Figure 2.

Examples of mechanisms mediating host–microbiota interactions. A diverse microbiota provides two signals for NLRP6 inflammasome activation in intestinal epithelial cells: signal 1 is in the form of LPS, and signal 2 is in the form of metabolites such as the bile-acid conjugate taurine. Together, these signals activate the NLRP6 inflammasome in intestinal epithelial cells and lead to the production of epithelial IL-18 and downstream antimicrobial peptides (AMP). Under dysbiotic conditions, such as those in mice lacking the inflammasome adaptor ASC, microbiota-derived histamine, putrescine and spermine are increased, thus suppressing NLRP6 inflammasome signaling in intestinal epithelial cells, decreasing production of epithelial IL-18 and AMP in the colon and promoting intestinal inflammation⁷⁰. B. thetaiotamicron induces the transcription factor HIF-1α in intestinal epithelial cells, thereby activating transcription and production of the antimicrobial peptide LL-37 (CRAMP in mice), which in turn promotes resistance to C. albicans colonization52. Gut anaerobic Firmicutes from the class Clostridia, and several clusters in Gram-negative Bacteroides and Desulfovibrio, express nonribosomal peptide synthetase–encoding gene clusters that mediate the synthesis of dipeptide aldehydes⁷⁹. The dipeptide aldehyde Phe-Phe-H is cell permeable and has been shown to inhibit cathepsins in macrophages, an activity that might modulate antigen processing and innate immune function⁷⁹. The generation of the nonproteinogenic amino acid trans-4-hydroxy-L-proline (t4L Hyp) is one of the most common post-translational modifications in eukaryotic cells but is rare in bacteria. Intestinal commensals such as Clostridiales and human pathogens such as C. difficile chemically reverse proline hydroxylation through the activity of the GRE trans-4-hydroxy-L-proline dehydratase, which generates L-proline⁷⁷. Many Clostridiales then use L-proline as an electron acceptor in amino acid fermentation.