Differences in the effects and action modes of gut commensals against dextran sulfate sodium-induced intestinal inflammation

Inflammatory bowel disease(IBD)is a complex relapsing inflammatory disease in the gut and is driven by complicated host-gut microbiome interactions.Gut commensals have shown different functions in IBD prevention and treatment.To gain a mechanistic understanding of how different commensals affect intestinal inflammation,we compared the protective effects of 6 probiotics(belonging to the genera Akkermansia,Bifidobacterium,Clostridium,and Enterococcus)on dextran sulfate sodium(DSS)-induced colitis in mice with or without gut microbiota.Anti-inflammatory properties(ratio of interleukin(IL)-10 and IL-12)of these strains were also evaluated in an in vitro mesenteric lymph nodes(MLN)co-culture system.Results showed that 4 probiotics(belonging to the species Bifidobacterium breve,Bifidobacterium bifidum,and Enterococcus faecalis)can alleviate colitis in normal mice.The probiotic strains differed in regulating the intestinal microbiota,cytokines(IL-10,IL-1βand interferon(IFN)-γ),and tight junction function(Zonulin-1 and Occludin).By constrast,Akkermansia muciniphila AH39 and Clostridium butyricum FHuNHHMY49T1 were not protective.Interestingly,B.breve JSNJJNM2 with high anti-inflammatory potential in the MLN model could relieve colitis symptoms in antibiotic cocktail(Abx)-treated mice.Meanwhile,E.faecalis FJSWX25M1induced low levels of cytokines in vitro and showed no beneficial effects.Therefore,we provided insight into the clinical application of probiotics in IBD treatment.

Feeding ecology and interactions with mammal hosts in a symbiotic genus of birds(Buphagus spp.)in Namibia

As the sole obligate symbiotic birds in Africa,oxpeckers offer a unique model for studying symbiotic relationships.Due to the multitrophic level they occupy and the context dependent foraging behavior they exhibit,the type of symbiotic relationship can be variable.In addition to providing a cleaning service to the host by removing ticks,oxpeckers frequently feed on blood,mucus,and saliva,inflicting potential damage on the host.Here,we used DNA metabarcoding on faecal samples to analyze the taxonomic composition of the trophic interactions of the Yellow-billed Oxpecker(Buphagus africanus)and Red-billed Oxpecker(B.erythrorhynchus)in northeastern Namibia.In contrast to conventional methods,DNA metabarcoding allows for a detailed identification of dietary resources encompassing both mammal hosts and consumed arthropods within the same samples.With this information,we examined differences in the diet composition between oxpecker species and localities,as well as the co-occurrence between host and arthropod species.Our findings revealed that oxpeckers predominantly source their diet from mammals,ticks,and flies;however,ticks and flies rarely co-occur in the diet of an individual.We observed variability among individuals in their feeding ecology,which is strongly correlated with locality and,to a lesser extent,with the mammal host.We noted a high degree of mobility between hosts within relatively short periods,with 32%of the samples showing traces of at least two mammal hosts.This study illustrates the dynamic foraging behavior of these specialized symbiotic birds,shedding light on their potential role in pest control services and disease transmission.

Co-infection with Neisseria mucosa in a patient with tuberculous otitis media

Tuberculous otitis media(TOM) is a rare manifestation caused by Mycobacterium tuberculosis with low incidence rates among extrapulmonary tuberculosis cases. Diagnosis is often delayed because of the presence of several clinical manifestations and the high prevalence of secondary bacterial infections. Few reports have attributed secondary bacterial infections in patients with TOM to commensal Neisseria. Thus, understanding the pathogenic mechanisms and clinical features of commensal Neisseria is important, considering its recent presentation as an infection-causing pathogen. Neisseria mucosa is a commensal inhabitant in humans and is generally considered non-pathogenic but can cause infection in rare cases. Here, we report an atypical secondary infection caused by Neisseria mucosa in an 81-year-old woman with TOM being treated for pulmonary tuberculosis. Direct purulent otorrhea smear microscopy revealed no acid-fast bacilli using Ziehl-Neelsen staining, whereas the phagocytosis of gram-negative cocci by white blood cells was confirmed using Gram staining. Otorrhea culture revealed the growth of N. mucosa. Subsequently, M. tuberculosis infection in the otorrhea was identified using a culture-based method. Vigilance is critical for the early detection of TOM to prevent further complications. This report raises awareness regarding TOM and provides insight into the pathogenicity of N. mucosa in otitis media.

