From Fecal Microbiota Transplantation to Probiotics to Microbiota-Preserving Antimicrobial Agents
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pathogens Review Application of Microbiome Management in Therapy for Clostridioides difficile Infections: From Fecal Microbiota Transplantation to Probiotics to Microbiota-Preserving Antimicrobial Agents Chun-Wei Chiu 1, Pei-Jane Tsai 2, Ching-Chi Lee 3,4 , Wen-Chien Ko 4,5,* and Yuan-Pin Hung 1,4,5,* 1 Department of Internal Medicine, Tainan Hospital, Ministry of Health and Welfare, Tainan 700, Taiwan; [email protected] 2 Department of Medical Laboratory Science and Biotechnology, National Cheng Kung University, Medical College, Tainan 704, Taiwan; [email protected] 3 Clinical Medicine Research Center, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 704, Taiwan; [email protected] 4 Department of Internal Medicine, College of Medicine, National Cheng Kung University Hospital, Tainan 704, Taiwan 5 Department of Medicine, College of Medicine, National Cheng Kung University, Tainan 704, Taiwan * Correspondence: [email protected] (W.-C.K.); [email protected] (Y.-P.H.) Abstract: Oral vancomycin and metronidazole, though they are the therapeutic choice for Clostrid- Citation: Chiu, C.-W.; Tsai, P.-J.; Lee, ioides difficile infections (CDIs), also markedly disturb microbiota, leading to a prolonged loss of C.-C.; Ko, W.-C.; Hung, Y.-P. colonization resistance to C. difficile after therapy; as a result, their use is associated with a high Application of Microbiome treatment failure rate and high recurrent rate. An alternative for CDIs therapy contains the delivery Management in Therapy for of beneficial (probiotic) microorganisms into the intestinal tract to restore the microbial balance. Clostridioides difficile Infections: From Fecal Microbiota Transplantation to Recently, mixture regimens containing Lactobacillus species, Saccharomyces boulardii, or Clostridium Probiotics to Microbiota-Preserving butyricum have been extensively studied for the prophylaxis of CDIs. Fecal microbiota transplantation Antimicrobial Agents. Pathogens 2021, (FMT), the transfer of (processed) fecal material from healthy donors to patients for treating CDIs, 10, 649. https://doi.org/10.3390/ combined with vancomycin was recommended as the primary therapy for multiple recurrent CDIs pathogens10060649 (rCDIs). Either probiotics or FMT have been utilized extensively in preventing or treating CDIs, aiming at less disturbance in the microbiota to prevent rCDIs after therapy cessation. Otherwise, Academic Editors: Valentina many newly developed therapeutic agents have been developed and aim to preserve microbiota Virginia Ebani and Luis M. during CDI treatment to prevent disease recurrence and might be useful in clinical patients with Cintas Izarra rCDIs in the future. Received: 26 March 2021 Keywords: Clostridioides difficile; Clostridioides difficile infection; microbiome; probiotics; recurrence; Accepted: 19 May 2021 fecal microbiota transplantation Published: 24 May 2021 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affil- 1. Disruption of Gut Microbiota after Antibiotic Exposure Results in Recurrent C. difficile Infection iations. Clostridioides difficile, as the major cause of antibiotic-associated diarrhea, has clinical symptoms ranging from diarrhea to pseudomembranous colitis or toxic megacolon, with a mortality rate of up to 25–40% [1–5]. In the “Clinical Practice Guidelines for Clostridioides difficile Infections (CDIs) in Adults and Children: 2017 Update” by the Infectious Diseases Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA), This article is an open access article vancomycin replaced metronidazole as the therapeutic choice for either mild-to-moderate distributed under the terms and or severe CDIs [6]. Nevertheless, oral vancomycin and metronidazole markedly disturbed conditions of the Creative Commons the microbiota, which resulted in the dense colonization by vancomycin-resistant Entero- Attribution (CC BY) license (https:// coccus, Klebsiella pneumoniae, and Escherichia coli, and, more importantly, the prolonged loss creativecommons.org/licenses/by/ of colonization resistance to C. difficile [7]. Although antimicrobial resistance is not clinically 4.0/). problematic, treating CDIs with metronidazole and vancomycin is associated with a high Pathogens 2021, 10, 649. https://doi.org/10.3390/pathogens10060649 https://www.mdpi.com/journal/pathogens Pathogens 2021, 10, x FOR PEER REVIEW 2 of 14 Pathogens 2021, 10, 649 loss of colonization resistance to C. difficile [7]. Although antimicrobial resistance is 2not of 14 clinically problematic, treating CDIs with metronidazole and vancomycin is associated with a high treatment failure rate and recurrence rate [8]. For recurrent CDIs (rCDIs), ac- cordingtreatment to the failure Clinical rate andPractice recurrence Guidelines rate [ 8by]. ForIDSA/SHEA, recurrent CDIs oral (rCDIs),vancomycin according is still to the the drugClinical of choice, Practice but Guidelines the rate of by the IDSA/SHEA, sequential oralrecurrence vancomycin is as high is still as the 22.6–41.8% drug of choice, despite but successfulthe rate of treatment the sequential with vancomycin recurrence is [9]. as high as 22.6–41.8% despite successful treatment withThere vancomycin are more [9 than]. 