Bacterial Processing of Glycans
Dietary carbohydrates are essential for the gut microbiota201. Many gut commensals have carbohydrate-active enzymes (CAZymes), which facilitate the processing of a range of glycans (Fig. 1G)202,203. CAZymes vary among individuals depending on factors such as age and geography204. Differential glycan preferences are exhibited by the various microbes found in the gut, resulting in diverse metabolism203. For example, Bacteroidetes thetaitaomicron, B. fragilis, and Ruminococcus torques can break down molecules such as mucin163,205,206. B .thetaitaomicron can metabolize L-fucose as an energy source and induce host FUTs to increase mucosal fucosylation, creating a beneficial environment for itself62,207. Additionally, B .thetaitaomicron can help increase sialic acid-carrying glycan expression208. Bacterial exoglycosidases release monosaccharide residues from mucin for the bacteria to use as an energy source under homeostatic conditions (Fig. 1G)209.
On the other hand, Bifidobacteria can break down human milk oligosaccharides (HMOs) to aid in their digestion, a process important for infants who lack the enzymatic capability to process HMOs210,211. Exposure to HMOs in breast milk in infancy helps Bifidobacteria to colonize the gut and help the host develop an immune tolerance towards commensal bacteria since HMOs act as a carbon source for the gut microbiota and host212. HMO metabolism is a virulence-suppressing process and is required to prevent the adhesion of pathogens to the intestinal epithelia as HMOs resemble epithelial surface glycans, allowing them to act as decoy receptors for bacteria (like E. coli and Vibrio cholerae ), and hence, preventing the attachment of the bacteria to the gut211,213. HMOs assert their anti-inflammatory effects by regulating interleukin production and lymphocyte activation. Additionally, sialylated HMOs can help maintain a Th1/Th2 balance214,215.
The process of dietary fiber fermentation by the gut microbiota starts with the breakdown of complex glycans into simpler sugars, which are then fermented by the intestinal anaerobic microorganisms (Fig. 1G). This fermentation process causes the production of short-chain fatty acids (SCFAs), which are absorbed from the colon to be used in numerous metabolic processes216,217. One such SCFA is butyrate. It is the preferred energy source of colonocytes, and it facilitates the maturation of the colonic mucus barrier218,219. However, deviations from its physiological concentrations may cause colon cancer220. Impaired butyrate oxidation is also evident in patients with ulcerative colitis (Fig. 2G)221. A low-fiber diet has been associated with reduced beneficial gut bacteria and increased risk for IBD222. Comparably, a high-fiber diet can promote an increase in the Prevotella genus, which has reduced colonization in individuals with low-fiber diets223,224. A high-fiber diet stimulates an increase in glycan metabolism by the gut bacteria and helps up-regulate SCFA production, thereby reducing inflammation225.
Due to its high glycan content, the mucus layer serves as a nutrient source for the inhabitant bacteria202. Mucin glycan utilization gives bacteria a consistent nutrient supply and helps the bacteria colonize the mucus layer226. In the hGM, due to their diverse CAZymes, Bacteroidetes are general glycan degraders that can use both dietary and host glycans (Fig. 1G)227. Bifidobacteria and Firmicutes genera show similar glycan degradation patterns since they both use carbohydrates with low levels of polymerization227.Akkermansia muciniphila is another important bacterial species that degrades mucus glycans into acetate to support butyrate-producing bacteria228,229. Conversely, A.muciniphila can show mucus thinning effects in low-fiber diets and dysbiosis230. Mucolytic bacteria can also generate SCFAs through fermentation. These SCFAs can be utilized by non-mucolytic bacteria or used by the host to recover the energy that was used in the mucin synthesis and secretion231. MUC2 expression can also be increased by SCFAs232.
Mucin degradation by bacteria is an essential process in establishing a stable microbiota168. The symbiotic relationship between the host and the microbiota relies on the microbes’ capabilities of host glycan digestion and the host’s ability to secrete mucin glycans for microbial stimuli17. If the dietary polysaccharides were to be depleted from the host’s diet, this would result in a significant shift to gut bacterial consumption of host mucus8. If the host has a low-fiber diet, this results in decreased microbial diversity and a shift in microbial composition to sole reliance on host mucus8,149. Increased reliance on host mucus eventually wears down the mucus barrier and causes an inevitable breach of the mucus layer, as observed in ulcerative colitis patients149. This data also supports the finding that the low fiber content in the Western diet leads to increased IBD prevalence149.