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A special issue of Microorganisms (ISSN 2076-2607). This special issue belongs to the section "Gut Microbiota".

Deadline for manuscript submissions: closed (1 May 2020) | Viewed by 35168

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Dr. Łukasz M. Grześkowiak

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Institute of Animal Nutrition, Freie Universität Berlin, 14195 Berlin, Germany
Interests: microbial ecology; microbiota-host cross-talk; health
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Clostridium (syn. Clostridioides) difficile inhabits the gut of humans and animals. The sporulation/germination life cycle allows this bacterium to survive in harsh environments and colonise host niches when conditions are favourable. Virulent ribotypes of C. difficile are common pathogens and are involved in serious gastrointestinal infections. C. difficile has emerged as an important pathogen in clinical settings and is a severe threat in veterinary medicine, where it often spontaneously causes diseases of unknown aetiology in farm animals. The zoonotic potential of C. difficile and resistant pathogens is of major importance for human and animal health. There are still fundamental knowledge gaps that have spurred an urgent need to explore C. difficile's biology and factors that contribute to the transmission and development of infection.

This Special Issue, entitled "Clostridium difficile", aims to present recent research on various aspects of C. difficile, including ecology, virulence, and infection course under in vivo and in vitro conditions. Some of its central topics include but are not limited to C. difficile colonization, interaction with the gut microbiota and the host, immune response, strategies to reduce C. difficile infections in humans and animals, and problems of antibiotic resistance and zoonosis.

Research articles, review articles, and short communications are welcome. We look forward to publishing your work.

Dr. Łukasz M. Grześkowiak
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Microorganisms is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

Clostridium difficile
Clostridioides difficile
gut microbiota
virulence
toxins
infection
antibiotics

Published Papers (10 papers)

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Editorial

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3 pages, 201 KiB

Open AccessEditorial

Editorial for the Special Issue: Clostridium difficile

by Łukasz M. Grześkowiak

Microorganisms 2021, 9(2), 368; https://doi.org/10.3390/microorganisms9020368 - 12 Feb 2021

Viewed by 1303

Abstract

Clostridium difficile (reclassified as Clostridioides difficile [...] Full article

(This article belongs to the Special Issue Clostridium difficile)

Research

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9 pages, 480 KiB

Open AccessCommunication

Decreased Expression of the High Mobility Group Box 1 (HMGB1) Gene in Peripheral Blood in Patients with Mild or Moderate Clostridioides difficile Infection

by Jacek Czepiel, Grażyna Biesiada, Ewelina Pitera, Paweł P. Wołkow, Mateusz Michalak and Aleksander Garlicki

Microorganisms 2020, 8(8), 1217; https://doi.org/10.3390/microorganisms8081217 - 11 Aug 2020

Cited by 1 | Viewed by 1642

Abstract

Cytokines are mediators of inflammation induced in the course of Clostridioides difficile infection (CDI). High Mobility Group Box 1 (HMGB1) is a cytokine playing an important role in the pathogenesis of numerous inflammatory and autoimmune diseases. The aim of the study was to assess the HMGB1 gene expression in the course of CDI. We have performed a prospective case-control study- including 55 adult patients, among them 27 with CDI, who were hospitalized from October 2018 to February 2020 and 28 healthy volunteers. We assessed: a complete blood count with differential leukocyte count, blood creatinine, albumin, and C-reactive protein (CRP) levels. Then, the expression of the HMGB1 gene was evaluated using quantitative Real-Time PCR. Patients with CDI were found to have a significant increase in white blood cells (WBC), neutrophil count, and CRP levels, they also exhibited decreased levels of albumin compared with controls. The HMGB1 gene expression was significantly lower among patients with CDI compared with the control group and significantly, inversely correlated with CRP level in blood. In conclusion, we have observed a decreased expression of the HMGB1 gene in peripheral blood of patients with mild or moderate CDI, which hypothetically could reflect their diminished capability to fight the pathogen. Full article

