From Bile Acids to a Gas-Producing Microbiome Phenotype: A Novel Mechanism of Host–Microbiome Communication
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Background
Microbiome-derived metabolites regulate host physiology, yet bacterial gaseous metabolites remain largely overlooked. Traditionally regarded as fermentation end-products, bacterial gases may act as biologically active mediators of host–microbiome communication. We hypothesized that bile acids regulate bacterial gaseous metabolism and influence host epithelial responses.
Methods
A high gas-producing clinical Escherichia coli isolate from a patient with moderately severe acute pancreatitis was cultured with selected primary and secondary bile acids. Gas production was assessed by pressure measurements, GC–TCD and GC–MS. Biological activity was evaluated by indirect exposure of Caco-2 and PANC-1 epithelial cells, followed by apoptosis/necrosis assays and whole-transcriptome RNA sequencing.
Results
Bile acids markedly reshaped bacterial gaseous metabolism. Cholic acid and deoxycholic acid promoted intense gas production, whereas chenodeoxycholic acid almost completely abolished it. Despite minimal apoptosis and necrosis, bacterial gaseous metabolites induced extensive transcriptional remodeling. Caco-2 cells showed stronger responses than PANC-1 cells, particularly to deoxycholic acid-derived gases, involving inflammatory signaling, extracellular matrix remodeling, epithelial plasticity, stress responses, and cancer-associated genes including PTGS2, MMP1, PLAUR, NR4A2 , and SERPINE1 . PANC-1 cells exhibited a more restricted response involving oxidative stress, proteostasis, and autophagy-associated pathways.
Conclusions
Our findings indicate that bacterial gases are a previously underrecognized class of microbiome-derived signaling molecules capable of modulating host gene expression independently of direct bacterial contact. We identify a gas-producing microbiome phenotype regulated by bile acid composition, linking microbial metabolism with epithelial signaling. These findings expand the concept of host–microbiome communication and provide a framework for investigating bacterial gaseous metabolites in intestinal and pancreatic diseases.
Importance
The gut microbiome produces numerous substances that can influence human health, but most research has focused on soluble metabolites such as short-chain fatty acids and bile acid derivatives. Bacterial gases, including hydrogen and carbon dioxide, have largely been considered metabolic waste products. Our study shows that this view may be incomplete. We demonstrate that bile acids can substantially change the amount and composition of gases produced by Escherichia coli , and that these bacterial gases can alter gene activity in human intestinal and pancreatic cells without direct bacterial contact. These findings identify bacterial gaseous metabolites as a previously underrecognized component of microbiome– host communication and suggest that differences in bacterial gas production may contribute to variation in epithelial responses along the gastrointestinal tract.
