Associate Professor of Surgery University of Alabama Vestavis, Alabama, United States
Disclosure: I do not have any relevant financial / non-financial relationships with any proprietary interests.
Participants should be aware of the following financial/non-financial relationships:
Tejeshwar Jain, MBBS: I do not have any relevant financial / non-financial relationships with any proprietary interests.
Introduction: Cigarette smoke is a major cancer risk factor, however, there is a dearth of clinically actionable targets. Smoking is known to alter the gut microbiome and gut microbiome has been linked to cancer progression. Herein, we evaluate gut microbiome-targeting as a potential therapy against smoking-induced cancer progression.
Methods: C57BL/6J mice were randomized to room air (controls)/cigarette smoke exposure (CSE) for 4 weeks. Gut microbiome and metabolome were analyzed using 16s rRNA sequencing and untargeted LC-MS metabolomics, respectively. To confirm the tumorigenic potential of CSE gut microbiome, fecal matter from control or CSE mice was transplanted (FMT) into C57BL/6J mice followed by subcutaneous KPC pancreatic cancer implantation. Tumors were immunophenotyped by flow cytometry. To evaluate the role of adaptive immune system, FMT experiment was repeated in Rag1 knockout mice. To evaluate therapeutic potential of gut microbial targeting, control or CSE mice were further randomized to receive oral gavage with saline or broad-spectrum non-absorbable antibiotics followed by KPC tumor implantation
Results: CSE led to significantly altered beta diversity and differential species enrichment of the gut microbiome, while the gut metabolome was also severely dysregulated, dominated by alterations in the arachidonic acid pathway metabolites. FMT from CSE mice was sufficient to drive increased tumor growth in recipient mice when compared to FMT from control mice. Immunophenotyping of tumors revealed decreased CD8+ T cell as well as increased CD11b+Ly6G+ MDSC infiltration in CSE FMT mice. CSE FMT was unable to promote tumor growth in Rag1 KO mice, suggesting that this effect is dependent on a functional adaptive immune system. Finally, gut microbiome ablation of CSE mice with broad spectrum antibiotics led to inhibition of smoking-induced tumor growth as well stimulation of anti-tumor immunity with increased CD8+ T-cell infiltration and decreased MDSCs
Conclusions: Cigarette smoke induces severe alterations in the gut microbiome and metabolome, which can drive tumor progression. Gut microbiome can emerge as a novel biological target to ameliorate smoking-induced tumor growth
Learning Objectives:
Upon completion, participant will be able to understand the role of gut microbiome as a novel therapy against cigarette smoking induced cancer progression
Upon completion, participant will be able to get an introduction about preclinical models to study the gut microbiome
Upon completion, participant will be able to get a preliminary understanding of gut microbiome analysis techniques such as 16s rRNA sequencing and LC-MS metabolomics
