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1、PEARLSThe cross-kingdom interaction betweenHelicobacter pylori and Candida albicansXi Chen1,2,Xuedong ZhouID1,2,Binyou LiaoID1,Yujie Zhou1,2,Lei ChengID1,2*,Biao RenID1*1 State Key Laboratory of Oral Diseases&National Clinical Research Center for Oral Diseases&WestChina School of Stomatology,Sichuan
2、 University,Chengdu,China,2 Department of Operative Dentistry andEndodontics,West China Hospital of Stomatology,Sichuan University,Chengdu,China These authors contributed equally to this work.*(LC);(BR)Helicobacter pylori infection and transmission routesHelicobacter pylori is a gram-negative microa
3、erophilic bacterium.The infection of H.pylorican increase the risk of gastric cancer which is the second leading cause of cancer death world-wide 1.The World Health Organizations International Agency for Research on Cancer(IARC)has classified H.pylori as a type I(definite)carcinogen since 1994.H.pyl
4、ori infectionis a global health problem.In developed countries,its infection rate is 20%to 50%,while indeveloping countries,the infection rate of middle-aged people has reached 80%2.The fecaloral and the oraloral routes are considered as the main transmission routes of H.pylori 3.Nevertheless,only H
5、.pylori genes have been detected in saliva and dental plaques,but cultur-able H.pylori has not been isolated yet in large quantities 4,indicating that there may besome new strategies of H.pylori to implement its transmission through oral cavity.Candida albicans,a dimorphic fungus,is one of the most
6、common fungi in the humanbody 5.It was noteworthy that C.albicans and H.pylori were abundant in certain humanniches,such as the root canal necrotic pulp,stomach,duodenum,and vagina 6,suggestingthat C.albicans may interact with H.pylori to promote the growth,spread,and infection of H.pylori in some n
7、onadaptive condition,such as the oral cavity and vagina.The synergy between H.pylori and C.albicans in gastric diseasesH.pylori infection is positively correlated with yeast in gastric diseases 7.A total of 36%gas-tric ulcers patients,2%non-ulcerative dyspepsia patients,and 56%large-scale gastric ul
8、cers(greater than 2 cm)patients with H.pylori have fungal co-colonization in the upper gastroin-testinal tract,such as C.albicans and Candida krusei,indicating the strong relationshipbetween fungi and H.pylori in ulcerative lesions 8.C.albicans is highly correlated with H.pylori in gastric cancer,pe
9、ptic ulcer,and chronic gastritis patients.The gastric ulcer patientwith C.albicans and H.pylori in the stomach developed even larger ulcers.The presence of C.albicans was closely related to the prolongation of gastric diseases by the increase of healingtime and persistence of clinical symptoms 9,10.
10、The strong positive correlation between C.albicans and H.pylori in the development of gastric diseases indicates their synergistic patho-genesis 7.C.albicans may enhance the colonization,toxicity,and pathogenicity of H.pyloriespecially in gastrointestinal diseases through adhesion and the formation
11、of a mixed species,like that C.albicans promotes the pathogenicity of other bacteria 11.PLOS Pathogens|https:/doi.org/10.1371/journal.ppat.1009515May 6,20211/6a1111111111a1111111111a1111111111a1111111111a1111111111OPEN ACCESSCitation:ChenX,ZhouX,LiaoB,ZhouY,ChengL,RenB(2021)Thecross-kingdominteracti
12、onbetweenHelicobacterpyloriandCandidaalbicans.PLoSPathog17(5):e1009515.https:/doi.org/10.1371/journal.ppat.1009515Editor:DeborahA.Hogan,GeiselSchoolofMedicineatDartmouth,UNITEDSTATESPublished:May6,2021Copyright:2021Chenetal.ThisisanopenaccessarticledistributedunderthetermsoftheCreativeCommonsAttribu
13、tionLicense,whichpermitsunrestricteduse,distribution,andreproductioninanymedium,providedtheoriginalauthorandsourcearecredited.Funding:ThisresearchreceivedfundingfromNationalNaturalScienceFoundationofChina,Grantnumber:81870778,81600858toBR,AppliedBasicResearchProgramsofSichuanProvince,Grantnumber2020
14、YJ0227toBR,NationalNaturalScienceFoundationofChina,Grantnumber81870759toLC.Thefundershadnoroleinstudydesign,datacollectionandanalysis,decisiontopublish,orpreparationofthemanuscript.Competinginterests:Theauthorshavedeclaredthatnocompetinginterestsexist.Potential for H.pylori residence within C.albica
15、ns vacuolesH.pylori is an invading intracellular pathogen,and its entry into cells such as gastric epithelialcells,dendritic cells,and macrophages is one of the reasons for the failure of antibiotics treat-ment 12.Interestingly,H.pylori was also found to enter C.albicans yeast cells.Moving“bacte-ria
