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Introduction: Smoking and unhealthy diet (SCUD) are risk factors involved in chronic obstructive pulmonary disease or obesity. Our aim is to better describe the impact of cigarette smoke (CS), associated with High Fat Diet (HFD), on pulmonary, intestinal and metabolic homeostasis and to identify physiopathologic mechanisms. Methods: C57Bl6 mice were subjected for 18 weeks to a HFD at 45% Kcal vs Low Fat Diet (LFD) at 10% Kcal. After 4 weeks, mice were exposed to CS or to filtered air. Lung function, anatomic, inflammatory and immune alterations as well as multi-omics studies were performed in these compartments. Results: SCUD revealed cumulative effect on the lung, with emphysema, tissues damage and immune cell recruitment. HFD induced weight gain, insulin resistance and glucose intolerance whereas CS limited these negative effects. However, SCUD induced visceral fat accumulation and inflammation vs HFD alone, associated with a specific metabolomics signature in the serum. Transcriptome analysis essentially revealed a HFD-related signature. Colon damage was moderate. However, metagenomics and metabolomics analyses in the caecum showed a specific signature due to SCUD, associated with some modifications in the colon transcriptoma. Conclusion: These results identify SCUD impacts on lung, metabolic and intestinal functions and reveal specific signatures related to combined exposure to unhealthy diet and CS. Bioinformatic analysis is ongoing to decipher the interactions between these compartments. These data will also allow to identify targets for preventive/therapeutic tools controling lung, intestinal and metabolic disorders due to SCUD.

Background: Cigarette smoking (CS) and obesity are leading causes of morbidity and mortality worldwide and are frequently associated. Both behaviors provoke inflammation and induce lung, metabolic, intestine and cardiovascular dysfunctions leading to e.g. chronic obstructive pulmonary disease and metabolic syndrome. However, the effect of combined exposure is not well unraveled. Objectives: We aimed to define the effect of combined exposure to CS and high fat diet (HFD) on the cardiovascular, metabolic, respiratory and intestinal functions. Moreover, we evaluate if smoking cessation may limit the dysfunctions due to this exposure. Methods: C57BL6 mice were exposed to 4 weeks of HFD followed by 12 weeks of combined exposure to CS and HFD. Then, some mice were submitted to CS cessation during 8 weeks. Metabolic, immunological and inflammatory parameters were evaluated. Results: Conjugated exposure increases lung inflammatory cell recruitment and activation as well as tissue lesions compared with exposure to CS and HFD alone. CS limits the body weight, affects adipose tissue repartition and reduces HFD-induced glucose intolerance. CS/HFD combination leads to cardiomyocyte hypertrophy. CS decreases colonic inflammation and the number of commensal bacteria in the caecum. Smoking cessation was not able to reverse these effects. Conclusion: Our murine model reproduced the human situation. While combined exposure leads to strong cardiovascular and lung dysfunctions, it had a mild impact on metabolic and intestinal compartment. In this context, CS cessation is not able to reverse the lesions related to combined exposure. We will now focus on the role of oxidative stress on these effects.