Inflammatory bowel disease (IBD) is a term that covers different chronic inflammatory disorders of the digestive system, including Crohn’s disease and ulcerative colitis. Opportunistic microbes, known as pathobionts, are thought to contribute to uncontrolled inflammation in patients’ gut. But is it possible to target IBD-associated microbes without damaging the microbiome?
To answer this question, Eran Elinav from the Weizmann Institute of Science in Rehovot, Israel, and his team have tested a cocktail of five phages that specifically target Klebsiella pneumoniae, one of the bacterial pathogens related to intestinal inflammation. «Specificity is one of the main advantages of phages and phage-derived products, such as endolysins, over conventional antibiotics», says Roberto Díez, CEO of Telum Therapeutics. «Evidence suggests that microbial depletion by antibiotic treatment improves intestinal inflammation in animal models of IBD. However, this strategy is associated with adverse effects, alterations in the microbiome, and the emergence of antibiotic-resistant strains. Therefore, this work is of special relevance, since it explores phages as a therapeutic alternative».
An alternative that works, according to the results published in the journal Cell. The five-phage cocktail designed by researchers reduced colon inflammation and tissue damage in mice colonized with a Klepsiella Pneumonae strain found in the stools of more than 500 patients from that were suffering a flare of IBD. «This strain features a unique antibiotic resistance signature. Moreover, patients came from four countries, France, Israel, the US, and Germany, which suggest an association between this strain and disease severity across geography», points out Díez. «Therefore, it appears to be a target to be considered for treating the disease and, interestingly, there was no evidence that these microbes developed antiphagic resistance».
Also interesting were the results of experiments with a simulator of the human intestinal microbial ecosystem, as well as in human volunteers, as the cocktail proved to be safe, retaining viability in the digestive tract and accumulating in the intestine. «The volunteers were healthy individuals, so we do not know whether the phage cocktail reduces Klepsiella pneumonae-associated IBD inflammation in humans as it did in mice. What we do know is that none of the participants presented alterations in their microbiota, which is good news», stated Díez. «Nonetheless, However, future studies may reveal possible off-target effects induced by the complete phage combination. Endolysins, phage-derived lytic enzymes, on the other hand, tend to have very few adverse effects while retaining the advantages of phage therapy over conventional antibiotics».
Federici S, Kredo-Russo S, Valdés-Mas R, Kviatcovsky D, Weinstock E, Matiuhin Y, Silberberg Y, Atarashi K, Furuichi M, Oka A, Liu B, Fibelman M, Weiner IN, Khabra E, Cullin N, Ben-Yishai N, Inbar D, Ben-David H, Nicenboim J, Kowalsman N, Lieb W, Kario E, Cohen T, Geffen YF, Zelcbuch L, Cohen A, Rappo U, Gahali-Sass I, Golembo M, Lev V, Dori-Bachash M, Shapiro H, Moresi C, Cuevas-Sierra A, Mohapatra G, Kern L, Zheng D, Nobs SP, Suez J, Stettner N, Harmelin A, Zak N, Puttagunta S, Bassan M, Honda K, Sokol H, Bang C, Franke A, Schramm C, Maharshak N, Sartor RB, Sorek R, Elinav E. Targeted suppression of human IBD-associated gut microbiota commensals by phage consortia for treatment of intestinal inflammation. Cell. 2022 Aug 4;185(16):2879-2898.e24. doi: 10.1016/j.cell.2022.07.003. Epub 2022 Aug 4. PMID: 35931020.