16、l-like bodies”in the vacuoles of the C.albicans yeast cells from the stomach were observed,and these were identified as H.pylori by PCR and immunofluorescence 1315.These“invaded”C.albicans cells were able to survive from the exposure of high temperature,dryness,and antibiotics.The H.pylori in their
17、vacuole showed an active state of motion under these con-ditions 13,suggesting that the internalization of H.pylori into C.albicans can protect H.pylorifrom strict conditions.Meanwhile,the invading H.pylori seems to be vertically transmitted tothe daughter cells of C.albicans and continue to express
18、 its own proteins through its prolifera-tion within the yeast cells 16.The C.albicans containing H.pylori in this fast-moving state canalso be observed from other body sites,such as the oral cavity and vagina 17.The frequency ofH.pyloriinvaded C.albicans in the oral cavity of the normally born babie
19、s is higher than thatof cesarean birth,indicating that C.albicans in the vagina may be the main reservoir for trans-mitting H.pylori to the newborns through their oral cavity 17.Its possible that C.albicans canact as a shelter and an oral transmission promoter for H.pylori 16,18,19.Besides C.albican
20、s,clinical isolates of Candida dubliniensis,C.krusei,and Candida tropicalis have also found the H.pylori internalization by amplifying the 16S rDNA of H.pylori 20,21,suggesting that this kindof interaction manner between H.pylori and yeast can occur in different species.H.pyloriinvaded C.albicans is
21、 not only widely distributed in the human body,but alsoabundantly in food,such as yogurt,grape juice,bread,preserves,fruits,and honey 22.C.albicans may protect H.pylori against the environmental stresses in these habitats.The inter-nalization into C.albicans could be a crucial strategy for H.pylori
22、to survive and transmit in avariety of environments especially the nonadaptive conditions.Its still worthwhile to note that there are some moving volutin(polyphosphate)granulesknown as“dancing bodies”in the vacuoles of the C.albicans cells 23,which do not dependon the cell cycle phase,but on the gro
23、wth stage,metabolic level,and stress responses 24.Thepresence of H.pylori may induce a stress response that activate the formation of volutin gran-ules in the vacuoles of C.albicans.Therefore,more evidence is needed to distinguish the“dancing bodies”in the vacuole and evaluate the cross-kingdom inte
24、raction mechanismsbetween C.albicans and H.pylori.The pores of C.albicans cell wall may act as the channel which the H.pylori can passthrough.The FITC-IgY-H.pylori can enter into C.albicans yeast cells through the cell wall andeventually accumulated in the vacuoles 25.However,the specific mechanism
25、still needs fur-ther investigation,such as the cell wall/membrane remodeling of C.albicans when coculturedwith H.pylori.Theinternalization ofH.pyloriintoC.albicansishighlyinfluencedbypHstressasthepercent-ageof yeasts harboring bacteria at anacidic pH was nearly twice thanthat observed in the neutral
26、environment 26.But when the pH is lower than 4,the number ofyeasts harbored bacteria fallssharply.This maybe due to the change in thecell wall structure andthe surface electric charge ofC.albicans under acidic conditions,such as thesignificant loss ofthe fibrillar layer,theincreasedexposure of chiti
27、n and-glucans 26,and the change of zeta potential ofC.albicans 27.Possible relationship between the interaction of C.albicans and H.pyloriwith gastrointestinal floraThe clinical outcomes of the H.pyloriinfected patients were quite different due to the diver-sity of the gastric and intestinal microbi
28、ota 28.H.pylori infection can reduce the diversity ofPLOS PATHOGENSPLOS Pathogens|https:/doi.org/10.1371/journal.ppat.1009515May 6,20212/6gastrointestinal flora.The Actinobacteria,Bacteroidetes,Firmicutes,and Proteobacteriashowed a decreased abundance,while Spirochetes and Acidobacteria showed an in
29、creasedabundance 29.The eradication of H.pylori can significantly increase the abundance of thegastric and downstream intestinal flora 30,such as Clostridium,Bacillus,etc.,while the abun-dance of fungi such as yeast was significantly increased 31.Disorders of the intestinal micro-biota from H.pylori
