Dextran Sulfate

Akkermansia muciniphila has been proved to play a crucial role in the progression of colitis, but its underlying mechanism remains inconclusive. In this study, we aim to investigate the effect of A. muciniphila on the development of acute colitis and explore the underlying mechanism. We found that the fecal level of A. muciniphila was decreased in ulcerative colitis (UC) patients compared to the healthy people in the GMrepo database. Oral administration of A. muciniphila strain BAA-835 significantly ameliorated the symptoms in dextran sulfate sodium (DSS)-induced acute colitis, evidenced by decreased body weight loss, colon length shortening, and colon histological inflammatory score. In addition, the number of goblet cells and the mucin family were enhanced after A. muciniphila treatment. Furthermore, proinflammatory cytokines such as tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6), and monocyte chemoattractant protein 1 (MCP-1) had a downward trend. Mechanistically, the expression of NLRP3, caspase-1 p20, and IL-1β p17 were upregulated in A. muciniphila-treated mice. Additionally, the colon tissues from high-A. muciniphila UC patients had a higher NLRP3 expression than that from low-A. muciniphila UC patients. Moreover, the upregulation of NLRP3 was observed in mouse macrophage Raw264.7 cells and bone marrow-derived macrophage (BMDM) cells after incubation with A. muciniphila. To clarify whether the protective effect of A. muciniphila in colitis depends on NLRP3, we performed the NLRP3-deficient assay in NLRP3-/- mice in vivo. The evidence showed that NLRP3 deficiency eliminated the protective effects of A. muciniphila in acute colitis. In conclusion, A. muciniphila alleviates DSS-induced acute colitis by NLRP3 activation, which enriches the mechanism and provides a new prospect for the probiotic-based treatment of colitis. IMPORTANCE The gut microbiota and host immune response interaction influences the progression of intestinal inflammatory disease. As a well-recognized next-generation probiotic, Akkermansia muciniphila has been proved to play a crucial role in the progression of colitis, but its underlying mechanism remains inconclusive. We found that oral administration of A. muciniphila strain BAA-835 significantly ameliorated the symptoms of acute colitis. Mechanistically, the expression of NLRP3 was upregulated in the A. muciniphila group, and the protective effect of A. muciniphila in colitis depends on NLRP3 activation. This enriches the mechanism and provides a new prospect for the probiotic-based treatment of colitis, which would promote a deeper understanding of the complex characteristics of A. muciniphila and provide guidance for the treatment of human colitis in the future.

Macrophages are commonly classified as M1 macrophages or M2 macrophages. The M2 macrophages are further sub-categorized into M2a, M2b, M2c, and M2d subtypes. The M2a, M2b, and M2c subtypes play roles in anti-inflammatory activity, tissue remodeling, type 2 T helper cell (Th2) activation, and immunoregulation. Previous studies have shown that macrophage exosomes can affect some disease processes. Exosomes are 30-150-nm lipid bilayer membrane vesicles derived from most living cells, with important biological functions. The role of exosomes in preventing the development of autoimmune diseases, including inflammatory bowel disease (IBD), has evoked increasing interest. Here, we analyze the roles of exosomes derived from M2a, M2b, and M2c macrophage phenotypes in dextran sulfate sodium (DSS)-induced colitis. Exosomes were isolated from the supernatant of different types of macrophages and identified via transmission electron microscopy (TEM), western blotting, and NanoSight. The results showed that M2b macrophage exosomes significantly attenuated the severity of DSS-induced colitis in mice. The number of regulatory T (Treg) cells in the spleens of mice with colitis and levels of IL-4 both increased following treatment with M2b macrophage exosomes. In addition, key cytokines associated with colitis (IL-1β, IL-6, and IL-17A) were significantly suppressed, following treatment with M2b macrophage exosomes. The M2b macrophage exosomes exerted protective effects on DSS-induced colitis, mainly mediated by the CC chemokine 1 (CCL1)/CCR8 axis. These findings provide a novel approach for the treatment of IBD.

The gut microbiota, including probiotics and pathogenic microorganisms, is involved in ulcerative colitis (UC) by regulating pathogenic microorganisms and the production of intestinal mucosal antibodies. Huangqin decoction (HQD), a traditional Chinese formula chronicled in the Shanghan lun, has been recognized as an effective drug for UC, owing to its anti-inflammatory and anti-oxidative properties. In the present study, we investigated whether HQD ameliorates dextran sulphate sodium (DSS)-induced colitis through alteration of the gut microbiota. We found that HQD significantly inhibited colitis, alleviating the loss of body weight, disease activity index, colon shortening, tissue injury, and inflammatory cytokine changes induced by DSS treatment. Principal component analysis and principal co-ordinate analysis showed an obvious difference among the groups, with increased diversity in the DSS and DSS+HQD groups. Linear discriminant analysis effect size was used to determine differences between the groups. The relative abundance of Lactococcus was higher in the DSS+HQD group than in the DSS group, whereas Desulfovibrio and Helicobacter were decreased. Furthermore, the protective effect of HQD was attenuated only in antibiotic-treated mice. In conclusion, our results suggest that HQD could ameliorate DSS-induced inflammation through alteration of the gut microbiota.

BackgroundEmerging evidence supports a bidirectional link between periodontitis and inflammatory bowel disease (IBD). To investigate this relationship, experimental models commonly use dextran sodium sulfate (DSS) to induce colitis. However, DSS is presumed to selectively affect the colon, and its potential off-target effects on the oral cavity remain poorly understood. We examined whether DSS disrupts oral health, potentially confounding oral-gut axis research.MethodsC57BL/6 mice received 2% DSS in drinking water for 8 days, followed by 2 days of untreated water. Colitis severity was assessed by weight loss, colon length, histopathology, and quantitative real-time-polymerase chain reaction (qRT-PCR). Oral health was evaluated via micro-computed tomography (micro-CT) analysis of alveolar bone, gingival histology, cytokine expression, and 16S rRNA sequencing of the oral microbiome.ResultsDSS induced hallmark features of colitis, including weight loss, colon shortening, epithelial crypt damage, and mucosal inflammation. Strikingly, DSS also induced significant oral pathology, including alveolar bone loss, gingival epithelial hyperplasia, inflammatory infiltration, and upregulated gingival pro-inflammatory cytokines (interleukin [IL] -6, IL-17, tumor necrosis factor-alpha [TNF-α]). DSS further altered the oral microbiota causing reduced alpha-diversity and a dysbiotic shift, with enrichment of Streptococcus danieliae and depletion of commensals such as Lactobacillus murinus and Clostridium ASF502. These microbial changes were accompanied by upregulated pathways involved in carbohydrate metabolism, oxidative stress response, and environmental sensing.ConclusionDSS induces periodontal inflammation and oral dysbiosis, independent of colitis. These findings expose a critical confounder in oral-gut axis models and highlight the need to include DSS-only or periodontitis-only controls and alternative models to accurately distinguish systemic effects of DSS from true oral-gut interactions.Plain language summaryThis study shows that dextran sodium sulfate (DSS), a chemical used to model gut inflammation in mice, also causes gum disease-like changes-including bone loss, inflammation, and changes in oral bacteria. These findings reveal that DSS alone can affect the mouth and may confound studies investigating links between gum disease and inflammatory bowel disease, highlighting the need for better-controlled models.