Article Contents
REVIEW   Open Access     Cite

Exploring the epidemiology, pathogenesis, and immunotherapeutic advancements in Clostridium difficile infection

More Information
  • DownLoad: Full size image
    1. Impact of C. difficile: C. difficile is a leading cause of severe gastrointestinal disease with significant complications.

      Traditional antibiotics disrupt the gut microbiota, increasing the risk of recurrent C. difficile infection (CDI).

      Emerging immunotherapies aim to reduce CDI recurrence.

      Long-term immunity strategies aim to promote lasting immunity, improving outcomes and preventing recurrent CDI.

  • Clostridium difficile (C. difficile) is a gram-positive, spore-forming bacillus that thrives in anaerobic conditions. It serves as the primary causative agent for various diseases globally, including nosocomial antibiotic-associated diarrhea and pseudomembranous colitis, potentially leading to fatal outcomes. The production of up to three toxins by this bacterium is considered its primary virulence mechanism in C. difficile infection (CDI). These toxins initiate inflammation, cause tissue damage, and result in diarrhea. Conventional antibiotic treatments for CDI not only substantially reduce intestinal microbiota but also increase CDI recurrence rates. Immunotherapy has emerged as a promising approach for combating CDI, offering a novel strategy to target this challenging pathogen. Various immunotherapeutic modalities, such as monoclonal antibodies targeting specific C. difficile toxins, fecal microbiota transplantation (FMT) to restore microbial balance, and vaccines to stimulate protective immune responses, have shown potential in preclinical and clinical studies. This review examines the current landscape of immunotherapy for CDI, highlighting significant advancements, challenges, and future directions in utilizing the immune system to address this substantial healthcare burden.
  • 加载中
  • [1] McFee R.B. and Abdelsayed G.G. (2009). Clostridium difficile. Dis. Mon. 55:439−470. DOI:10.1016/j.disamonth.2009.04.010

    View in Article CrossRef Google Scholar Scopus

    [2] Kordus S.L., Thomas A.K. and Lacy D.B. (2021). Clostridioides difficile toxins: Mechanisms of action and antitoxin therapeutics. Nat. Rev. Microbiol. 20:285−298. DOI:10.1038/s41579-021-00660-2

    View in Article CrossRef Google Scholar

    [3] Buddle J.E. and Fagan, R.P. (2023). Pathogenicity and virulence of Clostridioides difficile. Virulence 14:2150452. DOI:10.1080/21505594.2022.2150452

    View in Article CrossRef Google Scholar Scopus

    [4] Davies K., Lawrence J., Berry C., et al. (2020). Risk factors for primary Clostridium difficile infection; results from the observational study of risk factors for Clostridium difficile infection in hospitalized patients with infective diarrhea (ORCHID). Front. Pub. Heal. 8:293. DOI:10.3389/fpubh.2020.00293

    View in Article CrossRef Google Scholar Scopus

    [5] Eyre D.W., Walker S., Wyllie D., et al. (2012). Predictors of first recurrence of Clostridium difficile infection: Implications for initial management. Clin Infect Dis. 55:S77−S87. DOI:10.1093/cid/cis356

    View in Article CrossRef Google Scholar Scopus

    [6] Etienne-Mesmin L., Chassaing B., Adekunle O., et al. (2018). Clostridium difficile toxin-positive latently infect mouse colonies and protect against highly pathogenic. Gut 67:860−871. DOI:10.1136/gutjnl-2016-313510

    View in Article CrossRef Google Scholar Scopus

    [7] Lessa F.C., Mu Y., Bamberg W.M., et al. (2015). Burden of Clostridium difficile infection in the United States. N. Engl. J. Med. 372:825−834. DOI:10.1056/NEJMoa1408913

    View in Article CrossRef Google Scholar Scopus

    [8] Guh A.Y., Mu Y., Winston L.G., et al. (2020). Trends in U. S. burden of Clostridioides difficile infection and outcomes. N. Engl. J. Med. 382:1320−1330. DOI:10.1056/NEJMoa1910215

    View in Article CrossRef Google Scholar Scopus

    [9] Dubberke E.R. and Olsen M.A. (2012). Burden of Clostridium difficile on the healthcare system. Clin Infect Dis. 55:S88−S92. DOI:10.1093/cid/cis335

    View in Article CrossRef Google Scholar Scopus

    [10] Collins D.A., Sohn K.M., Wu Y., et al. (2020). Clostridioides difficile infection in the Asia-Pacific region. Emerg. Microbes Infect. 9:42−52. DOI:10.1080/22221751.2019.1702480

    View in Article CrossRef Google Scholar Scopus

    [11] Warny M., Pepin J., Fang A., et al. (2005). Toxin production by an emerging strain of Clostridium difficile associated with outbreaks of severe disease in North America and Europe. Lancet 366:1079−1084. DOI:10.1016/S0140-6736(05)67420-X

    View in Article CrossRef Google Scholar Scopus

    [12] Tamez-Torres K.M., Torres-González P., Leal-Vega F., et al. (2017). Impact of Clostridium difficile infection caused by the NAP1/RT027 strain on severity and recurrence during an outbreak and transition to endemicity in a Mexican tertiary care center. Int. J. Infect. Dis. 65:44−49. DOI:10.1016/j.ijid.2017.09.022