Heat stress in pigs and broilers:role of gut dysbiosis in the impairment of the gut-liver axis and restoration of these effects by probiotics,prebiotics and synbiotics

Heat stress is one of the most challenging stressors for animal production due to high economic losses resulting from impaired animal’s productivity,health and welfare.Despite the fact that all farm animal species are susceptible to heat stress,birds and pigs are particularly sensitive to heat stress due to either lacking or non-functional sweat glands.Con-vincing evidence in the literature exists that gut dysbiosis,a term used to describe a perturbation of commensal gut microbiota,develops in broilers and pigs under heat stress.Owing to the protective role of commensal bacteria for the gut barrier,gut dysbiosis causes a disruption of the gut barrier leading to endotoxemia,which contributes to the typical characteristics of heat stressed broilers and growing and growing-finishing pigs,such as reduced feed intake,decreased growth and reduced lean carcass weight.A substantial number of studies have shown that feeding of probiotics,prebiotics and synbiotics is an efficacious strategy to protect broilers from heat stress-induced gut barrier disruption through altering the gut microbiota and promoting all decisive structural,biochemical,and immunologi-cal elements of the intestinal barrier.In most of the available studies in heat stressed broilers,the alterations of gut microbiota and improvements of gut barrier function induced by feeding of either probiotics,prebiotics or synbiot-ics were accompanied by an improved productivity,health and/or welfare when compared to non-supplemented broilers exposed to heat stress.These findings indicate that the restoration of gut homeostasis and function is a key target for dietary interventions aiming to provide at least partial protection of broilers from the detrimental impact of heat stress conditions.Despite the fact that the number of studies dealing with the same feeding strategy in heat stressed pigs is limited,the available few studies suggest that feeding of probiotics might also be a suitable approach to enhance productivity,health and welfare in pigs kept under heat stress conditions.

New observations-with older ones reviewed-on mass migrations in millipedes based on a recent outbreak on Hachijojima(Izu Islands) of the polydesmid diplopod(Chamberlinius hualienensis,Wang 1956):Nothing appears to make much sense

Mass aggregations and migrations of millipedes despite numerous attempts to find causes for their occurrences are still an enigma. They have been reported from both southern and northern hemisphere countries, from highlands and lowlands of both tropical and temperate regions and they can involve species belonging to the orders Julida and Spirobolida, Polydesmida and Glomerida. According to the main suggestions put forward in the past, mass occurrences in Diplopoda occur：（1） because of a lack of food and a population increase beyond sustainable levels;（2） for the purpose of reproduction and in order to locate suitable oviposition sites;（3） to find overwintering or aestivation sites;（4） because of habitat disruption and changes in the local environment;（5） as a consequence of weather conditions the year（or winter and spring） before. A recent outbreak（November 2014） of a mass migration of the polydesmid Chamberlinius hualienensis Wang 1956 on the Japanese Izu Island of Hachijojima 300 km to the south of Tokyo gave this author an opportunity to review the existing literature on millipede mass migrations and to carry out additional observations on the phenomenon in the field as well as the laboratory. Hitherto unreported heavy infestations with phoretic deutonymphs of the mite Histiostoma sp. as well as dense populations of internal rhabditid nematodes（Oscheius cf. necromena and an unidentified species of the genus Fictor）, suggest that infestations of this kind could be necromenic and either have been a contributing factor for the mass migration or been a consequence of so manyindividuals occurring together at close proximity. It is concluded that mass migrations and aggregations in millipedes do not have one common cause, but represent phenomena that often are seasonally recurring events and appear identical in their outcome, but which have evolved as responses to different causes in different millipede taxa and therefore need to be examined on a case-to-case basis.

