Probiotics: insights and new opportunities for <i>Clostridioides difficile</i> intervention

Pal, Rusha; Athamneh, Ahmad I. M.; Deshpande, Riddhi; Ramirez, Jose A R; Adu, Kayode T; Muthuirulan, Pushpanathan; Pawar, Shrikant; Biazzo, Manuele; Apidianakis, Yiorgos; Sundekilde, Ulrik Kræmer; Fuente-Núñez, César de la; Martens, Mark G.; Tegos, George P.; Seleem, Mohamed N.

doi:10.1080/1040841x.2022.2072705

Cited by 15 publications

(6 citation statements)

References 188 publications

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“…In conclusion, we also point out an excellent paper by Rusha et al [ 75 ] who expounded an excellent summary of probiotic strains used in human clinical trials to treat CDAD.…”

Section: New Therapeutic Strategiesmentioning

confidence: 62%

Gut Microbiota and Clostridium difficile: What We Know and the New Frontiers

Piccioni

Rosa

Manca

et al. 2022

IJMS

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Our digestive system, particularly our intestines, harbors a vast amount of microorganisms, whose genetic makeup is referred to as the microbiome. Clostridium difficile is a spore-forming Gram-positive bacterium, which can cause an infection whose symptoms range from asymptomatic colonization to fearsome complications such as the onset of toxic megacolon. The relationship between gut microbiota and Clostridium difficile infection has been studied from different perspectives. One of the proposed strategies is to be able to specifically identify which types of microbiota alterations are most at risk for the onset of CDI. In this article, we understood once again how crucial the role of the human microbiota is in health and especially how crucial it becomes, in the case of its alteration, for the individual’s disease. Clostridium difficile infection is an emblematic example of how a normal and physiological composition of the human microbiome can play a very important role in immune defense against such a fearsome disease.

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“…In conclusion, we also point out an excellent paper by Rusha et al [ 75 ] who expounded an excellent summary of probiotic strains used in human clinical trials to treat CDAD.…”

Section: New Therapeutic Strategiesmentioning

confidence: 62%

Gut Microbiota and Clostridium difficile: What We Know and the New Frontiers

Piccioni

Rosa

Manca

et al. 2022

IJMS

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“…Among these candidates, probiotics are among the most promising. Probiotics have a complex effect on the gastrointestinal tract and its microbiota, including selectively suppressing the growth of certain types of pathogenic and conditionally pathogenic microbiota [18][19][20][21][22]. Among the probiotic microbes of interest are Saccharomyces boulardii, which have already shown an antagonistic effect against Helicobacter pylori [23] and Clostridioides difficile [24,25].…”

Section: Introductionmentioning

confidence: 99%

Efficacy and Safety of a Probiotic Containing Saccharomyces boulardii CNCM I-745 in the Treatment of Small Intestinal Bacterial Overgrowth in Decompensated Cirrhosis: Randomized, Placebo-Controlled Study

Efremova,

Maslennikov,

Zharkova

et al. 2024

JCM

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(1) Background: The aim was to evaluate the effectiveness of the probiotic containing Saccharomyces boulardii in the treatment of small intestinal bacterial overgrowth (SIBO) in patients with decompensated cirrhosis. (2) Methods: This was a blinded, randomized, placebo-controlled study. (3) Results: After 3 months of treatment, SIBO was absent in 80.0% of patients in the probiotic group and in 23.1% of patients in the placebo group (p = 0.002). The patients with eliminated SIBO had decreased frequency of ascites and hepatic encephalopathy, the increased platelets and albumin levels, the decreased blood levels of total bilirubin, biomarkers of bacterial translocation (lipopolysaccharide [LPS]) and systemic inflammation (C-reactive protein), and positive changes in markers of hyperdynamic circulation compared with the state at inclusion. There were no significant changes in the claudin 3 level (the intestinal barrier biomarker) in these patients. No significant changes were observed in the group of patients with persistent SIBO. The serum level of nitrate (endothelial dysfunction biomarker) was lower in patients with eradicated SIBO than in patients with persistent SIBO. One (5.3%) patient with eradicated SIBO and six (42.9%) patients with persistent SIBO died within the first year of follow-up (p = 0.007). (4) Conclusions: SIBO eradication was an independent predictor of a favorable prognosis during the first year of follow-up.

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“…The use of broad-spectrum antibiotics perturbs the indigenous intestinal microbial community, which primes the human gut to become prone to C. difficile colonization and disease manifestation ( 2 ). Paradoxically, the treatment repertoire for C. difficile infection includes antibiotics like vancomycin and fidaxomicin ( 3 , 4 ).…”

Section: Introductionmentioning

confidence: 99%

Antisense inhibition of RNA polymerase α subunit of Clostridioides difficile

Pal,

Seleem

2023

Microbiol Spectr

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Clostridioides difficile, the causative agent of antibiotic-associated diarrhea and pseudomembranous colitis, has emerged as a major enteric pathogen in recent years. Antibiotic treatment perturbs the gut microbiome homeostasis, which facilitates the colonization and proliferation of the pathogen in the host intestine. Paradoxically, the clinical repertoire for C. difficile infection includes the antibiotics vancomycin and/or fidaxomicin. The current therapies do not address the perturbed gut microbiome, which supports the recurrence of infection after cessation of antibiotic therapy. Peptide nucleic acids (PNAs) are novel alternatives to traditional antimicrobial therapy capable of forming strong and stable complexes with RNA and DNA, thus permitting targeted inhibition of specific genes. Here, we report a novel PNA that can target the RNA polymerase α subunit ( rpoA ) in C. difficile . The designed anti- rpoA construct inhibited clinical isolates of C. difficile (minimum inhibitory concentration values ranged between 4 and 8 µM) and exhibited bactericidal activity. Furthermore, silencing of the rpoA gene suppressed the expression of genes that encode virulence factors [toxin A ( tcdA ), toxin B ( tcdB )] in C. difficile , and the gene that encodes the transcription factor stage 0 sporulation protein ( spoOA ). Interestingly, the efficacy of the designed PNA conjugate remained unaffected even when tested at different pH levels and against a high inoculum of the pathogen. The rpoA -TAT conjugate was very specific against C. difficile and did not inhibit members of the beneficial gut microflora. Taken altogether, our study confirms that the rpoA gene can be a promising narrow-spectrum therapeutic target to curb C. difficile infection. IMPORTANCE The widespread use of antibiotics can destroy beneficial intestinal microflora, opening the door for spores of Clostridioides difficile to run rampant in the digestive system, causing life-threatening diarrhea. Alternative approaches to target this deadly pathogen are urgently needed. We utilized targeted therapeutics called peptide nucleic acids (PNAs) to inhibit gene expression in C. difficile . Inhibition of the RNA polymerase α subunit gene ( rpo A) by PNA was found to be lethal for C. difficile and could also disarm its virulence factors. Additionally, antisense inhibition of the C. difficile rpo A gene did not impact healthy microflora. We also propose a novel approach to manipulate gene expression in C. difficile without the need for established genetic tools.

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Probiotics: insights and new opportunities for Clostridioides difficile intervention

Cited by 15 publications

References 188 publications

Gut Microbiota and Clostridium difficile: What We Know and the New Frontiers

Gut Microbiota and Clostridium difficile: What We Know and the New Frontiers

Efficacy and Safety of a Probiotic Containing Saccharomyces boulardii CNCM I-745 in the Treatment of Small Intestinal Bacterial Overgrowth in Decompensated Cirrhosis: Randomized, Placebo-Controlled Study

Antisense inhibition of RNA polymerase α subunit of Clostridioides difficile

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