    View in Article CrossRef Google Scholar Scopus

    [13] Gateau C., Deboscker S., Couturier J., et al. (2019). Local outbreak of Clostridioides difficile PCR-Ribotype 018 investigated by multi locus variable number tandem repeat analysis, whole genome multi locus sequence typing and core genome single nucleotide polymorphism typing. Anaerobe. 60:102087−102087. DOI:10.1016/j.anaerobe.2019.102087

    View in Article CrossRef Google Scholar Scopus

    [14] Kim J., Kim Y. and Pai H. (2016). Clinical characteristics and treatment outcomes of Clostridium difficile infections by PCR ribotype 017 and 018 strains. PloS One. 11:e0168849−e0168849. DOI:10.1371/journal.pone.0168849

    View in Article CrossRef Google Scholar Scopus

    [15] Hung Y.-P., Huang I.H., Lin H.-J., et al. (2016). Predominance of Clostridium difficile ribotypes 017 and 078 among toxigenic clinical isolates in southern Taiwan. PloS One 11:e0166159−e0166159. DOI:10.1371/journal.pone.0166159

    View in Article CrossRef Google Scholar Scopus

    [16] Shin B.-M., Kuak E.Y., Yoo S.J., et al. (2008). Emerging toxin A−B+ variant strain of Clostridium difficile responsible for pseudomembranous colitis at a tertiary care hospital in Korea. Diagn. Microbiol. Infect. Dis. 60:333−337. DOI:10.1016/j.diagmicrobio.2007.10.022

    View in Article CrossRef Google Scholar Scopus

    [17] Drudy D., Harnedy N., Fanning S., et al. (2007). Emergence and control of fluoroquinolone‐resistant, toxin A–aegative, toxin B–positive Clostridium difficile. Infect. Control Hosp. Epidemiol. 28:932−940. DOI:10.1086/519181

    View in Article CrossRef Google Scholar Scopus

    [18] Cheng V.C.C., Yam W.C., Chan J.F.W., et al. (2009). Clostridium difficile ribotype 027 arrives in Hong Kong. Int. J. Antimicrob. Agents. 34:492−493. DOI:10.1016/j.ijantimicag.2009.04.004

    View in Article CrossRef Google Scholar Scopus

    [19] Cao Y., Wang L., Ke S., et al. (2021). Fecal mycobiota combined with host immune factors distinguish Clostridioides difficile infection from asymptomatic carriage. Gastroenterology. 160:2328−2339.e2326. DOI:10.1053/j.gastro.2021.02.069

    View in Article CrossRef Google Scholar

    [20] Webb Brandon, J., Subramanian, A., Lopansri, B., et al. (2020). Antibiotic exposure and risk for hospital-associated Clostridioides difficile infection. Antimicrob. Agents Chemother. 64 :10.1128/aac.02169-02119. DOI:10.1128/aac.02169-19.

    View in Article Google Scholar

    [21] Fletcher J.R., Erwin S., Lanzas C., et al. (2018). Shifts in the gut metabolome and Clostridium difficile transcriptome throughout colonization and infection in a mouse model. mSphere 3:e00089−18. DOI:10.1128/mSphere.00089-18

    View in Article CrossRef Google Scholar Scopus

    [22] Allegretti J.R., Kearney S., Li, N., et al. (2016). 95 Clostridium difficile infection associates with distinct bile acid and microbiome profiles. Gastroenterology 150:S24. DOI:10.1016/S0016-5085(16)30206-2

    View in Article CrossRef Google Scholar Scopus

    [23] Schubert Alyxandria M., Sinani H. and Schloss Patrick, D. (2015). Antibiotic-induced alterations of the murine gut microbiota and subsequent effects on colonization resistance against Clostridium difficile. mBio 6 : 10.1128/mbio.00974-00915. DOI:10.1128/mbio.00974-15.

    View in Article Google Scholar

    [24] Lin C.-Y., Cheng, H.-T., Kuo C.-J., et al. (2022). Proton pump inhibitor-induced gut dysbiosis increases mortality rates for patients with Clostridioides difficile infection. Microbiol. Spectr. 10:e00486−00422. DOI:10.1128/spectrum.00486-22

    View in Article CrossRef Google Scholar

    [25] Dalal R.S. and Allegretti J.R. (2021). Diagnosis and management of Clostridioides difficile infection in patients with inflammatory bowel disease. Curr. Opin. Gastroenterol. 37:336−343. DOI:10.1097/mog.0000000000000739

    View in Article CrossRef Google Scholar Scopus

    [26] Sokol H., Jegou S., McQuitty C., et al. (2018). Specificities of the intestinal microbiota in patients with inflammatory bowel disease and Clostridium difficile infection. Gut Microbes 9:55−60. DOI:10.1080/19490976.2017.1361092

    View in Article CrossRef Google Scholar Scopus

    [27] Abernathy-Close L., Barron Madeline R., George James M., et al. (2021). Intestinal inflammation and altered gut microbiota associated with inflammatory bowel disease render mice susceptible to Clostridioides difficile colonization and infection. mBio 12 :10.1128/mbio.02733-02720. DOI:10.1128/mbio.02733-20.

