Mucin O-glycan-microbiota axis orchestrates gut homeostasis in a diarrheal pig model

Abstract

Background Post-weaning diarrhea in piglets reduces growth performance and increases mortality, thereby causing serious economic losses. The intestinal epithelial cells and microbiota reciprocally regulate each other in order to maintain intestinal homeostasis and control inflammation. However, a relative paucity of research has been focused on the host-derived regulatory network that controls mucin O-glycans and thereby changes gut microbiota during diarrhea in infancy. At the development stage just after birth, the ontogeny of intestinal epithelium, immune system, and gut microbiota appear similar in piglets and human infants. Here, we investigated the changes of mucin O-glycans associated with gut microbiota using a diarrheal post-weaned piglet model. Results We found that diarrhea disrupted the colonic mucus layer and caused aberrant mucin O-glycans, including reduced acidic glycans and truncated glycans, leading to an impaired gut microenvironment. Subsequently, the onset of diarrhea, changes in microbiota and bacterial translocation, resulting in compromised epithelial barrier integrity, enhanced susceptibility to inflammation, and mild growth faltering. Furthermore, we found the activation of NLRP3 inflammasome complexes in the diarrheal piglets when compared to the healthy counterparts, triggered the release of proinflammatory cytokines IL-1β and IL-18, and diminished autophagosome formation, specifically the defective conversion of LC3A/B I into LC3A/B II and the accumulation of p62. Additionally, selective blocking of the autophagy pathway by 3-MA led to the reduction in goblet cell-specific gene transcript levels in vitro. Conclusions We observed that diarrheal piglets exhibited colonic microbiota dysbiosis and mucosal barrier dysfunction. Our data demonstrated that diarrhea resulted in the activation of inflammasomes and autophagy restriction along with aberrant mucin O-glycans including reduced acidic glycans and truncated glycans. The results suggested the mucin O-glycans-microbiota axis is likely associated with diarrheal pathogenesis. Our study provides novel insights into the pathophysiology of early-weaning-induced diarrheal disease in piglets and potentially understanding of disease mechanisms of diarrhea for human infants. Understanding the molecular pathology and pathogenesis of diarrhea is a prerequisite for the development of novel and effective therapies. Our data suggest that facilitating O-glycan elongation, modifying the microbiota, and developing specific inhibitors to some key inflammasomes could be the options for therapy of diarrhea including human infants. Graphical abstract

Long-term chemically protected sodium butyrate supplementation in broilers as an antibiotic alternative to dynamically modulate gut microbiota

“…Concentrations of SCFA in cecal contents were measured using gas chromatography ( GC ) based on our previous study ( Xia et al, 2022 ). Briefly, cecal digesta was weighed into 1.5-mL centrifuge tubes and mixed with 1 mL ddH 2 O, homogenized, and centrifuged (10,000 rpm, 10 min, 4°C).…”

Mucin alleviates colonic barrier dysfunction by promoting spermine accumulation through enhanced arginine metabolism in Limosilactobacillus mucosae

“…Previous studies have reported that mucin O-glycans can influence the physiological behavior of microbes, including surface attachment, suppression of virulence genes, and regulation of quorum sensing signals ( 11 , 12 , 59 ). Given the complexity and diversity of mucin glycans and dynamic glycosylation changes based on different developmental stages, we posited that the presentation of complex mucin in the intestinal mucus contributes to a healthy mucosal environment, whereas degradation or modification of mucin may trigger Lactobacillus to transition arginine metabolism and further reduce its abundance ( 60 , 61 ). Based on our current experimental results, it is evident that this study did not identify the specific genes regulated by mucin in the activation of spermine metabolism in L. mucosae .…”

Probiotic Pediococcus pentosaceus restored gossypol-induced intestinal barrier injury by increasing propionate content in Nile tilapia

“…Dietary components and xenobiotics have the adverse effects on the intestinal health [ 46 – 48 ]. Gossypol, a toxic compound contained in CSM, has detrimental effects on the growth condition, intestinal immunity and barrier barrier integrity in various animals, how to decrease the deleterious effects of gossypol residue remains to be expolored [ 13 , 17 , 19 – 22 ].…”