病毒感染性疾病与肠道微生物关系研究进展

肠道微生物影响着人体的营养、代谢、免疫等多种生理活动,对人体健康有非常重要的影响.目前的研究表明,肠道微生物在病毒感染性疾病的感染及预后过程中发挥着重要的作用.本文分别总结了肠道病毒感染、非肠道病毒感染与肠道微生物的相互作用关系以及微生态调节干预病毒感染等内容,以期为相关研究的进一步深入和病毒感染性疾病的防治提供新思路...     

Gut microbiota composition before infection determines the Salmonella super- and low-shedder phenotypes in chicken

Heterogeneity of infection and extreme shedding patterns are common features of animal infectious diseases. Individual hosts that are super-shedders are key targets for control strategies. Nevertheless, the mechanisms associated with the emergence of super-shedders remain largely unknown. During chicken salmonellosis, a high heterogeneity of infection is observed when animal-to-animal cross-contaminations and reinfections are reduced. We hypothesized that unlike super-shedders, low-shedders would be able to block the first Salmonella colonization thanks to a different gut microbiota. The present study demonstrates that (i) axenic and antibiotic-treated chicks are more prone to become super-shedders; (ii) super or low-shedder phenotypes can be acquired through microbiota transfer; (iii) specific gut microbiota taxonomic features determine whether the chicks develop a low- and super-shedder phenotype after Salmonella infection in isolator; (iv) partial protection can be conferred by inoculation of four commensal bacteria prior to Salmonella infection. This study demonstrates the key role plays by gut microbiota composition in the heterogeneity of infection and pave the way for developing predictive biomarkers and protective probiotics.     

Western-style diet impedes colonization and clearance of Citrobacter rodentium

Western-style diet (WSD), which is high in fat and low in fiber, lacks nutrients to support gut microbiota. Consequently, WSD reduces microbiota density and promotes microbiota encroachment, potentially influencing colonization resistance, immune system readiness, and thus host defense against pathogenic bacteria. Here we examined the impact of WSD on infection and colitis in response to Citrobacter rodentium. We observed that, relative to mice consuming standard rodent grain-based chow (GBC), feeding WSD starkly altered the dynamics of Citrobacter infection, reducing initial colonization and inflammation but frequently resulting in persistent infection that associated with low-grade inflammation and insulin resistance. WSD’s reduction in initial Citrobacter virulence appeared to reflect that colons of GBC-fed mice contain microbiota metabolites, including short-chain fatty acids, especially acetate, that drive Citrobacter growth and virulence. Citrobacter persistence in WSD-fed mice reflected inability of resident microbiota to out-compete it from the gut lumen, likely reflecting the profound impacts of WSD on microbiota composition. These studies demonstrate potential of altering microbiota and their metabolites by diet to impact the course and consequence of infection following exposure to a gut pathogen.     

Gut microbiota,inflammation, and molecular signatures of host response to infection

Gut microbial dysbiosis has been linked to many noncommunicable diseases. However, little is known about specific gut microbiota composition and its correlated metabolites associated with molecular signatures underlying host response to infection. Here, we describe the construction of a proteomic risk score based on 20 blood proteomic biomarkers, which have recently been identified as molecular signatures predicting the progression of the COVID-19. We demonstrate that in our cohort of 990 healthy individuals without infection, this proteomic risk score is positively associated with proinflammatory cytokines mainly among older, but not younger, individuals. We further discover that a core set of gut microbiota can accurately predict the above proteomic biomarkers among 301 individuals using a machine learning model and that these gut microbiota features are highly correlated with proinflammatory cytokines in another independent set of 366 individuals. Fecal metabolomics analysis suggests potential amino acid-related pathways linking gut microbiota to host metabolism and inflammation. Overall, our multi-omics analyses suggest that gut microbiota composition and function are closely related to inflammation and molecular signatures of host response to infection among healthy individuals. These results may provide novel insights into the cross-talk between gut microbiota and host immune system.     

