Background Salivary agglutinin, also known as deleted in malignant brain tumors 1 (DMBT1), is an anti-microbial protein. DMBT1 is low in saliva from patients with oral squamous cell carcinoma (OSCC) and dramatically increases after treatment, with accompanying microbial changes. While this suggests an association between DMBT1 suppression and changes in the oral microbiota, causation has not been established. DMBT1 is also a tumor suppressor protein; its loss promotes OSCC progression, but its role in OSCC development is unknown. In this study, OSCC development was investigated in a murine carcinogen model that simulates human OSCC. Microbiota were standardized between Dmbt1 knockout (Dmbt1−/−) and wild-type (Dmbt1+/+) mice via interbreeding and co-housing. Saliva was collected at baseline and at 4, 8, 12, 16, and 22 weeks post-carcinogen initiation (stopped at 16 weeks). Tongues were harvested at week 22 for histopathology, and the salivary microbiome was profiled by 16S rRNA sequencing. Microbial diversity metrics and conditional dependence networks assessed community structure, while longitudinal patterns were analyzed using a locally sparse varying coefficient mixed model and functional principal component analysis (fPCA). Results Despite microbiota standardization, Dmbt1−/− and Dmbt1+/+ displayed differences in microbiome composition based on β-diversity metrics. At endpoint, carcinogen-treated Dmbt1−/− showed higher OSCC prevalence and more aggressive invasion than Dmbt1+/+. Several OTUs, including those from Lachnospiraceae, Sphingomonas, Carnobacteriaceae, and Candidatus Saccharibacteria families, demonstrated differential abundance patterns over time, either genotype-specific, diagnosis-specific, or both. Notably, Sphingomonas and Lachnospiraceae exhibited time-dependent abundance differences in mice that developed OSCC. fPCA identified taxa with abundance trajectories that were different between OSCC and precancer and genotype specific. Conclusions Thus, DMBT1 shapes salivary microbiota composition and protects against OSCC development. Dynamic, genotype-specific microbial shifts during carcinogenesis underscore the complex interplay between the oral microbiota and cancer progression. <MediaObject ID="MOESM2"> <VideoObject FileRef="MediaObjects/40168_2026_2337_MOESM2_ESM.mp4" VideoID="52sTgPoWwfY7A3YogZ1rT1"> <Caption Language="En" xml:lang="en"> <CaptionContent> Video Abstract </CaptionContent> </Caption> </VideoObject> </MediaObject> Graphical Abstract

Loss of salivary agglutinin induces changes in the salivary microbiome and accelerates development of oral cancer

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2026年4月10日

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Marcell Costa de Medeiros,
Simon Fontaine,
Erika Danella,
Ethan Hillman,
Thomas M. Schmidt,
Allison Furgal,
Deneen M. Wellik,
Naohiro Inohara,
Gabriel Núñez,
Gen Li,
Grace Y. Chen,
Nisha J. D’Silva

摘要

Background

Salivary agglutinin, also known as deleted in malignant brain tumors 1 (DMBT1), is an anti-microbial protein. DMBT1 is low in saliva from patients with oral squamous cell carcinoma (OSCC) and dramatically increases after treatment, with accompanying microbial changes. While this suggests an association between DMBT1 suppression and changes in the oral microbiota, causation has not been established. DMBT1 is also a tumor suppressor protein; its loss promotes OSCC progression, but its role in OSCC development is unknown. In this study, OSCC development was investigated in a murine carcinogen model that simulates human OSCC. Microbiota were standardized between Dmbt1 knockout (Dmbt1^−/−) and wild-type (Dmbt1^+/+) mice via interbreeding and co-housing. Saliva was collected at baseline and at 4, 8, 12, 16, and 22 weeks post-carcinogen initiation (stopped at 16 weeks). Tongues were harvested at week 22 for histopathology, and the salivary microbiome was profiled by 16S rRNA sequencing. Microbial diversity metrics and conditional dependence networks assessed community structure, while longitudinal patterns were analyzed using a locally sparse varying coefficient mixed model and functional principal component analysis (fPCA).

Results

Despite microbiota standardization, Dmbt1^−/− and Dmbt1^+/+ displayed differences in microbiome composition based on β-diversity metrics. At endpoint, carcinogen-treated Dmbt1^−/− showed higher OSCC prevalence and more aggressive invasion than Dmbt1^+/+. Several OTUs, including those from Lachnospiraceae, Sphingomonas, Carnobacteriaceae, and Candidatus Saccharibacteria families, demonstrated differential abundance patterns over time, either genotype-specific, diagnosis-specific, or both. Notably, Sphingomonas and Lachnospiraceae exhibited time-dependent abundance differences in mice that developed OSCC. fPCA identified taxa with abundance trajectories that were different between OSCC and precancer and genotype specific.

Conclusions

Thus, DMBT1 shapes salivary microbiota composition and protects against OSCC development. Dynamic, genotype-specific microbial shifts during carcinogenesis underscore the complex interplay between the oral microbiota and cancer progression.

Video Abstract

Graphical Abstract