Sub-acute endocarditis by Corynebacterium straitum : An often ignored pathogen

With the emergence of novel etiologic organisms, panresistance, and invasive medical care infective endocarditis continues to be evasive, requiring newer approaches and modified treatment guidelines. Presented here is the case of a 75-year-old male with history of systolic heart failure with an automatic internal cardioverter defibrillator(AICD) implantation and a prosthetic mitral valve who presented with generalized malaise and progressive shortness of breath for 6 d. He was found to have positive blood cultures for gram positive rod shaped bacteria identified as Corynebacterium straitum, but was not considered as the etiological pathogen initially as it a usual skin contaminant. Later this bacterium was found to be the causative agent for the patient's endocarditis. This case highlights the importance of identifying the role of this uncommon commensal in invasive disease. With the use of effective antibiotic regimen and awareness of these new pathogens in invasive disease, mortality and morbidity can be prevented with initiation of early appropriate therapy.

Microbiota,renal disease and renal transplantation

Aim of this frontier review has been to highlight the role of microbiota in healthy subjects and in patients affected by renal diseases with particular reference to renal transplantation.The microbiota has a relevant role in conditioning the healthy status and the diseases.In particular gut microbiota is essential in the metabolism of food and has a relevant role for its relationship with the immune system.The indigenous microbiota in patients with chronic renal failure is completely different than that of the healthy subjects and pathobionts appear.This abnormality in microbiota composition is called dysbiosis and may cause a rapid deterioration of the renal function both for activating the immune system and producing large quantity of uremic toxins.Similarly,after renal transplantation the microbiota changes with the appearance of pathobionts,principally in the first period because of the assumption of immunosuppressive drugs and antibiotics.These changes may deeply interfere with the graft outcome causing acute rejection,renal infections,diarrhea,and renal interstitial fibrosis.In addition,change in the microbiota may modify the metabolism of immunosuppressive drugs causing in some patients the need of modifying the immunosuppressant dosing.The restoration of the indigenous microbiota after transplantation is important,either to avoiding the complications that impair the normal renal graft,and because recent studies have documented the role of an indigenous microbiota in inducing tolerance towards the graft.The use of prebiotics,probiotics,smart bacteria and diet modification may restore the indigenous microbiota,but these studies are just at their beginning and more data are needed to draw definitive conclusions.

Etiopathogenesis of inflammatory bowel diseases

Theories explaining the etiopathogenesis of inflammatory bowel disease （IBD） have been proposed ever since Crohn＇s disease （CD） and ulcerative colitis （UC） were recognized as the two major forms of the disease. Although the exact cause（s） and mechanisms of tissue damage in CD and UC have yet to be completely understood, enough progress has occurred to accept the following hypothesis as valid： IBD is an inappropriate immune response that occurs in genetically susceptible individuals as the result of a complex interaction among environmental factors, microbial factors, and the intestinal immune system. Among an almost endless list of environmental factors, smoking has been identified as a risk factor for CD and a protective factor for UC. Among microbial factors, no convincing evidence indicates that classical infectious agents cause IBD, while mounting evidence points to an abnormal immune response against the normal enteric flora as being of central importance. Gut inflammation is mediated by cells of the innate as well as adaptive immune systems, with the additional contribution of non-immune cells, such as epithelial, mesenchymal and endothelial cells, and platelets.

Helicobacter pylori:Commensal,symbiont or pathogen?

This review considers the data on Helicobacter pylori(H.pylori),which have been accumulated over 40 years since its description as an etiological factor in gastrointestinal diseases.The majority of modern publications are devoted to the study of the pathogenic properties of the microorganism in the development of chronic gastritis,peptic ulcer disease,and gastric cancer,as well as methods for its eradication.However,in recent years,there have been more and more studies which have suggested that H.pylori has a beneficial,or potentially positive,effect on the human body.The authors have attempted to objectively analyze the information accumulated in the literature on H.pylori.Some studies consider it as one of the recently identified human bacterial pathogens,and special attention is paid to the evidence suggesting that it is probably part of the composition of the human microbiome as a commensal(commensal from French to English is a table companion)or even a symbiont.The presented data discussing the presence or absence of the effect of H.pylori on human health suggest that there is an apparent ambiguity of the problem.The re-assessment of the data available on H.pylori infection is important in order to answer the question of whether it is necessary to create a program of mass H.pylori eradication or to apply a more personalized approach to treating patients with H.pylori-associated gastrointestinal diseases and to perform eradication therapy.

