The human gut harbors a diverse virome, believed to play a crucial role in maintaining intestinal homeostasis. However, the magnitude of heterogeneity of the gut mucosal virome, and how it differentially regulates host inflammation phenotypes, such as those observed in Crohn's disease (CD), remains unclear. Here, we identify two mucosal DNA virome enterotypes (E1 and E2) in humans, with E2 subjects exhibiting higher virome diversity and nuanced bacteriophage-bacteria correlations. Moreover, E2-enterotyped CD patients exhibited higher Wulfhauvirus abundance than healthy controls. The E2 virome is causally more proinflammatory in inducing intestinal inflammation in mice. Mechanistically, the novel E2-virome-enriched phage øBTZT001P (belonging to Wulfhauvirus) lysogenically infects Bacteroides thetaiotaomicron, increasing sphingosine production. Downstream, sphingosine suppresses the commensal bacterium Blautia obeum in the gut, leading to worsened intestinal inflammation. Our findings reveal that configurational differences in the gut virome may dictate disease outcome through a phage-bacteria-metabolite-intestine axis, highlighting the importance of gut phage-bacteria crosstalk in health.

Crohn’s disease (CD) is a subtype of inflammatory bowel disease that most commonly affects the terminal ileum and is associated with abnormal gut microbiome composition. However, the fungi of the small bowel mucosa and their metabolic functions, particularly protective ones, remain largely unexplored. We enrolled patients with CD and healthy individuals from three independent cohorts and conducted multi-omics profiling of the ileal mucosal mycobiome and bacteriome, along with the faecal mycobiome, bacteriome and metabolome. We show that compared to a healthy mucosa, the fungus Cladosporium sphaerospermum is remarkably depleted in the mucosa of patients with CD, yet remains unchanged in faeces. Subsequent causality studies reveal that C. sphaerospermum occupies the intestinal crypt niche and counteracts intestinal inflammation partly by adenosine 5′-monophosphate (AMP) production, as demonstrated in mice, in vitro and in fungal cultures. Mechanistically, C. sphaerospermum upregulates epithelial cell junctions and the Wnt signalling pathway. Our study unveils a mucosa-associated beneficial fungus, suggesting potential novel microbial intervention strategies for CD. Multi-omics profiling of the mucosal mycobiome in individuals with Crohn’s disease identifies C. sphaerospermum as a protective fungal species that counteracts intestinal inflammation and reinforces the intestinal barrier.

Nanovaccines hold significant promise for the prevention and treatment of infectious diseases. However, the efficacy of many nanovaccines is often limited by inadequate stimulation of both innate and adaptive immune responses. Herein, we explore a rational vaccine strategy aimed at modulating innate cell microenvironments within lymph nodes (LNs) to enhance the generation of effective immune responses. Inspired by the structure and natural infection process of viruses, we developed a versatile antigen and adjuvant co-delivery platform, termed virus-mimetic vaccines (VMVs). Specifically, polyarginine-tagged antigens were noncovalently assembled onto nucleic acid nanogels containing cytosine-phosphate-guanine oligodeoxynucleotide via a salt-bridge zipper mechanism, which can activate Toll-like receptor 9. Upon intramuscular immunization, VMVs effectively drained into the LNs, recruiting and activating multiple innate cells, including CD8+ dendritic cells (DCs), CD103+ DCs, macrophages, plasmacytoid DCs, and neutrophils. This activation modulates the innate cell microenvironments and relocates antigen-presenting cells within LNs, optimizing adaptive immune responses. VMVs induced a robust antigen-specific immune response, characterized by high levels of neutralizing antibodies, augmented memory T cell activity, and enhanced development of germinal center B cells. Together, our findings demonstrate that dynamic modulation of innate cell microenvironments by VMVs leads to optimized generation of both humoral and cellular immunity against infectious diseases.

BACKGROUND:The gut microbiome and diet are important factors in the pathogenesis and management of Crohn's disease (CD). However, the role of the gut phageome under dietary influences is unknown. OBJECTIVE:We aim to explore the effect of diet on the gut phageome-bacteriome interaction linking to CD protection. DESIGN:We recruited CD patients and healthy subjects (n=140) and conducted a multiomics investigation, including paired ileal mucosa phageome and bacteriome profiling, dietary survey and phenome interrogation. We screened for the effect of diet on the gut phageome and bacteriome, as well as its epidemiological association with CD risks. The underlying mechanisms were explored in target phage-bacteria monocultures and cocultures in vitro and in two mouse models in vivo. RESULTS:On dietary screening in humans, whey protein (WP) consumption was found to profoundly impact the gut phageome and bacteriome (more pronounced on the phageome) and was associated with a lower CD risk. Indeed, the WP reshaped gut phageome can causally attenuate intestinal inflammation, as shown by faecal phageome versus bacteriome transplantation from WP-consuming versus WP-non-consuming mice to recipient mice. Mechanistically, WP induced phage (a newly isolated phage AkkZT003P herein) lysis of the mucin-foraging bacterium Akkermansia muciniphila, which unleashed the symbiotic bacterium Streptococcus thermophilus to counteract intestinal inflammation. CONCLUSION:Our study charted the importance of cross-kingdom interaction between gut phage and bacteria in mediating the dietary effect on CD protection. Importantly, we uncovered a beneficial dietary WP, a keystone phage AkkZT003P, and a probiotic S. thermophilus that can be used in CD management in the future.

Gut bacteriome dysbiosis is known to be implicated in the pathogenesis of inflammatory bowel disease (IBD). Crohn’s disease (CD) is an IBD subtype with extensive mucosal inflammation, yet the mucosal virome, an empirical modulator of the bacteriome and mucosal immunity, remains largely unclear regarding its composition and role. Here, we exploited trans-cohort CD patients and healthy individuals to compositionally and functionally investigate the small bowel (terminal ileum) virome and bacteriome. The CD ileal virome was characterised by an under-representation of both lytic and temperate bacteriophages (especially those targeting bacterial pathogens), particularly in patients with flare-up. Meanwhile, the virome-bacteriome ecology in CD ileal mucosa was featured by a lack of Bifidobacterium - and Lachnospiraceae-led mutualistic interactions between bacteria and bacteriophages; surprisingly it was more pronounced in CD remission than flare-up, underlining the refractory and recurrent nature of mucosal inflammation in CD. Lastly, we substantiated that ileal virions from CD patients causally exacerbated intestinal inflammation in IBD mouse models, by reshaping a gut virome-bacteriome ecology preceding intestinal inflammation (microbial trigger) and augmenting microbial sensing/defence pathways in the intestine cells (host response). Altogether, our results highlight the significance of mucosal virome in CD pathogenesis and importance of mucosal virome restoration in CD therapeutics.

2003年1月-2007年5月,我们采用高频电刀切除扁桃体保留悬雍垂治疗慢性扁桃体炎合并鼾症300例,现将结果报告如下.

在老年危重病人气道分泌物梗阻抢救中,可由麻醉医生先行气管插管,吸出气道分泌物后,再行规范气管切开术,既为病人赢得了抢救时机,又保证了呼吸道的通畅.现将我院2003年1月- 2007年1月对24例老年危重病人气管插管后再行气管切开术的体会介绍如下.

2006年1月-2008年2月,我们应用快速微创扁桃体截除器切除扁桃体1 000例,结果显示用该截除器手术安全、可靠,优于传统手术方法. 1 临床资料