Dietary Fucose Affects Macrophage Polarization and Reproductive Performance in Mice

Abstract

Intestinal mucus protects epithelial and immune cells from the gut resident microorganisms, and provides growth-promoting factors as mucus-derived O-glycans for beneficial bacteria. A lack of intestinal protective mucus results in changes in the commensal microflora composition, mucosal immune system reprogramming, and inflammation. Previous work has shown that fucose, the terminal glycan chain component of the intestinal glycoprotein Mucin2, and fucoidan polysaccharides have an anti-inflammatory effect in some mouse models of colitis. This study evaluates the effect of fucose on reproductive performance in heterozygous mutant Muc2 female mice. We found that even though Muc2+/− females are physiologically indistinguishable from C57Bl/6 mice, they have a significantly reduced reproductive performance upon dietary fucose supplementation. Metagenomic analysis reveals that the otherwise healthy wild-type siblings of Muc2−/− animals have reduced numbers of some of the intestinal commensal bacterial species, compared to C57BL/6 mice. We propose that the changes in beneficial microflora affect the immune status in Muc2+/− mice, which causes implantation impairment. In accordance with this hypothesis, we find that macrophage polarization during pregnancy is impaired in Muc2+/− females upon addition of fucose. Metabolic profiling of peritoneal macrophages from Muc2+/− females reveals their predisposition towards anaerobic glycolysis in favor of oxidative phosphorylation, compared to C57BL/6-derived cells. In vitro experiments on phagocytosis activity and mitochondrial respiration suggest that fucose affects oxidative phosphorylation in a genotype-specific manner, which might interfere with implantation depending on the initial status of macrophages. This hypothesis is further confirmed in BALB/c female mice, where fucose caused pregnancy loss and opposed implantation-associated M2 macrophage polarization. Taken together, these data suggest that intestinal microflora affects host immunity and pregnancy outcome. At the same time, dietary fucose might act as a differential regulator of macrophage polarization during implantation, depending on the immune status of the host.

L-fucose reduces gut inflammation due to T-regulatory response in Muc2 null mice

“…However, in our previous study, L-fucose improved inflammation neither in acute, nor in chronic DSS-induced colitis [27]. In our previous work we showed the importance of the immune context for the effect of L-fucose on macrophage polarization and pregnancy outcome: two prototypical mouse strains with Th1-and Th2-type of immune response demonstrated the opposite effect of L-fucose treatment [17]. These data suggest that L-fucose effects on inflammation are highly dependent on the current immune state and microenvironment which in in vivo context includes immune-system-microflora interactions.…”

“…Being the terminal glycan chain component of the glycoprotein Mucin2, orally administered L-fucose could play an important role in modulation of intestine microenvironment in Mucin2-deficient mice. L-fucose has been shown to inhibit macrophage M1 polarization [16,17]. The resolution of intestinal inflammation and mucosal healing is under the control of local macrophages which are divided into two categories: inflammatory recruited macrophages differentiated from monocytes which migrate to the cite of inflammation (M1 type) and resident macrophages with tolerant phenotype which produce anti-inflammatory cytokines such as IL-10 and TGF-β (M2 type).…”

Hepatopancreas Proteomic Analysis Reveals Key Proteins and Pathways in Regulatory of Ovary Maturation of Macrobrachium nipponense

“…The only enriched DEP was alpha-(1,6)-fucosyltransferase, which involved in the synthesis of active ribose, providing raw materials for the formation of precursor sugar nucleotides and participating in the synthesis and assembly of fucose [ 37 ]. Recent research has highlighted the involvement of fucose in reproductive performance in mice [ 38 ]. These findings further suggested that carbohydrate metabolism had a crucial part in oogenesis in M. nipponense and was perhaps major source of energy.…”

Fucose as a potential therapeutic molecule against the immune-mediated inflammation in IgA nepharopathy: An unrevealed link

“…Furthermore, fucose plays an important role in immunoregulation of renal disease by reducing the deposition of complement C3 on renal tubules and infiltration of immune cells ( 49 ), which is beneficial to the therapeutic intervention of IgAN ( 50 ). Moreover, the activation of macrophage can be inhibited by fucose, and it is an important regulator of intestinal mucosal immunity ( 51 ). Fucose plays a critical role in mucosal immunity through its immunocompetence of anti-infection and anti-inflammation ( 52 ), which is of great significance to prevent the occurrence and progression of IgAN from the pathogenesis.…”