百日咳鲍特菌感染婴幼儿口咽部的菌群变化

摘要：目的 通过比较健康婴幼儿与百日咳鲍特菌感染婴幼儿口咽部的菌群相对丰度,探讨百日咳鲍特菌感染对婴幼儿口咽部的菌群影响。方法 采用高通量测序技术,对53例百日咳鲍特菌感染婴幼儿和21例健康婴幼儿口咽标本进行16S rDNA测序,对测序序列进行分析,比较两组间的菌群多样性及在门、属水平上菌群结构差异。结果 健康婴幼儿与百日咳鲍特菌感染患儿在性别和年龄方面差异没有统计学意义。百日咳鲍特菌感染婴幼儿比健康婴幼儿口咽部菌群多样性显著增加。变形菌门（Proteobacteria）作为主要的门在百日咳鲍特菌感染患儿组中相对丰度显著高于健康婴幼儿组;两组排在相对丰度前15位的属,共有3个主要的属在百日咳鲍特菌感染患儿中显著增加,分别为盐单胞菌属（Halomonas）、嗜血杆菌属（Haemophilus）和鲍特菌属（Bordetella）;而罗氏菌属（Rothia）显著减少。结论 百日咳鲍特菌感染婴幼儿口咽部的菌群发生了显著的变化,百日咳鲍特菌感染患儿口咽部的菌群多样性比健康婴幼儿显著增加,在门和属水平百日咳鲍特菌感染患儿与健康婴幼儿主要组成方面均有显著性不同。     

Coinfection and infection duration shape how pathogens affect the African buffalo gut microbiota

Changes in the gut microbiota during pathogen infection are often predicted to influence disease outcomes. However, studies exploring whether pathogens induce microbiota shifts have yielded inconsistent results. This suggests that variation in infection, rather than the presence of infection alone, might shape pathogen–microbiota relationships. For example, most hosts are coinfected with multiple pathogens simultaneously, and hosts vary in how long they are infected, which may amplify or diminish microbial shifts expected in response to a focal pathogen. We used a longitudinal anthelmintic treatment study of free-ranging African buffalo (Syncerus caffer) to examine whether (i) coinfection with bovine tuberculosis (Mycobacterium bovis, TB) and gastrointestinal nematodes, and (ii) the duration of TB infection, modified effects of single pathogens on the gut microbiota. By accounting for the interaction between TB and nematodes, we found that coinfection affected changes in microbial abundance associated with single infections. Furthermore, the duration of TB infection predicted more microbiota variation than the presence of TB. Importantly, coinfection and infection duration had nearly as much influence on microbial patterns as demographic and environmental factors commonly examined in microbiota research. These findings demonstrate that acknowledging infection heterogeneities may be crucial to understanding relationships between pathogens and the gut microbiota.Subject terms: Microbiome, Infectious diseases     

The intestinal microbiota plays a role in Salmonella-induced colitis independent of pathogen colonization

The intestinal microbiota is composed of hundreds of species of bacteria, fungi and protozoa and is critical for numerous biological processes, such as nutrient acquisition, vitamin production, and colonization resistance against bacterial pathogens. We studied the role of the intestinal microbiota on host resistance to Salmonella enterica serovar Typhimurium-induced colitis. Using multiple antibiotic treatments in 129S1/SvImJ mice, we showed that disruption of the intestinal microbiota alters host susceptibility to infection. Although all antibiotic treatments caused similar increases in pathogen colonization, the development of enterocolitis was seen only when streptomycin or vancomycin was used; no significant pathology was observed with the use of metronidazole. Interestingly, metronidazole-treated and infected C57BL/6 mice developed severe pathology. We hypothesized that the intestinal microbiota confers resistance to infectious colitis without affecting the ability of S. Typhimurium to colonize the intestine. Indeed, different antibiotic treatments caused distinct shifts in the intestinal microbiota prior to infection. Through fluorescence in situ hybridization, terminal restriction fragment length polymorphism, and real-time PCR, we showed that there is a strong correlation between the intestinal microbiota composition before infection and susceptibility to Salmonella-induced colitis. Members of the Bacteroidetes phylum were present at significantly higher levels in mice resistant to colitis. Further analysis revealed that Porphyromonadaceae levels were also increased in these mice. Conversely, there was a positive correlation between the abundance of Lactobacillus sp. and predisposition to colitis. Our data suggests that different members of the microbiota might be associated with S. Typhimurium colonization and colitis. Dissecting the mechanisms involved in resistance to infection and inflammation will be critical for the development of therapeutic and preventative measures against enteric pathogens.     

Enteric pathogen exploitation of the microbiota-generated nutrient environment of the gut

Residing within the intestine is a large community of commensal organisms collectively termed the microbiota. This community generates a complex nutrient environment by breaking down indigestible food products into metabolites that are used by both the host and the microbiota. Both the invading intestinal pathogen and the microbiota compete for these metabolites, which can shape both the composition of the flora, as well as susceptibility to infection. After infection is established, pathogen mediated inflammation alters the composition of the microbiota, which further shifts the makeup of metabolites in the gastrointestinal tract. A greater understanding of the interplay between the microbiota, the metabolites they generate, and susceptibility to enteric disease will enable the discovery of novel therapies against infectious disease.     