    View in Article Google Scholar

    [28] Ananthakrishnan A.N., Oxford E.C., Nguyen D.D., et al. (2013). Genetic risk factors for Clostridium difficile infection in ulcerative colitis. Aliment. Pharmacol. Ther. 38:522−530. DOI:10.1111/apt.12425

    View in Article CrossRef Google Scholar Scopus

    [29] Spigaglia P. (2020). COVID-19 and Clostridioides difficile infection (CDI): Possible implications for elderly patients. Anaerobe 64:102233. DOI:10.1016/j.anaerobe.2020.102233

    View in Article CrossRef Google Scholar Scopus

    [30] Imlay H., Kaul D. and Rao K. (2016). Risk factors for Clostridium difficile infection in HIV-infected patients. SAGE Open Med. 4 :2050312116684295. DOI:10.1177/2050312116684295.

    View in Article Google Scholar

    [31] Miller A.C., Sewell D.K., Segre A.M., et al. (2021). Risk for Clostridioides difficile iinfection among hospitalized patients associated with multiple healthcare exposures prior to admission. J. Infect. Dis. 224:684−694. DOI:10.1093/infdis/jiaa773

    View in Article CrossRef Google Scholar

    [32] Tschudin-Sutter S., Kuijper E.J., Durovic A., et al. (2018). Guidance document for prevention of Clostridium difficile infection in acute healthcare settings. Clin. Microbiol. Infect. 24:1051−1054. DOI:10.1016/j.cmi.2018.02.020

    View in Article CrossRef Google Scholar Scopus

    [33] Asempa, T.E., and Nicolau, D.P. (2017). Clostridium difficile infection in the elderly: an update on management. Clin. Interv. Aging 12:1799−1809. DOI:10.2147/CIA.S149089

    View in Article CrossRef Google Scholar Scopus

    [34] Yoshikawa T.T. and Norman, D.C. (2017). Geriatric infectious diseases: current concepts on diagnosis and management. J. Am. Geriatr. Soc. 65:631−641. DOI:10.1111/jgs.14731

    View in Article CrossRef Google Scholar

    [35] Abernathy-Close L., Dieterle Michael G., Vendrov Kimberly C., et al. (2020). Aging dampens the intestinal innate immune response during severe Clostridioides difficile infection and is associated with altered cytokine levels and granulocyte mobilization. Infect. Immun. 88:e00960−19. DOI:10.1128/iai.00960-19

    View in Article CrossRef Google Scholar

    [36] Gregory A.L., Pensinger D.A. and Hryckowian A.J. (2021). A short chain fatty acid–centric view of Clostridioides difficile pathogenesis. PLoS Pathog. 17:e1009959. DOI:10.1371/journal.ppat.1009959

    View in Article CrossRef Google Scholar

    [37] Lv J., Da R., Cheng Y., et al. (2020). Mechanism of antibacterial activity of bacillus amyloliquefaciens C-1 lipopeptide toward anaerobic Clostridium difficile. Biomed. Res. Int. 2020:3104613. DOI:10.1155/2020/3104613

    View in Article CrossRef Google Scholar Scopus

    [38] Nagao-Kitamoto H., Leslie J.L., Kitamoto S., et al. (2020). Interleukin-22-mediated host glycosylation prevents Clostridioides difficile infection by modulating the metabolic activity of the gut microbiota. Nat. Med. 26:608−617. DOI:10.1038/s41591-020-0764-0

    View in Article CrossRef Google Scholar Scopus

    [39] Schumacher J., Nienhaus A., Heber S., et al. (2023). Exploring the inhibitory potential of the antiarrhythmic drug amiodarone against Clostridioides difficile toxins TcdA and TcdB. Gut Microbes 15:2256695. DOI:10.1080/19490976.2023.2256695

    View in Article CrossRef Google Scholar Scopus

    [40] Chandrasekaran R., Kenworthy A.K. and Lacy, D.B. (2016). Clostridium difficile toxin a undergoes clathrin-independent, PACSIN2-dependent endocytosis. PLoS Pathog. 12:e1006070. DOI:10.1371/journal.ppat.1006070

    View in Article CrossRef Google Scholar Scopus

    [41] Tao L., Tian S., Zhang J., et al. (2019). Sulfated glycosaminoglycans and low-density lipoprotein receptor contribute to Clostridium difficile toxin A entry into cells. Nat. Microbiol. 4:1760−1769. DOI:10.1038/s41564-019-0464-z

    View in Article CrossRef Google Scholar Scopus

    [42] Tian S., Xiong X., Zeng J., et al. (2022). Identification of TFPI as a receptor reveals recombination-driven receptor switching in Clostridioides difficile toxin B variants. Nat. Commun. 13:6786. DOI:10.1038/s41467-022-33964-9

    View in Article CrossRef Google Scholar Scopus

    [43] Luo J., Yang Q., Zhang X., et al. (2022). TFPI is a colonic crypt receptor for TcdB from hypervirulent clade 2 C. difficile. Cell 185:980−994.e915. DOI:10.1016/j.cell.2022.02.010

    View in Article CrossRef Google Scholar Scopus

    [44] Chen P., Zeng J., Liu Z., et al. (2021). Structural basis for CSPG4 as a receptor for TcdB and a therapeutic target in Clostridioides difficile infection. Nat. Commun. 12:3748. DOI:10.1038/s41467-021-23878-3

    View in Article CrossRef Google Scholar Scopus

    [45] Schöttelndreier D., Langejürgen A., Lindner R., et al (2020). Low density lipoprotein receptor-related protein-1 (LRP1) is involved in the uptake of Clostridioides difficile toxin A and serves as an internalizing receptor. Front. Cell. Infect. Microbiol. 10 :565465. DOI:10.3389/fcimb.2020.565465.