(This article belongs to the Special Issue Clostridium difficile)

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9 pages, 891 KiB

Open AccessArticle

The Colonisation of Calves in Czech Large-Scale Dairy Farms by Clonally-Related Clostridioides difficile of the Sequence Type 11 Represented by Ribotypes 033 and 126

by Martina Masarikova, Ivana Simkova, Martin Plesko, Veronika Eretova, Marcela Krutova and Alois Cizek

Microorganisms 2020, 8(6), 901; https://doi.org/10.3390/microorganisms8060901 - 15 Jun 2020

Cited by 7 | Viewed by 1818

Abstract

To investigate a possible Clostridioides difficile reservoir in the Czech Republic, we performed a study in 297 calves from 29 large-scale dairy farms. After enrichment, faecal samples were inoculated onto selective agar for C. difficile. From the 297 samples, 44 C. difficile isolates were cultured (prevalence of 14.8%, 10 farms). The Holstein breed and use of digestate were associated with C. difficile colonisation (p ˂ 0.05). C. difficile isolates belonged to the ribotype/sequence type: RT033/ST11 (n = 37), RT126/ST11 (n = 6) and RT046/ST35 (n = 1). A multiple-locus variable-number tandem-repeat analysis revealed four clonal complexes of RT033 isolates and one clonal complex of RT126 isolates. All isolates were sensitive to amoxicillin, metronidazole and vancomycin. Forty isolates were resistant to ciprofloxacin, twenty-one to clindamycin, seven to erythromycin, seven to tetracycline and six to moxifloxacin. Moxifloxacin resistant isolates revealed an amino-acid substitution Thr82Ile in the GyrA. In conclusion, the calves of Holstein breed from farms using digestate as a product of bio-gas plants are more likely to be colonised by clonally-related C. difficile of ST 11 represented by ribotypes 033 and 126. The identified resistance to moxifloxacin with a Thr82Ile substitution in the GyrA highlights the need for further monitoring by the “One health approach”. Full article

(This article belongs to the Special Issue Clostridium difficile)

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10 pages, 455 KiB

Open AccessArticle

Long-Term Antibiotic Prophylaxis in Urology and High Incidence of Clostridioides difficile Infections in Surgical Adult Patients

by Estera Jachowicz, Marta Wałaszek, Grzegorz Sulimka, Andrzej Maciejczak, Witold Zieńczuk, Damian Kołodziej, Jacek Karaś, Monika Pobiega and Jadwiga Wójkowska-Mach

Microorganisms 2020, 8(6), 810; https://doi.org/10.3390/microorganisms8060810 - 28 May 2020

Cited by 4 | Viewed by 1649

Abstract

Clostridioides difficile infections are the main cause of antibiotic-related diarrhea. Most of them come in the form of healthcare-associated Clostridioides difficile infections (HA-CDI). The aim of the study was to analyze HA-CDI epidemiology and the relationship between antibiotic consumption and CDI epidemiology at St Luke’s Provincial Hospital in Tarnow, Poland. In 2012–2018, surveillance of CDI was carried out in adult surgical wards at St Luke’s Provincial Hospital. The data were collected in accordance with the methodology of the Healthcare-Associated Infections Surveillance Network (HAI-Net), European Centre for Disease Prevention and Control (ECDC), and the ATC/DDD system (Anatomical Therapeutic Chemical Classification System) of the World Health Organization. In total, in the study period, 51 cases of CDI involved CA-CDI (24.5%) and 147 were HA-CDIs (75.5%). The most CA-CDIs were found in the general surgery (32.6%) and urology (17.0%) wards. CA-CDI incidence was 0.7/1000 patients and for HA-CDI it was 2/1000 patients (4.4/10,000 patientdays (pds)). The highest HA-CDI incidence was in the neurosurgical departments (18/10,000 pds) and oncological surgery (8.4/10,000) pds. There was a significant positive correlation between CA-CDI and HA-CDI (correlation of 0.943, p < 0.001) and between the number of patients hospitalized and HA-CDI (correlation of 0.865, p = 0.012). The total antibiotic consumption amounted to 0.7 DDD/10,000 pds; it was the highest in the urology ward (0.84/10,000 pds) and 49.5% of the antibiotics were fluoroquinolones (0.41/10,000 pds). On the basis of regression coefficients, a positive correlation was demonstrated between the use of fluoroquinolones and the HA-CDI incidence rate. Both a high percentage of CDI cases and a high intake of antibiotics were recorded in the urology department. About half of all antibiotics were fluoroquinolones. Full article