Diverse Vaginal Microbiomes in Reproductive-Age Women with Vulvovaginal Candidiasis

Vulvovaginal candidiasis (VVC) is one of the most prevalent vaginal infectious diseases, and there are controversial reports regarding the diversity of the associated vaginal microbiota. We determined the vaginal microbial community in patients with VVC, bacterial vaginosis (BV), and mixed infection of VVC and BV using Illumina sequencing of 16S rRNA tags. Our results revealed for the first time the highly variable patterns of the vaginal microbiome from VVC patients. In general, the alpha-diversity results of species richness and evenness showed the following order: normal control < VVC only < mixed BV and VVC infection < BV only. The beta-diversity comparison of community structures also showed an intermediate composition of VVC between the control and BV samples. A detailed comparison showed that, although the control and BV communities had typical patterns, the vaginal microbiota of VVC is complex. The mixed BV and VVC infection group showed a unique pattern, with a relatively higher abundance of Lactobacillus than the BV group and higher abundance of Prevotella, Gardnerella, and Atopobium than the normal control. In contrast, the VVC-only group could not be described by any single profile, ranging from a community structure similar to the normal control (predominated with Lactobacillus) to BV-like community structures (abundant with Gardnerella and Atopobium). Treatment of VVC resulted in inconsistent changes of the vaginal microbiota, with four BV/VVC samples recovering to a higher Lactobacillus level, whereas many VVC-only patients did not. These results will be useful for future studies on the role of vaginal microbiota in VVC and related infectious diseases.     

Exosomal miR-224 contributes to hemolymph microbiota homeostasis during bacterial infection in crustacean

It is well known that exosomes could serve as anti-microbial immune factors in animals. However, despite growing evidences have shown that the homeostasis of the hemolymph microbiota was vital for immune regulation in crustaceans, the relationship between exosomes and hemolymph microbiota homeostasis during pathogenic bacteria infection has not been addressed. Here, we reported that exosomes released from Vibrio parahaemolyticus-infected mud crabs (Scylla paramamosain) could help to maintain the homeostasis of hemolymph microbiota and have a protective effect on the mortality of the host during the infection process. We further confirmed that miR-224 was densely packaged in these exosomes, resulting in the suppression of HSP70 and disruption of the HSP70-TRAF6 complex, then the released TRAF6 further interacted with Ecsit to regulate the production of mitochondrial ROS (mROS) and the expression of Anti-lipopolysaccharide factors (ALFs) in recipient hemocytes, which eventually affected hemolymph microbiota homeostasis in response to the pathogenic bacteria infection in mud crab. To the best of our knowledge, this is the first document that reports the role of exosome in the hemolymph microbiota homeostasis modulation during pathogen infection, which reveals the crosstalk between exosomal miRNAs and innate immune response in crustaceans.     

肺部菌群与呼吸道疾病的相互关系

由于呼吸道黏膜免疫系统具有很好的防御保护作用和强大的清除病原体的能力,过去学术界曾经一度认为健康机体的肺是无菌的。随着不依赖于体外培养的第二代测序技术的发展,关于肺部共生微生物的结构组成及其免疫调节功能的研究越来越受重视。肺部菌群的结构组成与出生方式、饮食结构、生活环境和抗生素使用等多种因素有关,生命早期的肺部菌群的形成和发育会影响全生命周期的呼吸道疾病的发生和发展。肺部菌群通过与宿主免疫系统相互作用调节肺部免疫稳态,还可以与肠道菌群、呼吸道病毒相互作用影响呼吸道感染。因此,干预生命早期肺部菌群的结构组成可以成为预防和控制呼吸道疾病的有效策略和新靶点。     

Bacteria–bacteria interactions within the microbiota of the ancestral metazoan Hydra contribute to fungal resistance

Epithelial surfaces of most animals are colonized by diverse microbial communities. Although it is generally agreed that commensal bacteria can serve beneficial functions, the processes involved are poorly understood. Here we report that in the basal metazoan Hydra, ectodermal epithelial cells are covered with a multilayered glycocalyx that provides a habitat for a distinctive microbial community. Removing this epithelial microbiota results in lethal infection by the filamentous fungus Fusarium sp. Restoring the complex microbiota in gnotobiotic polyps prevents pathogen infection. Although mono-associations with distinct members of the microbiota fail to provide full protection, additive and synergistic interactions of commensal bacteria are contributing to full fungal resistance. Our results highlight the importance of resident microbiota diversity as a protective factor against pathogen infections. Besides revealing insights into the in vivo function of commensal microbes in Hydra, our findings indicate that interactions among commensal bacteria are essential to inhibit pathogen infection.     