    View in Article Google Scholar

    [46] Castro-Córdova P., Otto-Medina M., Montes-Bravo N., et al. (2023). Redistribution of the novel Clostridioides difficile spore adherence receptor E-cadherin by TcdA and TcdB increases spore binding to adherens junctions. Infect. Immun. 91:e00476−00422. DOI. DOI:10.1128/iai.00476-22

    View in Article CrossRef Google Scholar

    [47] Chen X., Yang X., de Anda J., et al. (2020). Clostridioides difficile toxin A remodels membranes and mediates DNA entry into cells to activate toll-like receptor 9 signaling. Gastroenterology 159:2181−2192.e2181. DOI:10.1053/j.gastro.2020.08.038

    View in Article CrossRef Google Scholar

    [48] Carter Glen, P., Chakravorty, A., Pham Nguyen Tu, A., et al. (2015). Defining the roles of TcdA and TcdB in localized gastrointestinal disease, systemic organ damage, and the host response during Clostridium difficile infections. mBio 6 : 10.1128/mbio.00551-00515. DOI:10.1128/mbio.00551-15.

    View in Article Google Scholar

    [49] Yu, H., Chen, K., Sun, Y., et al. (2017). Cytokines are markers of the Clostridium difficile-induced inflammatory response and predict disease severity. Clin Vaccine Immunol. 24:e00037−00017. DOI:10.1128/CVI.00037-17

    View in Article CrossRef Google Scholar Scopus

    [50] Huang J., Kelly C.P., Bakirtzi K., et al. (2019). Clostridium difficile toxins induce VEGF-A and vascular permeability to promote disease pathogenesis. Nat. Microbiol. 4:269−279. DOI:10.1038/s41564-018-0300-x

    View in Article CrossRef Google Scholar Scopus

    [51] Gerding D.N., Johnson S., Rupnik M. et al. (2014). Clostridium difficile binary toxin CDT: Mechanism, epidemiology, and potential clinical importance. Gut Microbes 5:15−27. DOI:10.4161/gmic.26854

    View in Article CrossRef Google Scholar Scopus

    [52] Boraschi D. and Tagliabue, A. (2023). Harnessing the power of inflammation in immunoprevention and immunotherapy. The Innovation Life 1:100025. DOI:10.59717/j.xinn-life.2023.100025

    View in Article CrossRef Google Scholar

    [53] Chen X. and Kelly C. (2018). C. difficile on and off: a dual role for cysteine protease autoprocessing of toxin B on cytotoxicity vs proinflammatory toxin actions? Cell. Mol. Gastroenterol. Hepatol. 5 :654-655. DOI:10.1016/j.jcmgh.2018.02.011.

    View in Article Google Scholar

    [54] Xu H., Yang J., Gao W., et al. (2014). Innate immune sensing of bacterial modifications of Rho GTPases by the Pyrin inflammasome. Nature 513:237−241. DOI:10.1038/nature13449

    View in Article CrossRef Google Scholar Scopus

    [55] Saavedra P.H.V., Huang L., Ghazavi F., et al. (2018). Apoptosis of intestinal epithelial cells restricts Clostridium difficile infection in a model of pseudomembranous colitis. Nat. Commun. 9:4846. DOI:10.1038/s41467-018-07386-5

    View in Article CrossRef Google Scholar Scopus

    [56] Lyerly D.M., Saum K.E., Macdonald D.K., et al. (1985). Effects of Clostridium difficile toxins given intragastrically to animals. Infect. Immun. 47:349−352. DOI:10.1128/IAI.47.2.349-352.1985

    View in Article CrossRef Google Scholar Scopus

    [57] Sambol S.P., Johnson S., Gerding D.N., et al. (2009). Toxin B is essential for virulence of Clostridium difficile. Nature 458:1176−1179. DOI:10.1038/nature07822

    View in Article CrossRef Google Scholar Scopus

    [58] Komatsu M., Kato H., Aihara M., et al. (2003). High frequency of antibiotic-associated diarrhea due to toxin A-negative, toxin B-positive Clostridium difficile in a hospital in Japan and risk factors for infection. Eur. J. Clin. Microbiol. Infect. Dis. 22:525−529. DOI:10.1007/s10096-003-0992-5

    View in Article CrossRef Google Scholar Scopus

    [59] Carter G.P., Rood J.I. and Lyras, D. (2010). The role of toxin A and toxin B in Clostridium difficile-associated disease. Gut Microbes 1:58−64. DOI:10.4161/gmic.1.1.10768

    View in Article CrossRef Google Scholar Scopus

    [60] Heap J.T., Kelly M.L., Minton N.P., et al. (2010). The role of toxin A and toxin B in Clostridium difficile infection. Nature 467:711−713. DOI:10.1038/nature09397

    View in Article CrossRef Google Scholar Scopus

    [61] Lin Q., Pollock N.R., Banz A., et al. (2020). Toxin A–predominant pathogenic Clostridioides difficile: a novel clinical phenotype. Clin. Infect. Dis. 70:2628−2633. DOI:10.1093/cid/ciz727

    View in Article CrossRef Google Scholar

    [62] Wang L., Cao Y., Lou, E., et al. (2023). The role of gut fungi in Clostridioides difficile infection. Biomed. J. 47:100686. DOI:10.1016/j.bj.2023.100686