Therapeutic approaches targeting intestinal microflora in inflammatory bowel disease

Inflammatory bowel diseases, ulcerative colitis, and Crohn＇s disease, are chronic intestinal disorders of unknown etiology in which in genetically susceptible individuals, the mucosal immune system shows an aberrant response towards commensal bacteria. The gastrointestinal tract has developed ingenious mechanisms to coexist with its autologous microflora, but rapidly responds to invading pathogens and then returns to homeostasis with its commensal bacteria after the pathogenic infection is cleared. In case of disruption of this tightly-regulated homeostasis, chronic intestinal inflammation may be induced. Previous studies showed that some commensal bacteria are detrimental while others have either no influence or have a protective action. In addition, each host has a genetically determined response to detrimental and protective bacterial species. These suggest that therapeutic manipulation of imbalance of microflora can influence health and disease. This review focuses on new insights into the role of commensal bacteria in gut health and disease, and presents recent findings in innate and adaptive immune interactions. Therapeutic approaches to modulate balance of intestinal microflora and their potential mechanisms of action are also discussed.

Role of mucosal dendritic cells in inflammatory bowel disease

The gastrointestinal innate and adaptive immune system continuously faces the challenge of potent stimuli from the commensal microflora and food constituents. These local immune responses require a tight control, the outcome of which is in most cases the induction of tolerance. Local T cell immunity is an important compartment of the specif ic intestinal immune system. T cell reactivity is programmed during the initial stage of its activation by professional presenting cells. Mucosal dendritic cells (DCs) are assumed to play key roles in regulating immune responses in the antigen-rich gastrointestinal environment. Mucosal DCs are a heterogeneous population that can either initiate (innate and adaptive) immune responses, or control intestinal inflammation and maintain tolerance. Defects in this regulation are supposed to lead to the two major forms of inflammatory bowel disease (IBD), Crohn's disease (CD) and ulcerative colitis (UC). This review will discuss the emerging role of mucosal DCs in regulating intestinal inflammation and immune responses.

Host-microbial interactions and regulation of intestinal epithelial barrier function: From physiology to pathology

The gastrointestinal tract is the largest reservoir of commensal bacteria in the human body, providing nutrients and space for the survival of microbes while concurrently operating mucosal barriers to confine the microbial population. The epithelial cells linked by tight junctions not only physically separate the microbiota from the lamina propria, but also secrete proinflammatory cytokines and reactive oxygen species in response to pathogen invasion and metabolic stress and serve as a sentinel to the underlying immune cells. Accumulating evidence indicates that commensal bacteria are involved in various physiological functions in the gut and microbial imbalances (dysbiosis) may cause pathology. Commensal bacteria are involved in the regulation of intestinal epithelial cell turnover, promotion of epithelial restitution and reorganization of tight junctions, all of which are pivotal for fortifying barrier function. Recent studies indicate that aberrant bacterial lipopolysaccharide-mediated signaling in gut mucosa may be involved in the pathogenesis of chronic inflammation and carcinogenesis. Our perception of enteric commensals has now changed from one of opportunistic pathogens to active participants in maintaining intestinal homeostasis. This review attempts to explain the dynamic interaction between the intestinal epithelium and commensal bacteria in disease and health status.

Different cytokine response of primary colonic epithelial cells to commensal bacteria

