Fucose promotes intestinal stem cell-mediated intestinal epithelial development through promoting Akkermansia-related propanoate metabolism.

Intestinal stem cells (ISCs) are critical for the development and rapid turnover of intestinal epithelium. The regulatory effects of gut microbiota and their metabolites on ISCs stemness remain elusive. Fucose has been demonstrated to mediate host-microbe interactions in the intestine. However, the association between fucose, gut bacteria, and ISCs stemness remains unclear. To investigate the effects of fucose on ISCs-mediated intestinal epithelial cells (IECs) development, we administered fucose to 4-week-old mice for 4 weeks. ISCs stemness, IECs proliferation, and differentiation were examined. Variations in gut microbes and metabolism were detected using 16S rDNA sequencing and metabolomic analysis. Fucose was added to the bacterial culture medium to further study its effects on metabolism. Crypts were isolated from the mouse ileum for organoids culture in vitro to evaluate the effects of metabolites and the underlying mechanism. The results showed that fucose accelerated ISCs proliferation and secretory lineage differentiation in mice, whereas antibiotics eliminated these effects. The composition and functions of gut bacteria were altered by fucose treatment, while significant increases in Akkermansia and propanoate metabolism were noted. Propionic acid and propionate have been shown to promote organoid development. Fucose fermentation increases the production of propionic acid in Akkermansia muciniphila and enhances its ability to increase the stemness of ISCs. Moreover, ileal contents from fucose-treated mice promoted organoid development in a Gpr41/Gpr43-dependent manner. Fucose administration activates the Wnt signaling pathway in ISCs, and Wnt inhibitors suppress the effects of fucose. We conclude that fucose accelerates ISC-mediated intestinal epithelial development by promoting Akkermansia-related propanoate metabolism. These findings provide new insights into the promotion of gut homeostasis and the application potential of fucose as a prebiotic.

Response rate and safety of antidepressants combined with electroconvulsive therapy in adolescent depression: Real-world clinical application.

BACKGROUND: METHODS: This study included 210 depression patients receiving antidepressants and ECT. The symptoms of depression were examined with the Hamilton Depression Scale (HAMD) and Clinical Global Impressions Scale (CGI) at baseline and the end of treatment. Response and safety were compared among adolescent and adult patients. RESULTS: For adolescents, the response rate (much improved or very much improved) was 80.9 %, and CGI-Severity (CGI-S), HAMD, and suicide factor scores were significantly changed as compared to baseline (P < 0.001), results of which were similar to the adult group. There were no significant differences in HAMD, CGI scores between adolescent and adult depression before or after treatment (P > 0.05). Notably, adolescents expressed stronger suicidal intent than adults, and ECT observably relieved it. Side effects (memory problems, headache, nausea/vomiting, muscle soreness) in adolescents were not statistically different from those in adults (P > 0.05). LIMITATIONS: As data were derived from a single center, the generalizability of results may be limited, and the potential factors affecting the efficacy of ECT were not further explored. CONCLUSION: Antidepressants combined with ECT are associated with high response rate and safety for treating depression, regardless of age. A stronger expression of suicide ideation was observed in depressed adolescents, and side effects of ECT were similar to the adults.

Fucose ameliorates the proinflammatory property of Fusobacterium nucleatum in colitis via altering its metabolism.

Introduction: Previous studies reported that fucose plays a protective role in inhibiting pathogens. Fusobacterium nucleatum (Fn) was recently found to promote the progression of colitis. However, the effects of fucose on Fn are poorly understood. This study aimed to explore whether fucose could ameliorate the proinflammatory property of Fn in colitis and the underlying mechanisms. Methods: To validate our hypothesis, mice were administrated with Fn and fucose-treated Fn (Fnf) before dextran sulfate sodium (DSS) treatment to establish Fn related colitis model. The metabolism variation of Fn was detected by metabolomic analysis. To verify the effects of bacterial metabolites on intestinal epithelial cells (IECs), Caco-2 cells were treated with bacterial supernatant. Results: More severe inflammation, intestinal barrier damage, autophagy block, and apoptosis in the colon were noted in DSS mice that were administrated with Fn or Fnf. However, the severity degree in Fnf+DSS group was less compared to Fn+DSS group. Metabolic pathways of Fn were altered after fucose treatment and proinflammatory metabolites were decreased. The supernatant of Fnf induced a lower level of inflammation than Fn in Caco-2 cells. One of the decreased metabolites, homocysteine thiolactone (HT), was proven to induce inflammatory effects in Caco-2 cells. Discussion: In conclusion, fucose ameliorates the proinflammatory property of Fn via altering its metabolism and these findings provide evidence for the application of fucose as functional food or prebiotic in the treatment of Fn related colitis.