    View in Article CrossRef Google Scholar Scopus

    [63] van Nood E., Vrieze A., Nieuwdorp M., et al. (2013). Duodenal infusion of donor feces for recurrent Clostridium difficile. N. Engl. J. Med. 368:407−415. DOI:10.1056/NEJMoa1205037

    View in Article CrossRef Google Scholar Scopus

    [64] Danne C., Rolhion N. and Sokol, H. (2021). Recipient factors in faecal microbiota transplantation: one stool does not fit all. Nat. Rev. Gastroenterol. Hepatol. 18:503−513. DOI:10.1038/s41575-021-00441-5

    View in Article CrossRef Google Scholar Scopus

    [65] Hamilton M.J., Weingarden A.R., Unno T., et al. (2013). High-throughput DNA sequence analysis reveals stable engraftment of gut microbiota following transplantation of previously frozen fecal bacteria. Gut Microbes 4:125−135. DOI:10.4161/gmic.23571

    View in Article CrossRef Google Scholar Scopus

    [66] Sehgal K. and Khanna, S. (2021). Gut microbiome and Clostridioides difficile infection: A closer look at the microscopic interface. Ther. Adv. Gastroenterol. 14 :1756284821994736. DOI:10.1177/1756284821994736.

    View in Article Google Scholar

    [67] Fachi J.L., Sécca C., Rodrigues P.B., et al. (2019). Acetate coordinates neutrophil and ILC3 responses against C. difficile through FFAR2. J. Exp. Med. 217 :e20190489. DOI:10.1084/jem.20190489.

    View in Article Google Scholar

    [68] Yang C., Mogno I., Contijoch E.J., et al. (2020). Fecal IgA levels are determined by strain-level differences in bacteroides ovatus and are modifiable by gut microbiota manipulation. Cell Host Microbe. 27:467−475.e466. DOI:10.1016/j.chom.2020.01.016

    View in Article CrossRef Google Scholar

    [69] Frisbee A.L. and Petri W.A. (2020). Considering the immune system during fecal microbiota transplantation for Clostridioides difficile infection. Trends Mol. Med. 26:496−507. DOI:10.1016/j.molmed.2020.01.009

    View in Article CrossRef Google Scholar

    [70] Yadegar A., Pakpoor S., Ibrahim F.F., et al. (2023). Beneficial effects of fecal microbiota transplantation in recurrent Clostridioides difficile infection. Cell Host Microbe. 31:695−711. DOI:10.1016/j.chom.2023.03.019

    View in Article CrossRef Google Scholar Scopus

    [71] Seekatz A.M., Aas J., Gessert C.E., et al. (2014). Recovery of the gut microbiome following fecal microbiota transplantation. mBio 5:e00893−00814. DOI:10.1128/mBio.00893-14

    View in Article CrossRef Google Scholar Scopus

    [72] Moreau G.B., Naz F. and Petri, W.A. (2024). Fecal microbiota transplantation stimulates type 2 and tolerogenic immune responses in a mouse model. Anaerobe 86:102841. DOI:10.1016/j.anaerobe.2024.102841

    View in Article CrossRef Google Scholar Scopus

    [73] Cook L., Rees W.D., Wong M.Q., et al. (2021). Fecal microbiota transplantation for recurrent Clostridioides difficile infection enhances adaptive immunity to C. difficile Toxin B. Gastroenterology 160:2155−2158.e2154. DOI:10.1053/j.gastro.2021.01.009

    View in Article CrossRef Google Scholar

    [74] Buffie C.G., Bucci V., Stein R.R., et al. (2015). Precision microbiome reconstitution restores bile acid mediated resistance to Clostridium difficile. Nature 517:205−208. DOI:10.1038/nature13828

    View in Article CrossRef Google Scholar Scopus

    [75] Jan N., Hays R.A., Oakland D.N., et al. (2021). Fecal microbiota transplantation increases colonic IL-25 and dampens tissue inflammation in patients with recurrent Clostridioides difficile. mSphere 6:e0066921. DOI:10.1128/msphere.00669-21

    View in Article CrossRef Google Scholar

    [76] Ghani R., Mullish B.H., Roberts L.A., et al. (2022). The potential utility of fecal (or intestinal) microbiota transplantation in controlling infectious diseases. Gut Microbes 14:2038856. DOI:10.1080/19490976.2022.2038856

    View in Article CrossRef Google Scholar Scopus

    [77] Burrello C., Garavaglia F., Cribiù F.M., et al. (2018). Therapeutic faecal microbiota transplantation controls intestinal inflammation through IL10 secretion by immune cells. Nat. Commun. 9:5184. DOI:10.1038/s41467-018-07359-8

    View in Article CrossRef Google Scholar Scopus

    [78] Nakajima A., Sasaki T., Itoh K., et al. (2020). A soluble fiber diet increases bacteroides fragilis group abundance and immunoglobulin a production in the Gut. Appl. Environ. Microbiol. 86:e00405−00420. DOI:10.1128/AEM.00405-20

    View in Article CrossRef Google Scholar

    [79] Segal J.P., Mullish B.H., Quraishi M.N., et al. (2020). Mechanisms underpinning the efficacy of faecal microbiota transplantation in treating gastrointestinal disease. Ther. Adv. Gastroenterol. 13 :1756284820946904. DOI: 10.1177/1756284820946904.

