Synthetic glycans control gut microbiome structure and mitigate colitis in mice

Abstract

Relative abundances of bacterial species in the gut microbiome have been linked to many diseases. Species of gut bacteria are ecologically differentiated by their abilities to metabolize different glycans, making glycan delivery a powerful way to alter the microbiome to promote health. Here, we study the properties and therapeutic potential of chemically diverse synthetic glycans (SGs). Fermentation of SGs by gut microbiome cultures results in compound-specific shifts in taxonomic and metabolite profiles not observed with reference glycans, including prebiotics. Model enteric pathogens grow poorly on most SGs, potentially increasing their safety for at-risk populations. SGs increase survival, reduce weight loss, and improve clinical scores in mouse models of colitis. Synthetic glycans are thus a promising modality to improve health through selective changes to the gut microbiome.

Modulation of the Gut Microbiome by Novel Synthetic Glycans for the Production of Propionate and the Reduction of Cardiometabolic Risk Factors

“…KB39 (average MW = 2260 g/mol) is composed of D-galactose and D-mannose (60/40 ratio) with complex distribution of glycosidic bonds linking the monosaccharides (Figure S2). The linkage and extensive branching contrast with known naturally occurring dietary fibers 31 .…”

“…A library of hundreds of synthetic glycans with diverse monosaccharide composition, bond type, branching, and degrees of polymerization was produced as previously described 31 , of which 593 compounds (Figure S1) were screened for their ability to promote propionate production in a semi-automated ex vivo fermentation assay using the fecal microbiota from a healthy human subject. While propionate could be identified in the culture supernatants, there was a wide-range of concentrations, with some glycans supporting 10-fold higher propionate production than others (Figure 1A).…”

“…However, in general, fibers as therapeutics are not chosen by rational design, selection or optimized to serve a specific function. In this study, we used an ex vivo fecal fermentation platform to screen a library of hundreds of novel synthetic and well-characterized glycans 31 for propionate production from which we identified KB39 as a high propionate-producing glycan. We also found that in vivo , KB39 promotes propionate production and the enrichment of propiogenic bacterial taxa and has beneficial effects on blood lipids and insulin, and preventing liver steatosis and inflammation as well as atherosclerosis in Ldlr -/- mice fed a high fat, high cholesterol western diet.…”

P2X4 receptor modulates gut inflammation and favours microbial homeostasis in colitis

“…As an intricate ecosystem, the gut has a large and diverse microbial community known as the gut microbiota. 17 , 18 The human gut microbiota contains probiotics and pathogenic bacteria that coexist harmoniously in a healthy body. However, this balance can be disrupted by abnormal environmental factors and genetic variations.…”

Tuning of Gene Expression in Clostridium phytofermentans Using Synthetic Promoters and CRISPRi

“…For example, the Clostridia are Gram-positive, anaerobic, spore-forming bacteria with important roles in industry and health. Clostridia include species that transform plant biomass or carbon dioxide into value-added chemicals, intestinal commensals that metabolize dietary fiber to produce health-promoting metabolites, and important pathogens. − Clostridium phytofermentans (also called Lachnoclostridium phytofermentans) is a member of the family Lachnospiraceae that is distinguished by its ability to ferment lignocellulosic biomass with ethanol, hydrogen, and acetate as major products. , …”