Targeted suppression of human IBD-associated gut microbiota commensals by phage consortia for treatment of intestinal inflammation

Federici, Sara; Kredo‐Russo, Sharon; Valdés-Mas, Rafael; Kviatcovsky, Denise; Weinstock, Eyal; Matiuhin, Yulia; Silberberg, Yael; Atarashi, Koji; Furuichi, Munehiro; Oka, Akihiko; Liu, Bo; Fibelman, Morine; Weiner, Iddo; Khabra, Efrat; Cullin, Nyssa; Ben-Yishai, Noa; Inbar, Dana; Ben-David, Hava; Nicenboim, Julian; Kowalsman, Noga; Lieb, Wolfgang; Kario, Edith; Cohen, T.; Geffen, Yael Friedman; Zelcbuch, Lior; Cohen, Ariel; Rappo, Urania; Gahali-Sass, Inbar; Golembo, Myriam; Lev, Vered; Dori-Bachash, Mally; Shapiro, Hagit; Moresi, Claudia; Cuevas-Sierra, Amanda; Mohapatra, Gayatree; Kern, Lara; Zheng, Danping; Nobs, Samuel Philip; Suez, Jotham; Stettner, Noa; Harmelin, Alon; Zak, Naomi B.; Puttagunta, Sailaja; Bassan, Merav; Honda, Kenya; Sokol, Harry; Bang, Corinna; Franke, André; Schramm, Christoph; Maharshak, Nitsan; Sartor, R. Balfour; Sorek, Rotem; Elinav, Eran

doi:10.1016/j.cell.2022.07.003

Cited by 187 publications

(127 citation statements)

References 120 publications

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“…Unlike other Enterobactericeae such as Salmonella typhimurium, Escherichia coli, Citrobacter rodentium and Vibrio cholerae (37-43), K. pneumoniae colonisation was not associated with histopathology changes and with an acute inflammatory response in either the small or the large intestine. This finding does not contradict the clinical reports showing that K. pneumoniae is one of the pathogens associated with inflammatory bowel disease (44). This inflammatory condition triggers a strong dysbiosis, which in turn favours the bloom of pathogens, such as Klebsiella , already present within the gastrointestinal tract.…”

Section: Discussionsupporting

confidence: 69%

Modelling the gastrointestinal carriage of Klebsiella pneumoniae infections

Calderon-Gonzalez

Lee

López–Campos

et al. 2022

Preprint

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Klebsiella pneumoniae is a leading cause of nosocomial and community acquired infections, making K. pneumoniae the second pathogen associated with the most deaths attributed to any antibiotic resistant infection. K. pneumoniae colonises the nasopharynx and the gastrointestinal tract in an asymptomatic manner without dissemination to other tissues; importantly gastrointestinal colonisation is a requisite for infection. Our understanding of K. pneumoniae colonisation is still based on interrogating mouse models in which animals are pre-treated with antibiotics to disturb the colonisation resistance imposed by the gut microbiome. In these models, infection disseminates to other tissues. Here, we report a murine model to allow for the study of the gastrointestinal colonisation of K. pneumoniae without tissue dissemination. Hypervirulent and antibiotic resistant strains stably colonise the gastrointestinal tract of in an inbred mouse population without antibiotic treatment. The small intestine is the primary site of colonisation followed by a transition to the colon over time without dissemination to other tissues. Our model also mimics the disease dynamics of metastatic K. pneumoniae strains able to disseminate from the gastrointestinal tract to other sterile sites. Colonisation is associated with mild to moderate histopathology, no significant inflammation, and no effect on the richness of the microbiome. Our model recapitulates the clinical scenario in which antibiotic treatment disturbs the colonisation of K. pneumoniae resulting in dissemination to other tissues. Finally, we establish that the capsule polysaccharide is necessary for the colonisation of the large intestine whereas the type VI secretion system contributes to colonisation across the gastrointestinal tract.

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Section: Discussionsupporting

confidence: 69%

Modelling the gastrointestinal carriage of Klebsiella pneumoniae infections

Calderon-Gonzalez

Lee

López–Campos

et al. 2022

Preprint

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“…It is now possible to analyze intestinal phages, which has been difficult in the past, and this is expected to become an extremely powerful analytical tool for the future practice of phage therapy, as well as leading to various industrial applications of phages. Recently, Federici et al have demonstrated the feasibility of combination phage therapy for pathobionts associated with inflammatory bowel disease (52). It would be an interesting direction to further phage therapies for other intestinal bacteria-mediated diseases including CDI.…”

Section: Discussionmentioning

confidence: 99%

Phage therapy for Clostridioides difficile infection

Fujimoto

Uematsu²

2022

Front. Immunol.

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Clostridioides difficile is endemic in the intestinal tract of healthy people. However, it is responsible for many healthcare-associated infections, such as nosocomial diarrhea following antibiotic treatment. Importantly, there have been cases of unsuccessful treatment and relapse related to the emergence of highly virulent strains of C. difficile and resistance to antimicrobial agents. Fecal microbiota transplantation (FMT) is considered an effective therapy for recurrent C. difficile infection. However, its safety is of concern because deaths caused by antibiotic-resistant bacterial infections after FMT were reported. Therefore, the development of effective C. difficile-specific treatments is urgently needed. In this review, we summarize the importance of phage therapy against C. difficile, and describe a novel next-generation phage therapy developed using metagenomic data.

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“…Another species targeted to reduce inflammation is Klebsiella pneumoniae. A consortium of five phage that target K. pneumoniae has been developed and shown to reduce the severity of DSS induced inflammation, and an initial human study has shown this consortium is safe for human use, and viable 173 .…”

Section: Phage Therapymentioning

confidence: 99%

Microbiome-based interventions to modulate gut ecology and the immune system

et al. 2022

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The gut microbiome lies at the intersection between the environment and the host, with the ability to modify host responses to disease-relevant exposures and stimuli. This is evident in how enteric microbes interact with the immune system, e.g., supporting immune maturation in early life, affecting drug efficacy via modulation of immune responses, or influencing development of immune cell populations and their mediators. Many factors modulate gut ecosystem dynamics during daily life and we are just beginning to realise the therapeutic and prophylactic potential of microbiome-based interventions. These approaches vary in application, goal, and mechanisms of action. Some modify the entire community, such as nutritional approaches or faecal microbiota transplantation, while others, such as phage therapy, probiotics, and prebiotics, target specific taxa or strains. In this review, we assessed the experimental evidence for microbiome-based interventions, with a particular focus on their clinical relevance, ecological effects, and modulation of the immune system.

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Targeted suppression of human IBD-associated gut microbiota commensals by phage consortia for treatment of intestinal inflammation

Cited by 187 publications

References 120 publications

Modelling the gastrointestinal carriage of Klebsiella pneumoniae infections

Modelling the gastrointestinal carriage of Klebsiella pneumoniae infections

Phage therapy for Clostridioides difficile infection

Microbiome-based interventions to modulate gut ecology and the immune system

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