1000 distinct species of bacteria inhabited in the human gastro- intestinalThere system are more with than a symbiotic 1000 distinct relationsh speciesip,of with bacteria the collection inhabited of in microbes the human called gastroin- the “microbiota”testinal system [10,11]. with The a symbiotic relative high relationship, susceptibility with theto infections collection in of neonates microbes might called be the due“microbiota” to the immaturity [10,11]. of The the relative immune high system susceptibility, and the mechanism to infections is inprobably neonates due might to the be relativedue to “immature” the immaturity microbiota of the immune [12]. By system, colonizing and theadult mechanism germ-free is mice probably with duethe cecal to the contentsrelative of “immature” neonatal mice, microbiota the microbiota [12]. By is colonizing unable to adultprevent germ-free colonization mice by with two the bacte- cecal rialcontents pathogens, of neonatal including mice, Citrobacter the microbiota rodentium is unable, a natural to prevent pathogen colonization of mice bythat two is used bacterial to modelpathogens, human including infectionsCitrobacter with the rodentiumenteropathogenic, a natural E. pathogen coli and Salmonella of mice that typhimurium is used to model that causehuman mortality infections in neonates with the [12]. enteropathogenic The lack of colonizationE. coli and Salmonella resistance typhimuriumwas correlatedthat to cause the absencemortality of Clostridiales in neonates [ 12in]. the The neonatal lack of microb colonizationiota, and resistance the administration was correlated of Clostridiales to the absence couldof Clostridiales protect neonatal in the neonatalmice from microbiota, pathogen andinfection the administration [12]. Thus, the of component Clostridiales of could gut microbiotaprotect neonatal is associated mice from with pathogen the immunity infection of the [12 ].host. Thus, the component of gut microbiota is associatedThe colonized with themicrobiota immunity in ofthe the mammalian host. gut occurs shortly after birth and re- mains Thewith colonized little fluctuation microbiota throughout in the mammalian the host’s gut life; occurs the microbiota shortly after is birthprimarily and remains com- posedwith littleof five fluctuation bacteria phyla throughout in healthy the host’sadults life;: Firmicutes the microbiota (79.4%), is Bacteroidetes primarily composed (16.9%), of Actinobacteriafive bacteria phyla (2.5%), in healthyProteobacteria adults: Firmicutes(1%), and (79.4%),Verrucomi Bacteroidetescrobia (0.1%) (16.9%), [13]. Actinobac-A wide rangeteria of (2.5%), host or Proteobacteria environment (1%), factors, and includ Verrucomicrobiaing diet, sleep, (0.1%) and [disease,13]. A wide can alter range the of mi- host crobiotaor environment diversity factors,and abundancy including [10,11]. diet, sleep, Of note, and the disease, rise of canantimicrobial alter the microbiota agent-resistant diver- pathogens,sity and abundancy combined with [10,11 reduction]. Of note, of themicrobio rise ofta antimicrobial diversity after agent-resistant antibiotic treatment, pathogens, has becomecombined a significant with reduction challenge of microbiota in the fight diversity against afterall kinds antibiotic of invasive treatment, infections has become world- a widesignificant [14]. To challenge prevent the in thedisruption fight against of the all microbiota, kinds of invasive some microbiota-based infections worldwide treatments, [14]. To suchprevent as fecal the microbiota disruption oftransplantation the microbiota, (FMT) some and microbiota-based the administration treatments, of probiotics, such as have fecal beenmicrobiota used to transplantation“rescue” the disrup (FMT)ted and microbiota the administration [14] (Figure of 1). probiotics, have been used to “rescue” the disrupted microbiota [14] (Figure1). Figure 1. Fecal microbiota transplantation for C. difficile infection therapy. FMT, the transfer of (processed) fecal material from healthy donors to CDI patients, combined with vancomycin have been recommended as the primary therapy for mul- Pathogens 2021, 10, 649 3 of 14 tiple