Altering host resistance to infections through microbial transplantation

Host resistance to bacterial infections is thought to be dictated by host genetic factors. Infections by the natural murine enteric pathogen Citrobacter rodentium (used as a model of human enteropathogenic and enterohaemorrhagic E. coli infections) vary between mice strains, from mild self-resolving colonization in NIH Swiss mice to lethality in C3H/HeJ mice. However, no clear genetic component had been shown to be responsible for the differences observed with C. rodentium infections. Because the intestinal microbiota is important in regulating resistance to infection, and microbial composition is dependent on host genotype, it was tested whether variations in microbial composition between mouse strains contributed to differences in "host" susceptibility by transferring the microbiota of resistant mice to lethally susceptible mice prior to infection. Successful transfer of the microbiota from resistant to susceptible mice resulted in delayed pathogen colonization and mortality. Delayed mortality was associated with increased IL-22 mediated innate defense including antimicrobial peptides Reg3γ and Reg3β, and immunono-neutralization of IL-22 abrogated the beneficial effect of microbiota transfer. Conversely, depletion of the native microbiota in resistant mice by antibiotics and transfer of the susceptible mouse microbiota resulted in reduced innate defenses and greater pathology upon infection. This work demonstrates the importance of the microbiota and how it regulates mucosal immunity, providing an important factor in susceptibility to enteric infection. Transfer of resistance through microbial transplantation (bacteriotherapy) provides additional mechanisms to alter "host" resistance, and a novel means to alter enteric infection and to study host-pathogen interactions.     

Colonic microbiota alters host susceptibility to infectious colitis by modulating inflammation, redox status, and ion transporter gene expression

Individuals vary in their resistance to enteric infections. The role of the intestinal microbiota in altering susceptibility to enteric infection is relatively unknown. Previous studies have identified that C3H/HeOuJ mice suffer 100% mortality during Citrobacter rodentium-induced colitis, whereas C57BL/6 mice recover from infection. The basis for their differences in susceptibility is unclear and has been mainly attributed to differences in host genetics. This study investigated the role of the intestinal microbiota in altering susceptibility to C. rodentium-induced colitis. When the feces of C57BL/6 mice were gavaged into antibiotic treated C3H/HeOuJ mice, the C57BL/6 microflora led to a complete reversal in mortality patterns where 100% of the C3H/HeOuJ mice survived infection. This protection corresponded with reduced colonic pathology and less systemic pathogen load and was associated with increased inflammatory and redox responses with reduced epithelial cell death. C3H/HeOuJ mice are normally susceptible to infection-induced dehydration due to defective expression of colonic ion transporters such as Dra, CA IV, and CA I; expression of these genes was normalized when C3H/HeOuJ mice were colonized with the C57BL/6 microflora. Together, these data reveal that the colonic microbiota play a critical role in protecting against intestinal infection by inducing proinflammatory and prooxidant responses that control pathogen load as well as ion transporter gene expression previously shown to prevent fatal dehydration. Protection of mice from lethal colitis was associated with higher levels of bacteria from Bacteroidetes. This study reveals that the microbiota is sufficient to overcome inherent genetic susceptibility patterns in C3H/HeOuJ mice that cause mortality during C. rodentium infection.     

Neutrophil Elastase Alters the Murine Gut Microbiota Resulting in Enhanced Salmonella Colonization

The intestinal microbiota has been found to play a central role in the colonization of Salmonella enterica serovar Typhimurium in the gastrointestinal tract. In this study, we present a novel process through which Salmonella benefit from inflammatory induced changes in the microbiota in order to facilitate disease. We show that Salmonella infection in mice causes recruitment of neutrophils to the gut lumen, resulting in significant changes in the composition of the intestinal microbiota. This occurs through the production of the enzyme elastase by neutrophils. Administration of recombinant neutrophil elastase to infected animals under conditions that do not elicit neutrophil recruitment caused shifts in microbiota composition that favored Salmonella colonization, while inhibition of neutrophil elastase reduced colonization. This study reveals a new relationship between the microbiota and the host during infection.     

