Sunday, September 04, 2022

Targeted and personalized bacteriophage treatment of intestinal inflammation

Amazing stuff! This seems to be very promising approach!

"... researchers have demonstrated the feasibility of a potential therapy for killing inflammation-causing gut bacteria in a targeted manner: by using viruses that infect them. ...
“There are thousands of different phages, and their big advantage is that each of them specializes in attacking a different type of bacteria,” ...
They compared the composition of gut microbes in healthy volunteers to that in people with two major forms of inflammatory bowel disease, ulcerative colitis and Crohn’s disease. A detailed computational analysis helped them zero in on several bacterial strains not found in the healthy individuals that were substantially enriched in people with the disease, particularly in those whose condition was worsening. The study participants were recruited from four countries in different parts of the world – France, Germany, Israel and the United States – to make sure that the results would hold true regardless of locale. After identifying several strains of the Klebsiella pneumoniae bacterium as likely contributors to intestinal inflammation, the researchers confirmed this finding by implanting these bacteria into mice used for the study of inflammatory bowel disease. Indeed, the human Klebsiella pneumoniae strains associated with this disease worsened inflammation and intestinal damage in recipient mice.
They compared the composition of gut microbes in healthy volunteers to that in people with two major forms
Next, the researchers screened thousands of phages, selecting about 40 that were most active against the human bacterial strains they had identified as being related to intestinal inflammation. ... scientists used recent insights into the molecular mechanisms of this arms race in order to give their phages the upper hand against the bacteria. That is, they looked for the ideal combination of phages that would prevent the bacteria from fighting back. A cocktail of 5 phages was selected based on genetic profiles, structural features revealed through electron microscopy and extensive combinatorial screening for activity against a variety of Klebsiella pneumoniae strains, including ones resistant to antibiotics. Taken together, these 5 phages prevented the emergence of bacterial mutants that could spread resistance. ..."

From the abstract:
"Human gut commensals are increasingly suggested to impact non-communicable diseases, such as inflammatory bowel diseases (IBD), yet their targeted suppression remains a daunting unmet challenge. In four geographically distinct IBD cohorts (n = 537), we identify a clade of Klebsiella pneumoniae (Kp) strains, featuring a unique antibiotics resistance and mobilome signature, to be strongly associated with disease exacerbation and severity. Transfer of clinical IBD-associated Kp strains into colitis-prone, germ-free, and colonized mice enhances intestinal inflammation. Stepwise generation of a lytic five-phage combination, targeting sensitive and resistant IBD-associated Kp clade members through distinct mechanisms, enables effective Kp suppression in colitis-prone mice, driving an attenuated inflammation and disease severity. Proof-of-concept assessment of Kp-targeting phages in an artificial human gut and in healthy volunteers demonstrates gastric acid-dependent phage resilience, safety, and viability in the lower gut. Collectively, we demonstrate the feasibility of orally administered combination phage therapy in avoiding resistance, while effectively inhibiting non-communicable disease-contributing pathobionts."

The Viruses That Fight Disease - Life Sciences | Weizmann Wonder Wander - News, Features and Discoveries




Members of the 5-phage cocktail for treating inflammatory bowel disease, viewed with an electron microscope


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