    View in Article Google Scholar

    [80] Johal S.S., Lambert C.P., Hammond J., et al. (2004). Colonic IgA producing cells and macrophages are reduced in recurrent and non-recurrent Clostridium difficile associated diarrhoea. J. Clin. Pathol. 57:973−979. DOI:10.1136/jcp.2003.015875

    View in Article CrossRef Google Scholar Scopus

    [81] Warny M., Vaerman J.P., Avesani V., et al (1994). Human antibody response to Clostridium difficile toxin A in relation to clinical course of infection. Infect. Immun. 62 :384-389. DOI:10.1128/IAI.62.2.384-389.1994.

    View in Article Google Scholar

    [82] Kyne L., Warny M., Qamar A., et al. (2001). Association between antibody response to toxin A and protection against recurrent Clostridium difficile diarrhoea. Lancet 357:189−193. DOI:10.1016/S0140-6736(00)03592-3

    View in Article CrossRef Google Scholar Scopus

    [83] Qiu H., Cassan R., Johnstone D., et al. (2016). Novel Clostridium difficile anti-toxin (TcdA and TcdB) humanized monoclonal antibodies demonstrate in vitro neutralization across a broad spectrum of clinical strains and in vivo potency in a hamster spore challenge model. Plos One 11:e0157970. DOI:10.1371/journal.pone.0157970

    View in Article CrossRef Google Scholar Scopus

    [84] Humphreys David P. and Wilcox Mark, H. (2014). Antibodies for treatment of Clostridium difficile infection. Clin. Vaccine Immunol. 21:913−923. DOI:10.1128/CVI.00116-14

    View in Article CrossRef Google Scholar Scopus

    [85] Israel L., Deborah C M., Brett A L., et al. (2010). Treatment with monoclonal antibodies against Clostridium difficile toxins. N. Engl. J. Med. 362:197−205. DOI:10.1056/NEJMoa0907635

    View in Article CrossRef Google Scholar Scopus

    [86] Warn P., Thommes P., Sattar A., et al. (2016). Disease progression and resolution in rodent models of Clostridium difficile infection and impact of antitoxin antibodies and vancomycin. Antimicrob. Agents Chemother. 60:6471−6482. DOI:10.1128/aac.00974-16

    View in Article CrossRef Google Scholar Scopus

    [87] Marozsan A.J., Ma D., Nagashima K.A., et al. (2012). Protection against Clostridium difficile infection with broadly neutralizing antitoxin monoclonal antibodies. J. Infect. Dis. 206:706−713. DOI:10.1093/infdis/jis416

    View in Article CrossRef Google Scholar Scopus

    [88] Davies N.L., Compson J.E., MacKenzie B., et al. (2013). A mixture of functionally oligoclonal humanized monoclonal antibodies that neutralize Clostridium difficile TcdA and TcdB with high levels of in vitro potency shows in vivo protection in a hamster infection model. Clin. Vaccine Immunol. 20:377−390. DOI:10.1128/CVI.00625-12

    View in Article CrossRef Google Scholar Scopus

    [89] Wilcox M.H., Gerding D.N., Poxton I.R., et al. (2017). Bezlotoxumab for prevention of recurrent Clostridium difficile infection. N. Engl. J. Med. 376:305−317. DOI:10.1056/NEJMoa1602615

    View in Article CrossRef Google Scholar Scopus

    [90] Yang Z., Shi L., Yu H., et al. (2016). Intravenous adenovirus expressing a multi-specific, single-domain antibody neutralizing TcdA and TcdB protects mice from Clostridium difficile infection. FEMS Pathog. Dis. 74:ftw078. DOI:10.1093/femspd/ftw078

    View in Article CrossRef Google Scholar Scopus

    [91] Kelly C.P., Poxton I.R., Shen J., et al. (2019). Effect of Endogenous Clostridioides difficile Toxin Antibodies on Recurrence of C. difficile Infection. . Clin. Infect. Dis. 71:81−86. DOI:10.1093/cid/ciz809

    View in Article CrossRef Google Scholar

    [92] Hernandez L., Kroh H., Hsieh E., et al. (2017). Epitopes and mechanism of action of the Clostridium difficile toxin A-neutralizing antibody actoxumab. J. Mol. Biol. 429:1030−1044. DOI:10.1016/j.jmb.2017.02.010

    View in Article CrossRef Google Scholar Scopus

    [93] Babcock Gregory J., Broering Teresa J., Hernandez Hector J., et al. (2006). Human monoclonal antibodies directed against toxins A and B prevent Clostridium difficile-induced mortality in hamsters. Infect. Immun. 74:6339−6347. DOI:10.1128/iai.00982-06

    View in Article CrossRef Google Scholar Scopus

    [94] Zhang Q., Widmer G. and Tzipori S. (2013). A pig model of the human gastrointestinal tract. Gut Microbes 4:193−200. DOI:10.4161/gmic.23867

    View in Article CrossRef Google Scholar Scopus

    [95] Steele J., Mukherjee J., Parry N., et al. (2013). Antibody against TcdB, but not TcdA, prevents development of gastrointestinal and systemic Clostridium difficile disease. J. Infect. Dis. 207:323−330. DOI:10.1093/infdis/jis669

    View in Article CrossRef Google Scholar Scopus

    [96] Abramowicz M., Zuccotti G. and Pflomm, J.-M. (2017). Bezlotoxumab (Zinplava) for prevention of recurrent Clostridium difficile infection. JAMA 318:659−660. DOI:10.1001/jama.2017.10092