AIM: To determine if primary murine colonic epithelial cells (CEC) respond to commensal bacteria and discriminate between different types of bacteria. METHODS: A novel CEC: bacteria co-culture system was used to compare the ability of the colonic commensal bacteria, Bacteroides ovatus, E coli(SLF) and Lactobacillus rhamnosus (LGG) to modulate production of different cytokines (n = 15) by primary CEC. Antibody staining and flow cytometry were used to investigate Toll-like receptor (TLR) expression by CEC directly ex vivo and TLR responsiveness was determined by examining the ability of TLR ligands to influence CEC cytokine production. RESULTS: Primary CEC constitutively expressed functional TLR2 and TLR4. Cultured in complete medium alone, CEC secreted IL-6, MCP-1 and IP-10 the levels of which were significantly increased upon addition of the TLR ligands peptidoglycan (PGN) and lipopolysaccharide (LPS). Exposure to the commensal bacteria induced or up-regulated different patterns of cytokine production and secretion.E coli induced production of MIP-1α/β and p defensin3 whereas B. ovatus and L. rhamnosus exclusively induced MCP-1 and MIP-2α expression, respectively. TNFa, RANTES and MEC were induced or up-regulated in response to some but not all of the bacteria whereas ENA78 and IP-10 were up-regulated in response to all bacteria. Evidence of bacterial interference and suppression of cytokine production was obtained from mixed bacterial: CEC co-cultures. Probiotic LGG suppressed E coli- and B. ovatus-induced cytokine mRNA accumulation and protein secretion. CONCLUSION: These observations demonstrate the ability of primary CEC to respond to and discriminate between different strains of commensal bacteria and identify a mechanism by which probiotic bacteria (LGG) may exert anti-inflammatory effects in vivo.

Bacteria,inflammation,and colon cancer

Our relationship with the colonic bacterial flora has long been viewed as benign, but recent studies suggest that this symbiosis has risks as well as benefits. This relationship requires that the host not only provide a supportive environment for the symbiotic bacteria, but also actively maintain intact mechanisms for properly managing the physiologic stresses that are closely associated with the symbiont’s essential survival functions. Failure to do so breaches the host- symbiont contract, and can result in serious effects on the health of the host. Recent investigations that employ several knockout mouse models reveal the consequences of genetic deficiency in the host regarding these mechanisms, and the latent, pro-inflammatory, tumorigenic nature of normal bacterial flora. Further study of the interactions between normal bacterial flora and hosts could shed light on the etiologies and pathogenesis of inflammatory diseases and related cancers, with implications for human health.

The oral commensal Streptococcus mitis activates the aryl hydrocarbon receptor in human oral epithelial cells

Streptococcus mitis （S. mitis） is a pioneer commensal bacterial species colonizing many of the surfaces of the oral cavity in healthy individuals. Yet, not much information is available regarding its interaction with the host. We used examination of its transcriptional regulation in oral keratinocytes to elucidate some of its potential roles in the oral cavity. Transcription factor analysis of oral keratinocytes predicted S. mitis.mediated activation of aryl hydrocarbon receptor （AhR）, Activation and functionality of AhR was confirmed through nuclear translocation determined by immunofluorescence microscopy and real-time polymerase chain reaction with reverse transcription analysis of CYPIA1, the hallmark gene for AhR activation. Addition of Streptococcus mutans or Streptococcus gordonfi did not induce CYPIA1 transcription in the keratinocyte cultures. Introduction of an AhR-specific inhibitor revealed that S. mitis-mediated transcription of CXCL2 and CXCL8 was regulated by AhR. Elevated levels of pmstaglandin E2 （enzyme-linked immunosorbent assay） in supernatants from S. mitis-treated oral epithelial cells were also attenuated by inhibition of AhR activity. The observed AhR-regulated activities point to a contribution of S. mitis in the regulation of inflammatory responses and thereby to wound healing in the oral cavity. The concept that the oral commensal microbiota can induce AhR activation is important, also in view of the role that AhR has in modulation of T-cell differentiation and as an anti-inflammatory factor in macrophaees.

Commensal Oral Candida in Asian Cohorts

Samaranayake L. Commensal Oral Candida in Asian Cohorts. International Journal of Oral Science, 1 （1）： 2-5, 2009The oral carriage rate of Candida in healthy humans ranges from 40% to 60%. However for a prolonged period, the oral candidal prevalence in humans was documented essentially using data from studies in the West as their prevalence in inhabitants in different regions of the world,including Asia was not known. Yet, recent reports from a number of studies indicate the quality, quantity and prevalence of oral yeasts differ between Asia and other regions for reason that are still unclear. This mini review on such data from Asian studies on oral carriage of Candida provides another intriguing facet of the behavior of this ubiquitous yeast.