NLRP6-associated host microbiota composition impacts in the intestinal barrier to systemic dissemination of Brucella abortus

Brucella abortus is a Gram-negative bacterium responsible for a worldwide zoonotic infection—Brucellosis, which has been associated with high morbidity rate in humans and severe economic losses in infected livestock. The natural route of infection is through oral and nasal mucosa but the invasion process through host gut mucosa is yet to be understood. Studies have examined the role of NLRP6 (NOD-like receptor family pyrin domain-containing-6 protein) in gut homeostasis and defense against pathogens. Here, we investigated the impact of gut microbiota and NLRP6 in a murine model of Ba oral infection. Nlrp6^-/- and wild-type (WT) mice were infected by oral gavage with Ba and tissues samples were collected at different time points. Our results suggest that Ba oral infection leads to significant alterations in gut microbiota. Moreover, Nlrp6^-/- mice were more resistant to infection, with decreased CFU in the liver and reduction in gut permeability when compared to the control group. Fecal microbiota transplantation from WT and Nlrp6^-/- into germ-free mice reflected the gut permeability phenotype from the donors. Additionally, depletion of gut microbiota by broad-spectrum-antibiotic treatment prevented Ba replication in WT while favoring bacterial growth in Nlrp6^-/-. Finally, we observed higher eosinophils in the gut and leukocytes in the blood of infected Nlrp6^-/- compared to WT-infected mice, which might be associated to the Nlrp6^-/- resistance phenotype. Altogether, these results indicated that gut microbiota composition is the major factor involved in the initial stages of pathogen host replication and partially also by the resistance phenotype observed in Nlrp6 -/- mice regulating host inflammation against Ba infection.     

Roles of the gut microbiota in severe SARS-CoV-2 infection

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread worldwide. The pathophysiological mechanisms linking gut dysbiosis and severe SARS-CoV-2 infection are poorly understood, although gut microbiota disorders are related to severe SARS-CoV-2 infections. The roles of the gut microbiota in severe SARS-CoV-2 infection were compared with those in respiratory viral infection, which is an easily understood and enlightening analogy. Secondary bacterial infections caused by immune disorders and antibiotic abuse can lead to dysregulation of the gut microbiota in patients with respiratory viral infections. The gut microbiota can influence the progression of respiratory viral infections through metabolites and the immune response, which is known as the gut–lung axis. Angiotensin-converting enzyme 2 is expressed in both the lungs and the small intestine, which may be a bridge between the lung and the gut. Similarly, SARS-CoV-2 infection has been shown to disturb the gut microbiota, which may be the cause of cytokine storms. Bacteria in the gut, lung, and other tissues and respiratory viruses can be considered microecosystems and may exert overall effects on the host. By referencing respiratory viral infections, this review focused on the mechanisms involved in the interaction between SARS-CoV-2 infections and the gut microbiota and provides new strategies for the treatment or prevention of severe SARS-CoV-2 infections by improving gut microbial homeostasis.     

Chronic Trichuris muris Infection in C57BL/6 Mice Causes Significant Changes in Host Microbiota and Metabolome: Effects Reversed by Pathogen Clearance

Trichuris species are a globally important and prevalent group of intestinal helminth parasites, in which Trichuris muris (mouse whipworm) is an ideal model for this disease. This paper describes the first ever highly controlled and comprehensive investigation into the effects of T. muris infection on the faecal microbiota of mice and the effects on the microbiota following successful clearance of the infection. Communities were profiled using DGGE, 454 pyrosequencing, and metabolomics. Changes in microbial composition occurred between 14 and 28 days post infection, resulting in significant changes in α and β- diversity. This impact was dominated by a reduction in the diversity and abundance of Bacteroidetes, specifically Prevotella and Parabacteroides. Metabolomic analysis of stool samples of infected mice at day 41 showed significant differences to uninfected controls with a significant increase in the levels of a number of essential amino acids and a reduction in breakdown of dietary plant derived carbohydrates. The significant reduction in weight gain by infected mice probably reflects these metabolic changes and the incomplete digestion of dietary polysaccharides. Following clearance of infection the intestinal microbiota underwent additional changes gradually transitioning by day 91 towards a microbiota of an uninfected animal. These data indicate that the changes in microbiota as a consequence of infection were transitory requiring the presence of the pathogen for maintenance. Interestingly this was not observed for all of the key immune cell populations associated with chronic T. muris infection. This reflects the highly regulated chronic response and potential lasting immunological consequences of dysbiosis in the microbiota. Thus infection of T. muris causes a significant and substantial impact on intestinal microbiota and digestive function of mice with affects in long term immune regulation.