(This article belongs to the Special Issue Clostridium difficile)

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13 pages, 2787 KiB

Open AccessArticle

The Bacterial Gut Microbiota of Adult Patients Infected, Colonized or Noncolonized by Clostridioides difficile

by Monique J. T. Crobach, Quinten R. Ducarmon, Elisabeth M. Terveer, Celine Harmanus, Ingrid M. J. G. Sanders, Kees M. Verduin, Ed J. Kuijper and Romy D. Zwittink

Microorganisms 2020, 8(5), 677; https://doi.org/10.3390/microorganisms8050677 - 06 May 2020

Cited by 23 | Viewed by 3552

Abstract

Gut microbiota composition in patients with Clostridioides difficile colonization is not well investigated. We aimed to identify bacterial signatures associated with resistance and susceptibility to C. difficile colonization (CDC) and infection (CDI). Therefore, gut microbiota composition from patients with CDC (n = 41), with CDI (n = 41), and without CDC (controls, n = 43) was determined through 16S rRNA gene amplicon sequencing. Bacterial diversity was decreased in CDC and CDI patients (p < 0.01). Overall microbiota composition was significantly different between control, CDC, and CDI patients (p = 0.001). Relative abundance of Clostridioides (most likely C. difficile) increased stepwise from controls to CDC and CDI patients. In addition, differential abundance analysis revealed that CDI patients’ gut microbiota was characterized by significantly higher relative abundance of Bacteroides and Veillonella than CDC patients and controls. Control patients had significantly higher Eubacterium hallii and Fusicatenibacter abundance than colonized patients. Network analysis indicated that Fusicatenibacter was negatively associated with Clostridioides in CDI patients, while Veillonella was positively associated with Clostridioides in CDC patients. Bacterial microbiota diversity decreased in both CDC and CDI patients, but harbored a distinct microbiota. Eubacterium hallii and Fusicatenibacter may indicate resistance against C. difficile colonization and subsequent infection, while Veillonella may indicate susceptibility to colonization and infection by C. difficile. Full article

(This article belongs to the Special Issue Clostridium difficile)

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14 pages, 4386 KiB

Open AccessArticle

Porcine Colostrum Protects the IPEC-J2 Cells and Piglet Colon Epithelium against Clostridioides (syn. Clostridium) difficile Toxin-Induced Effects

by Łukasz Grześkowiak, Robert Pieper, Susan Kröger, Beatriz Martínez-Vallespín, Anja E. Hauser, Raluca Niesner, Wilfried Vahjen and Jürgen Zentek

Microorganisms 2020, 8(1), 142; https://doi.org/10.3390/microorganisms8010142 - 20 Jan 2020