Production of corticotropin-releasing factor and urocortin from human monocyte-derived dendritic cells is stimulated by commensal bacteria in intestine

AIM: To examine whether commensal bacteria are a contributing cause of stress-related mucosal inflammation.

The commensal consortium of the gut microbiome is associated with favorable responses to anti-programmed death protein 1 (PD-1) therapy in thoracic neoplasms

Objective:Immune checkpoint inhibitors have revolutionized cancer therapy for multiple types of solid tumors,but as expected,a large percentage of patients do not show durable responses.Biomarkers that can predict clinical responses to immunotherapies at diagnosis are therefore urgently needed.Herein,we determined the associations between baseline gut commensal microbes and the clinical treatment efficiencies of patients with thoracic neoplasms during anti-programmed death protein 1(PD-1)therapy.Methods:Forty-two patients with advanced thoracic carcinoma who received anti-PD-1 treatment were enrolled in the study.Baseline and time-serial stool samples were analyzed using 16S ribosomal RNA gene sequencing.Tumor responses,patient progression-free survival,and overall survival were used to measure clinical outcomes.Results:The diversities of the baseline gut microbiota were similar between responders(n=23)and nonresponders(n=19).The relative abundances of the Akkermansiaceae,Enterococcaceae,Enterobacteriaceae,Carnobacteriaceae and Clostridiales Family XI bacterial families were significantly higher in the responder group.These 5 bacterial families acted as a commensal consortium and better stratified patients according to clinical responses(P=0.014).Patients with a higher abundance of commensal microbes had prolonged PFS(P=0.00016).Using multivariable analysis,the abundance of the commensal consortium was identified as an independent predictor of anti-PD-1 immunotherapy in thoracic neoplasms(hazard ratio:0.17;95%confidence interval:0.05–0.55;P=0.003).Conclusions:Baseline gut microbiota may have a critical impact on anti-PD-1 treatment in thoracic neoplasms.The abundance of gut commensal microbes at diagnosis might be useful for the early prediction of anti-PD-1 immunotherapy responses.

Alentiana palinpoda,a new commensal polynoid species from a seamount in the Northwest Pacific Ocean

Alentiana has only one member,A.aurantiaca(Verrill,1885),commensal with sea anemone(Bolocera tuediae).Here,Alentiana palinpoda sp.nov.,a second member in the genus Alentiana(subfamily Lepidastheniinae),a new commensal polynoid is described,based on a specimen collected from a deep-water seamount in the Northwest Pacific Ocean.The new species is characterized by large elytra that completely cover the dorsum and are present in every third segment in the posterior regions.Neuropodia are truncated,with two types of neurochaetae;supraacicular chaetae toothed on one side with a slightly inflated end,and subacicular chaetae that are heavy and smooth;the prechaetal lobe is larger than the postchaetal lobe,with the ventral part rolling upward and backward.

Corticotropin-releasing factor secretion from dendritic cells stimulated by commensal bacteria

AIM:To study the production and secretion of corticotropin-releasing factor (CRF) by dendritic cells and the influence of commensal bacteria.METHODS:JAWSⅡ cells (ATCC CRL-11904),a mouse dendritic cell line,were seeded into 24-well culture plates and grown for 3 d.Commensal bacterial strains of Clostridium clostrodiiforme (JCM1291),Bacteroides vulgatus (B.vulgatus) (JCM5856),Escherichia coli (JCM1649),or Fusobacterium varium (F.varium) (ATCC8501) were added to the cells except for the control well,and incubated for 2 h.After incubation,we performed enzyme-linked immunosorbent assay for the cultured medium and reverse transcription polymerase chain reaction for the dendritic cells,and compared these values with controls.RESULTS:The level of CRF secretion by control dendritic cells was 40.4±6.2 pg/mL.The CRF levels for cells incubated with F.varium and B.vulgatus were significantly higher than that of the control (P<0.0001).CRF mRNA was present in the control sample without bacteria,and CRF mRNA levels in all samples treated with bacteria were above that of the control sample.F.varium caused the greatest increase in CRF mRNA expression.CONCLUSION:Our results suggest that dendritic cells produce CRF,a process augmented by commensal bacteria.