FUT2-dependent fucosylation of HYOU1 protects intestinal stem cells against inflammatory injury by regulating unfolded protein response.

The intestinal epithelial repair after injury is coordinated by intestinal stem cells (ISCs). Fucosylation catalyzed by fucosyltransferase 2 (FUT2) of the intestinal epithelium is beneficial to mucosal healing but poorly defined is the influence on ISCs. The dextran sulfate sodium (DSS) and lipopolysaccharide (LPS) model were used to assess the role of FUT2 on ISCs after injury. The apoptosis, function, and stemness of ISCs were analyzed using intestinal organoids from WT and Fut2ΔISC (ISC-specific Fut2 knockout) mice incubated with LPS and fucose. N-glycoproteomics, UEA-1 chromatography, and site-directed mutagenesis were monitored to dissect the regulatory mechanism, identify the target fucosylated protein and the corresponding modification site. Fucose could alleviate intestinal epithelial damage via upregulating FUT2 and α-1,2-fucosylation of ISCs. Oxidative stress, mitochondrial dysfunction, and cell apoptosis were impeded by fucose. Meanwhile, fucose sustained the growth and proliferation capacity of intestinal organoids treated with LPS. Contrarily, FUT2 depletion in ISCs aggravated the epithelial damage and disrupted the growth and proliferation capacity of ISCs via escalating LPS-induced endoplasmic reticulum (ER) stress and initiating the IRE1/TRAF2/ASK1/JNK branch of unfolded protein response (UPR). Fucosylation of the chaperone protein HYOU1 at the N-glycosylation site of asparagine (Asn) 862 mediated by FUT2 was identified to facilitate ISCs survival and self-renewal, and improve ISCs resistance to ER stress and inflammatory injury. Our study highlights a fucosylation-dependent protective mechanism of ISCs against inflammation, which may provide a fascinating strategy for treating intestinal injury disorders.

Promoting Effect of L-Fucose on the Regeneration of Intestinal Stem Cells through AHR/IL-22 Pathway of Intestinal Lamina Propria Monocytes.

The recovery of the intestinal epithelial barrier is the goal for curing various intestinal injurious diseases, especially IBD. However, there are limited therapeutics for restoring intestinal epithelial barrier function in IBD. The stemness of intestinal stem cells (ISCs) can differentiate into various mature intestinal epithelial cells, thus playing a key role in the rapid regeneration of the intestinal epithelium. IL-22 secreted by CD4+ T cells and ILC3 cells was reported to maintain the stemness of ISCs. Our previous study found that L-fucose significantly ameliorated DSS-induced colonic inflammation and intestinal epithelial injury. In this study, we discovered enhanced ISC regeneration and increased intestinal IL-22 secretion and its related transcription factor AHR in colitis mice after L-fucose treatment. Further studies showed that L-fucose promoted IL-22 release from CD4+ T cells and intestinal lamina propria monocytes (LPMCs) via activation of nuclear AHR. The coculture system of LPMCs and intestinal organoids demonstrated that L-fucose stimulated the proliferation of ISCs through an indirect manner of IL-22 from LPMCs via the IL-22R-p-STAT3 pathway, and restored TNF-α-induced organoid damage via IL-22-IL-22R signaling. These results revealed that L-fucose helped to heal the epithelial barrier by accelerating ISC proliferation, probably through the AHR/IL-22 pathway of LPMCs, which provides a novel therapy for IBD in the clinic.

Phylogenomic Analyses of a Clade Within the Family Flavobacteriaceae Suggest Taxonomic Reassignments of Species of the Genera Algibacter, Hyunsoonleella, Jejuia, and Flavivirga, and the Proposal of Pseudalgibacter gen. nov. and Pseudalgibacter alginicilyticus comb. nov.

The family Flavobacteriaceae forms a major branch within the phylum Bacteroidetes. Whole-genome sequence-based analysis could significantly improve the accuracy of taxonomic assignments. In this study, phylogenomic analyses were carried out to revisit the taxonomic status of a clade of the family Flavobacteriaceae. Taking genome-based phylogeny as the primary guideline and average amino acid identity and phenotypic information as supplements, the following taxonomic proposals were put forward: Arenitalea lutea should be reclassified into the genus Algibacter; Algibacter aquaticus should be reclassified into the genus Flavivirga; Jejuia pallidilutea and Algibacter aestuarii should be reclassified into the genus Hyunsoonleella; Algibacter alginicilyticus should be reclassified into the novel genus Pseudalgibacter gen. nov. This study builds up a solid framework for taxonomic decisions of a clade of the family Flavobacteriaceae and will contribute to further insights into the evolution of this family.