Cited by 8 | Viewed by 3483

Abstract

Clostridioides difficile toxins are one of the main causative agents for the clinical symptoms observed during C. difficile infection in piglets. Porcine milk has been shown to strengthen the epithelial barrier function in the piglet’s intestine and may have the potential to neutralise clostridial toxins. We hypothesised that porcine colostrum exerts protective effects against those toxins in the IPEC-J2 cells and in the colon epithelium of healthy piglets. The IPEC-J2 cells were treated with either the toxins or porcine colostrum or their combination. Analyses included measurement of trans-epithelial electrical resistance (TEER), cell viability using propidium iodide by flow cytometry, gene expression of tight junction (TJ) proteins and immune markers, immunofluorescence (IF) histology of the cytoskeleton and a TJ protein assessment. Colon tissue explants from one- and two-week-old suckling piglets and from five-week-old weaned piglets were treated with C. difficile toxins in Ussing chamber assays to assess the permeability to macromolecules (FITC-dextran, HRP), followed by analysis of gene expression of TJ proteins and immune markers. Toxins decreased viability and integrity of IPEC-J2 cells in a time-dependent manner. Porcine colostrum exerted a protective effect against toxins as indicated by TEER and IF in IPEC-J2 cells. Toxins tended to increase paracellular permeability to macromolecules in colon tissues of two-week-old piglets and downregulated gene expression of occludin in colon tissues of five-week-old piglets (p = 0.05). Porcine milk including colostrum, besides other maternal factors, may be one of the important determinants of early immune programming towards protection from C. difficile infections in the offspring. Full article

(This article belongs to the Special Issue Clostridium difficile)

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17 pages, 3343 KiB

Open AccessArticle

Mapping Epitopes of a Novel Peptidoglycan Cross-Linking Enzyme Cwp22 Recognized by Human Sera Obtained from Patients with Clostridioides difficile Infection and Cord Blood

by Agnieszka Razim, Katarzyna Pacyga, Gajane Martirosian, Andrzej Szuba, Andrzej Gamian, Andrzej Myc and Sabina Górska

Microorganisms 2019, 7(11), 565; https://doi.org/10.3390/microorganisms7110565 - 14 Nov 2019

Cited by 5 | Viewed by 2769

Abstract

Clostridioides difficile (CD) cause a severe diarrhea which can lead to pseudomembranous colitis and even patient death. CD infection (CDI) is connected mainly with changes in intestinal microbiota as a consequence of antibiotic treatment. The growing resistance to antibiotics, justifies the search for new methods of combating CD. Despite of ongoing research on the immunity against the pathogen, there is still lack of any reliable vaccine. Most recently, Cwp22, that is a cross-linking enzyme involved in the production of CD peptidoglycan, seems to be a promising target to prevent CDI in high-risk patients. In this paper, the Cwp22 protein polypeptide-specific epitopes were mapped in silico and using PEPSCAN procedure. They were recognized not only by antibodies from CDI patients’ but also by umbilical cord blood sera. We identified three epitopes ⁵⁴EFRVAT⁵⁹, ²⁰¹KVNGKM²⁰⁶ and ²⁶⁸WQEKNGKKYY²⁷⁷ of Cwp22 protein. Since Cwp22 protein has key functionality and the described above epitopes are also recognized by umbilical cord blood serum, we postulate that they could have important protective properties. In this paper, we propose Cwp22 protein as a good antigen candidate for CDI preventive vaccine. Our results open the possibility to use ⁵⁴EFRVAT⁵⁹, ²⁰¹KVNGKM²⁰⁶ and ²⁶⁸WQEKNGKKYY²⁷⁷, epitopes as suitable anti-CD vaccine antigens. Full article

(This article belongs to the Special Issue Clostridium difficile)

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11 pages, 1727 KiB

Open AccessArticle

Developing Gut Microbiota Exerts Colonisation Resistance to Clostridium (syn. Clostridioides) difficile in Piglets

by Łukasz Grześkowiak, Temesgen Hailemariam Dadi, Jürgen Zentek and Wilfried Vahjen

Microorganisms 2019, 7(8), 218; https://doi.org/10.3390/microorganisms7080218 - 26 Jul 2019