    View in Article CrossRef Google Scholar Scopus

    [97] Mullard A. (2016). FDA approves antitoxin antibody. Nat. Rev. Drug Discov. 15:811. DOI:10.1038/nrd.2016.257

    View in Article CrossRef Google Scholar Scopus

    [98] Donald R.G.K., Flint M., Kalyan N., et al. (2013). A novel approach to generate a recombinant toxoid vaccine against Clostridium difficile. Microbiology 159:1254−1266. DOI:10.1099/mic.0.066712-0

    View in Article CrossRef Google Scholar Scopus

    [99] Kitchin N., Remich S.A., Peterson J., et al. (2020). A phase 2 study evaluating the safety, tolerability, and immunogenicity of two 3-dose regimens of a Clostridium difficile vaccine in healthy US adults aged 65 to 85 years. Clin. Infect. Dis. 70:1−10. DOI:10.1093/cid/ciz153

    View in Article CrossRef Google Scholar Scopus

    [100] de Bruyn G., Gordon D.L., Steiner T., et al. (2021). Safety, immunogenicity, and efficacy of a Clostridioides difficile toxoid vaccine candidate: A phase 3 multicentre, observer-blind, randomised, controlled trial. Lancet Infect. Dis. 21:252−262. DOI:10.1016/S1473-3099(20)30331-5

    View in Article CrossRef Google Scholar

    [101] de Bruyn G., Saleh J., Workman D., et al. (2016). Defining the optimal formulation and schedule of a candidate toxoid vaccine against Clostridium difficile infection: A randomized Phase 2 clinical trial. Vaccine 34:2170−2178. DOI:10.1016/j.vaccine.2016.03.028

    View in Article CrossRef Google Scholar Scopus

    [102] Foglia G., Shah S., Luxemburger C., et al. (2012). Clostridium difficile: Development of a novel candidate vaccine. Vaccine 30:4307−4309. DOI:10.1016/j.vaccine.2012.01.056

    View in Article CrossRef Google Scholar Scopus

    [103] Feuerstadt P., Louie T.J., Lashner B., et al. (2022). SER-109, an oral microbiome therapy for recurrent Clostridioides difficile infection. N. Engl. J. Med. 386:220−229. DOI:10.1056/NEJMoa2106516

    View in Article CrossRef Google Scholar

    [104] Chandrabali G., Janneke M.V., Xinhua C., et al. (2013). Toll-like receptor 5-dependent immunogenicity and protective efficacy of a recombinant fusion protein vaccine containing the nontoxic domains of Clostridium difficile toxins A and B and salmonella enterica serovar typhimurium flagellin in a mouse model of Clostridium difficile disease. Infect. Immun. 81:2190−2196. DOI:10.1128/IAI.01074-12

    View in Article CrossRef Google Scholar Scopus

    [105] Wang S., Heuler J., Wickramage I., et al. (2022). Genomic and phenotypic characterization of the nontoxigenic Clostridioides difficile strain CCUG37785 and demonstration of its therapeutic potential for the prevention of C. difficile infection. Microbiol. Spectr. 10:e0178821−e0178821. DOI:10.1128/spectrum.01788-21

    View in Article CrossRef Google Scholar

    [106] Zheng L., Kelly C.J., Battista K.D., et al. (2017). Microbial-derived butyrate promotes epithelial barrier function through IL-10 receptor-dependent repression of claudin-2. J. Immunol. 199:2976−2984. DOI:10.4049/jimmunol.1700105

    View in Article CrossRef Google Scholar Scopus

    [107] Inan M.S., Rasoulpour R.J., Yin L., et al. (2000). The luminal short-chain fatty acid butyrate modulates NF-κB activity in a human colonic epithelial cell line. Gastroenterology 118:724−734. DOI:10.1016/S0016-5085(00)70142-9

    View in Article CrossRef Google Scholar Scopus

    [108] Hayashi A., Nagao-Kitamoto H., Kitamoto S., et al. (2021). The butyrate-producing bacterium Clostridium butyricum suppresses Clostridioides difficile infection via neutrophiland antimicrobial cytokine-dependent but GPR43/109a-independent mechanisms. J. Immunol. 206:1576−1585. DOI:10.4049/jimmunol.2000353

    View in Article CrossRef Google Scholar

    [109] Best E.L., Freeman J. and Wilcox, M.H. (2012). Models for the study of Clostridium difficile infection. Gut Microbes 3:145−167. DOI:10.4161/gmic.19526

    View in Article CrossRef Google Scholar Scopus

    [110] Gardiner D.F., Rosenberg T., Zaharatos J., et al. (2009). A DNA vaccine targeting the receptor-binding domain of Clostridium difficile toxin A. Vaccine 27:3598−3604. DOI:10.1016/j.vaccine.2009.03.058

    View in Article CrossRef Google Scholar Scopus

    [111] Matchett W.E., Anguiano-Zarate S., Malewana G.B.R., et al. (2020). A replicating single-cycle adenovirus vaccine effective against Clostridium difficile. Vaccines 8:470. DOI:10.3390/vaccines8030470

    View in Article CrossRef Google Scholar Scopus

    [112] Zhang B.-Z., Cai J., Yu B., et al. (2016). A DNA vaccine targeting TcdA and TcdB induces protective immunity against Clostridium difficile. BMC Infect. Dis. 16:596. DOI:10.1186/s12879-016-1924-1

