An orally active carbon monoxide-releasing molecule enhances beneficial gut microbial species to combat obesity in mice

Article Article scientifique Article An orally active carbon monoxide-releasing molecule enhances beneficial gut microbial species to combat obesity in mice eng 2024-04-09 2024-06 author Benrahla Djamal Eddine author Mohan Shruti author Trickovic Matija 967963 Département de physiologie cellulaire et métabolisme (PHYME) author Castelli Florence Anne author Alloul Ghida author Sobngwi Arielle author Abdiche Rosa author Kieser Silas 0000-0002-5935-9734 868273 author Demontant Vanessa author Trawinski Elisabeth author Chollet Céline author Rodriguez Christophe author Kitagishi Hiroaki author Fenaille François author Trajkovski Mirko 0000-0002-3152-9551 810468 Département de physiologie cellulaire et métabolisme (PHYME) author Motterlini Roberto 0000-0003-2684-2612 author Foresti Roberta 0000-0002-0836-7937 103153 10.1016/j.redox.2024.103153 38608580 2213-2317 PMC11025006 https://linkinghub.elsevier.com/retrieve/pii/S2213231724001290 Carbon monoxide (CO), a gaseous signaling molecule, has shown promise in preventing body weight gain and metabolic dysfunction induced by high fat diet (HFD), but the mechanisms underlying these effects are largely unknown. An essential component in response to HFD is the gut microbiome, which is significantly altered during obesity and represents a target for developing new therapeutic interventions to fight metabolic diseases. Here, we show that CO delivered to the gut by oral administration with a CO-releasing molecule (CORM-401) accumulates in faeces and enriches a variety of microbial species that were perturbed by a HFD regimen. Notably, Akkermansia muciniphila, which exerts salutary metabolic effects in mice and humans, was strongly depleted by HFD but was the most abundant gut species detected after CORM-401 treatment. Analysis of bacterial transcripts revealed a restoration of microbial functional activity, with partial or full recovery of the Krebs cycle, β-oxidation, respiratory chain and glycolysis. Mice treated with CORM-401 exhibited normalization of several plasma and fecal metabolites that were disrupted by HFD and are dependent on Akkermansia muciniphila’s metabolic activity, including indoles and tryptophan derivatives. Finally, CORM-401 treatment led to an improvement in gut morphology as well as reduction of inflammatory markers in colon and cecum and restoration of metabolic profiles in these tissues. Our findings provide therapeutic insights on the efficacy of CO as a potential prebiotic to combat obesity, identifying the gut microbiota as a crucial target for CO-mediated pharmacological activities against metabolic disorders. Administration, Oral Akkermansia / drug effects Animals Carbon Monoxide / metabolism Diet, High-Fat / adverse effects Disease Models, Animal Feces / microbiology Gastrointestinal Microbiome / drug effects Male Mice Mice, Inbred C57BL Obesity / drug therapy Obesity / metabolism Obesity / microbiology Dewey 612 Swiss National Science Foundation Integrative analysis of visceral adipose tissue browning 205042 CH Projects European Commission Microbiota-host interactions for integrative metabolic health reprogramming 815962 Healthybiota EU H2020 134 Département de physiologie cellulaire et métabolisme 21C false 724 Laboratory of metabolic diseases 934 Redox biology 72 2abd2d29-662a-431d-8c2f-45d48b3b028c Article (Published version) Public 1-s2.0-S2213231724001290-main_(1).pdf 11405605 application/pdf CC BY-NC-4.0 fe4661e64660143ebcc3240f0b82e56485c7bcb5671162cb8aecfbf803b5a1f0 714ecd8b-0d76-4dc5-be00-a5dca1a20fa5 Supplemental data Public ScienceDirect_files_11Sep2024_07-15.zip 5854472 application/zip f781ab80171230fabc51fd65c8de8e2913452c49d46812579e1b43bd954b9953 openAccess Faculté de médecine / Section de médecine fondamentale / Département de physiologie cellulaire et métabolisme

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An orally active carbon monoxide-releasing molecule enhances beneficial gut microbial species to combat obesity in mice	Redox biology			2024	36	6

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Trickovic, Matija