polygalacturonic-acid and Disease-Models--Animal

Enteric pathogens sense the complex chemistry within the gastrointestinal tract to efficiently compete with the resident microbiota and establish a colonization niche. Here, we show that enterohaemorrhagic Escherichia coli and Citrobacter rodentium, its surrogate in a mouse infection model, sense galacturonic acid to initiate a multi-layered program towards successful mammalian infection. Galacturonic acid utilization as a carbon source aids the initial pathogen expansion. The main source of galacturonic acid is dietary pectin, which is converted to galacturonic acid by the prominent member of the microbiota, Bacteroides thetaiotamicron. This is regulated by the ExuR transcription factor. However, galacturonic acid is also sensed as a signal through ExuR to modulate the expression of the genes encoding a molecular syringe known as a type III secretion system, leading to infectious colitis and inflammation. Galacturonic acid acts as both a nutrient and a signal directing the exquisite microbiota-pathogen relationships within the gastrointestinal tract. This work highlights that differential dietary sugar availability influences the relationship between the microbiota and enteric pathogens, as well as disease outcomes.

Topics: Animals; Bacteroides thetaiotaomicron; Citrobacter rodentium; Diet; Disease Models, Animal; Enterobacteriaceae Infections; Enterohemorrhagic Escherichia coli; Escherichia coli Infections; Female; Gastrointestinal Microbiome; Genes, Bacterial; HeLa Cells; Hexuronic Acids; Host-Pathogen Interactions; Humans; Mice; Mice, Inbred C3H; Mice, Inbred C57BL; Pectins; Virulence

Dietary carbohydrate fibers are known to prevent immunological diseases common in Western countries such as allergy and asthma but the underlying mechanisms are largely unknown. Until now beneficial effects of dietary fibers are mainly attributed to fermentation products of the fibers such as anti-inflammatory short-chain fatty acids (SCFAs). Here, we found and present a new mechanism by which dietary fibers can be anti-inflammatory: a commonly consumed fiber, pectin, blocks innate immune receptors. We show that pectin binds and inhibits, toll-like receptor 2 (TLR2) and specifically inhibits the proinflammatory TLR2-TLR1 pathway while the tolerogenic TLR2-TLR6 pathway remains unaltered. This effect is most pronounced with pectins having a low degree of methyl esterification (DM). Low-DM pectin interacts with TLR2 through electrostatic forces between non-esterified galacturonic acids on the pectin and positive charges on the TLR2 ectodomain, as confirmed by testing pectin binding on mutated TLR2. The anti-inflammatory effect of low-DM pectins was first studied in human dendritic cells and mouse macrophages

Topics: Animals; Diet, Western; Dietary Fiber; Disease Models, Animal; Doxorubicin; Esterification; Fatty Acids, Volatile; Female; HEK293 Cells; Hexuronic Acids; Humans; Ileitis; Mice; Mice, Inbred C57BL; Pectins; Signal Transduction; Toll-Like Receptor 1; Toll-Like Receptor 2