan Alkharaan, Liyan Lu, Giorgio Gabarrini, Asif Halimi, Zeeshan Ateeb, Michał J. Sobkowiak, Haleh Davanian, Carlos Fernández Moro, Leif Jansson, Marco Del Chiaro, Volkan Özenci, Margaret Sällberg Chen. Circulating and Salivary Antibodies to Fusobacterium nucleatum Are Associated with Cystic Pancreatic Neoplasm Malignancy. Front Immunol. 2020;11:2003.
https://doi.org/10.3389/fimmu.2020.02003

II. Haleh Davanian, Rogier Aäron Gaiser, Mikael Silfverberg, Luisa W. Hugerth, Michał J. Sobkowiak, Liyan Lu, Katie Healy, Johan K. Sandberg, Peggy Näsman, Jörgen Karlsson, Leif Jansson, Lars Engstrand, Margaret Sällberg Chen. Mucosal-associated invariant T cells and oral microbiome in persistent apical periodontitis. Int J Oral Sci. 2019;11(2):16.
https://doi.org/10.1038/s41368-019-0049-y

III. Chao Yao, Liyan Lu, Dongmei Lan, Xueqin Zhu, Xue Li, Yaohui Gao, Yingqun Zhou, Yan Wang, Yuanzhi Xu, Shengcai Qi. Porphyromonas gingivalis as a promotor in the development of the alcoholic liver disease via ferroptosis. Microbes Infect. 2024;26(3):105250.
https://doi.org/10.1016/j.micinf.2023.105250

IV. Liyan Lu, Lingjun Yan, Amir Sohrab, Karin Lindahl, Susanne Cederberg, Raorao Wang, Weimin Ye, Soo Aleman, Margaret Sällberg Chen. The salivary microbiome and oral health status in HBeAg-negative chronic hepatitis B. [Accepted]