    View in Article CrossRef Google Scholar Scopus

    [113] Dieterle M.G., Rao K. and Young, V.B. (2019). Novel therapies and preventative strategies for primary and recurrent Clostridium difficile infections: Novel therapies for C. difficile infections. Ann. N. Y. Acad. Sci. 1435:110−138. DOI:10.1111/nyas.13958

    View in Article CrossRef Google Scholar Scopus

    [114] Cammarota G., Ianiro G., Tilg H., et al. (2017). European consensus conference on faecal microbiota transplantation in clinical practice. Gut 66:569. DOI:10.1136/gutjnl-2016-313017

    View in Article CrossRef Google Scholar Scopus

    [115] Kelly C.R., Khoruts A., Staley C., et al. (2016). Effect of fecal microbiota transplantation on recurrence in multiply recurrent Clostridium difficile infectionAnn. Intern. Med. 165:609−616. DOI:10.7326/m16-0271%m27547925

    View in Article Google Scholar

    [116] Bryce K P., Brendan C., Emmalee P., et al. (2020). Long-term efficacy and safety of fecal microbiota transplantation for treatment of recurrent Clostridioides difficile infection. J. Clin. Gastroenterol. 54:701−706. DOI:10.1097/MCG.0000000000001281

    View in Article CrossRef Google Scholar

    [117] Zhu G., Hu J. and Xi R. (2021). The cellular niche for intestinal stem cells: A team effort. Cell Regen. 10:1. DOI:10.1186/s13619-020-00061-5

    View in Article CrossRef Google Scholar

    [118] Barker N. (2014). Adult intestinal stem cells: Critical drivers of epithelial homeostasis and regeneration. Nat. Rev. Mol. Cell Biol. 15:19−33. DOI:10.1038/nrm3721

    View in Article CrossRef Google Scholar Scopus

    [119] Cribas E.S. (2023). Intestinal immune and epithelial responses to Clostridioides difficile infection.

    View in Article Google Scholar

    [120] Mileto S.J., Jardé T., Childress K.O., et al. (2020). Clostridioides difficile infection damages colonic stem cells via TcdB, impairing epithelial repair and recovery from disease. Proc. Natl. Acad. Sci. USA 117:8064−8073. DOI:10.1073/pnas.1915255117

    View in Article CrossRef Google Scholar

    [121] Holmberg F.E.O., Seidelin J.B., Yin X., et al. (2017). Culturing human intestinal stem cells for regenerative applications in the treatment of inflammatory bowel disease. EMBO Mol. Med. 9:558−570-570. DOI:10.15252/emmm.201607260

    View in Article CrossRef Google Scholar Scopus

    [122] Hanash, Alan M., Dudakov, Jarrod A., Hua, G., et al. (2012). Interleukin-22 protects intestinal stem cells from immune-mediated tissue damage and regulates sensitivity to graft versus host disease. Immunity. 37:339−350. DOI:10.1016/j.immuni.2012.05.028

    View in Article CrossRef Google Scholar

    [123] Uddin Md J., Thompson B., Leslie Jhansi L., et al. (2024). Investigating the impact of antibiotic-induced dysbiosis on protection from Clostridium difficile colitis by mouse colonic innate lymphoid cells. mBio 15:e03338−03323. DOI:10.1128/mbio.03338-23

    View in Article CrossRef Google Scholar Scopus

    [124] Xie J., Li L.-f., Dai T.-y., et al. (2022). Short-chain fatty acids produced by ruminococcaceae mediate α-linolenic acid promote intestinal stem cells proliferation. Mol. Nutr. Food Res. 66:2100408. DOI:10.1002/mnfr.202100408

    View in Article CrossRef Google Scholar

    [125] Markandey M., Bajaj A., Ilott N.E., et al. (2021). Gut microbiota: Sculptors of the intestinal stem cell niche in health and inflammatory bowel disease. Gut Microbes 13:1990827. DOI:10.1080/19490976.2021.1990827

    View in Article CrossRef Google Scholar

    [126] Nigro G. and Sansonetti P.J. (2015). Microbiota and gut stem cells cross-talks: A new view of epithelial homeostasis. Curr. Stem Cell Rep. 1:48−52. DOI:10.1007/s40778-014-0005-x

    View in Article CrossRef Google Scholar

  • Cite this article:

    Wang L., Lee C., Gálvez J., et al. (2025). Exploring the epidemiology, pathogenesis, and immunotherapeutic advancements in Clostridium difficile infection. The Innovation Life 3:100107. https://doi.org/10.59717/j.xinn-life.2024.100107
    Wang L., Lee C., Gálvez J., et al. (2025). Exploring the epidemiology, pathogenesis, and immunotherapeutic advancements in Clostridium difficile infection. The Innovation Life 3:100107. https://doi.org/10.59717/j.xinn-life.2024.100107

Welcome!

To request copyright permission to republish or share portions of our works, please visit Copyright Clearance Center's (CCC) Marketplace website at marketplace.copyright.com.

Figures(4)     Tables(1)

Share

  • Share the QR code with wechat scanning code to friends and circle of friends.

Article Metrics

Article views(6681) PDF downloads(2035)

Relative Articles

Cited by

Catalog

    /

    DownLoad:  Full-Size Img  PowerPoint