Cited by 23 | Viewed by 4160

Abstract

Clostridium (syn. Clostridioides) difficile is considered a pioneer colonizer and may cause gut infection in neonatal piglets. The aim of this study was to explore the microbiota-C. difficile associations in pigs. We used the DNA from the faeces of four sows collected during the periparturient period and from two to three of their piglets (collected weekly until nine weeks of age) for the determination of bacterial community composition (sequencing) and C. difficile concentration (qPCR). Furthermore, C. difficile-negative faeces were enriched in a growth medium, followed by qPCR to verify the presence of this bacterium. Clostridium-sensu-stricto-1 and Lactobacillus spp. predominated the gut microbiota of the sows and their offspring. C. difficile was detected at least once in the faeces of all sows during the entire sampling period, albeit at low concentrations. Suckling piglets harboured C. difficile in high concentrations (up to log₁₀ 9.29 copy number/g faeces), which gradually decreased as the piglets aged. Enrichment revealed the presence of C. difficile in previously C. difficile-negative sow and offspring faeces. In suckling piglets, the C. difficile level was negatively correlated with carbohydrate-fermenting bacteria, and it was positively associated with potential pathogens. Shannon and richness diversity indices were negatively associated with the C. difficile counts in suckling piglets. This study showed that gut microbiota seems to set conditions for colonisation resistance against C. difficile in the offspring. However, this conclusion requires further research to include host-specific factors. Full article

(This article belongs to the Special Issue Clostridium difficile)

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Review

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16 pages, 1554 KiB

Open AccessReview

Insights into the Role of Human Gut Microbiota in Clostridioides difficile Infection

by Melina Kachrimanidou and Eleftherios Tsintarakis

Microorganisms 2020, 8(2), 200; https://doi.org/10.3390/microorganisms8020200 - 31 Jan 2020

Cited by 40 | Viewed by 9063

Abstract

Clostridioides difficile infection (CDI) has emerged as a major health problem worldwide. A major risk factor for disease development is prior antibiotic use, which disrupts the normal gut microbiota by altering its composition and the gut’s metabolic functions, leading to the loss of colonization resistance and subsequent CDI. Data from human studies have shown that the presence of C. difficile, either as a colonizer or as a pathogen, is associated with a decreased level of gut microbiota diversity. The investigation of the gut’s microbial communities, in both healthy subjects and patients with CDI, elucidate the role of microbiota and improve the current biotherapeutics for patients with CDI. Fecal microbiota transplantation has a major role in managing CDI, aiming at re-establishing colonization resistance in the host gastrointestinal tract by replenishing the gut microbiota. New techniques, such as post-genomics, proteomics and metabolomics analyses, can possibly determine in the future the way in which C. difficile eradicates colonization resistance, paving the way for the development of new, more successful treatments and prevention. The aim of the present review is to present recent data concerning the human gut microbiota with a focus on its important role in health and disease. Full article

(This article belongs to the Special Issue Clostridium difficile)

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19 pages, 370 KiB

Open AccessReview

Clostridioides (Clostridium) Difficile in Food-Producing Animals, Horses and Household Pets: A Comprehensive Review

by Melina Kachrimanidou, Eleni Tzika and George Filioussis

Microorganisms 2019, 7(12), 667; https://doi.org/10.3390/microorganisms7120667 - 09 Dec 2019

Cited by 28 | Viewed by 5127

Abstract

Clostridioides (Clostridium) difficile is ubiquitous in the environment and is also considered as a bacterium of great importance in diarrhea-associated disease for humans and different animal species. Food animals and household pets are frequently found positive for toxigenic C. difficile without exposing clinical signs of infection. Humans and animals share common C. difficile ribotypes (RTs) suggesting potential zoonotic transmission. However, the role of animals for the development of human infection due to C. difficile remains unclear. One major public health issue is the existence of asymptomatic animals that carry and shed the bacterium to the environment, and infect individuals or populations, directly or through the food chain. C. difficile ribotype 078 is frequently isolated from food animals and household pets as well as from their environment. Nevertheless, direct evidence for the transmission of this particular ribotype from animals to humans has never been established. This review will summarize the current available data on epidemiology, clinical presentations, risk factors and laboratory diagnosis of C. difficile infection in food animals and household pets, outline potential prevention and control strategies, and also describe the current evidence towards a zoonotic potential of C. difficile infection. Full article

(This article belongs to the Special Issue Clostridium difficile)

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