30、infected patients may lead to the destruction of the intestinal barrier,thereby increasing the susceptibility to inflammatory bowel diseases 28.The colonization ofC.albicans in the gastrointestinal tract can also influence gastrointestinal flora.C.albicans cre-ates a niche to increase the growth and
31、 survival of various microorganisms through the forma-tion of the poly-species biofilms with bacteria,such as Bacteroides spp.and Firmicutes spp.32.However,C.albicans can reduce intestinal colonization of Clostridium difficile,a patho-genic agent of inflammatory bowel diseases 33.The“standard triple
32、 treatment”of H.pylori infection recommended a composition of aproton pump inhibitor plus clarithromycin,together with amoxicillin or metronidazole.How-ever,the effectiveness of this treatment declined to unacceptably low levels due to the antibi-otic resistance in less than a decade 34.Moreover,the
33、 use of antibiotics from the“standardtriple treatment”significantly reduced the alpha and beta diversity of gastrointestinal flora,mainly including Bifidobacterium bifidum,Lactobacillus acidophilus,and Escherichia coli.Thesurviving bacteria,such as E.coli,increased the resistant capability to these
34、antibiotics 35.The antibiotics-affected gastrointestinal flora became more vulnerable to the colonization ofC.albicans 36.C.albicans colonized in the gastrointestinal tract may protect H.pylori fromantibiotics killing through endosymbiosis or biofilm formation,then disrupt gastrointestinalmetabolism
35、 and immunity to increase the risk of other diseases.Probiotics may serve as a potential treatmentProbiotics have some natural advantages,such as safety,immunomodulation,and anti-pathogen abilities.They are usually used alone or in combination with drugs to treat gastro-intestinal diseases.Lactobaci
36、llus spp.resided in the human stomach can inhibit H.pylori bysecreting antibacterial substances,competing for binding sites,or interfering with the adhe-sion process to prevent H.pylori colonization,enhance the mucus barrier function,andreduce the hosts inflammatory response 37.The triple therapy su
37、pplied with probiotic,including Saccharomyces boulardii,Limosilactobacillus reuteri,and Lactobacillus casei,forthe treatment of H.pylori infection has the best therapeutic effect with the least adverseevents 34.Meanwhile,probiotics,such as Lactobacillus sp.,can inhibit the adherence,bio-films,hyphae
38、 formation,and virulence expression of C.albicans 38.Lactobacillus rhamno-sus L34 can attenuate local inflammation,severity of intestinal leakage,fecal malnutrition,and systemic inflammation in mice infected with C.albicans 39.Accordingly,the applica-tion of probiotics may be served as a potential t
39、reatment to inhibit the synergistic infectionscaused by H.pylori and C.albicans.More than 50%of people were infected with H.pylori worldwide 2.The triple or quadru-ple therapy with different antibiotics in clinical has gradually failed to eradicate the H.pyloriinfection mainly due to the increased d
40、rug resistance of H.pylori 40.Moreover,these antibi-otics disrupted the balance of the gastrointestinal flora,metabolism,and immunity and evenincreased the risk of other diseases 28,36.The investigation of the interaction between H.pylori and other microorganisms can be one of the new ways to treat
41、H.pylori infection.C.albicans may increase the expression of virulence factors and the growth and colonization ofH.pylori in different environmental conditions to promote its pathogenicity and transmission(Fig 1),since C.albicans synergized with H.pylori to resist its unsuitable living environmentPL
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48、ic ulcer associated with Candida infection.IndianJ Med Microbiol.2007;25(1):578.https:/doi.org/10.4103/0255-0857.31064 PMID:17377355Fig 1.The cross-kingdom interaction between Helicobacter pylori and Candida albicans and the possible mechanisms and outcomes.Thereis a strong positive correlation betw
49、een H.pylori and C.albicans in the colonization and synergistic pathogenesis.H.pylori potentially inhabitwithin C.albicans vacuoles through the endocytosis pathway.The interactions between H.pylori and C.albicans may increase the resistance tothe killing effect of antibiotics and unfavorable living
50、environment through endosymbiosis,adhesion,or formation of mixed biofilms,thenpromote the spread and colonization and increase the virulence factors to affect the occurrence and development of diseases.https:/doi.org/10.1371/journal.ppat.1009515.g001PLOS PATHOGENSPLOS Pathogens|https:/doi.org/10.137