Human gut commensals are increasingly suggested to impact non-communicable diseases, such as 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.
Next-Generation Sequencing is widely used as a tool for identifying and quantifying microorganisms pooled together in either natural or designed samples. However, a prominent obstacle is achieving correct quantification when the pooled microbes are genetically related. In such cases, the outcome mostly depends on the method used for assigning reads to the individual targets. To address this challenge, we have developed Exodus—a reference-based Python algorithm for quantification of genomes, including those that are highly similar, when they are sequenced together in a single mix.
BX001, a formulated phage cocktail, was designed to target a wide host range of C. acnes and was demonstrated to be safe for topical use by comprehensive preclinical in silico and ex vivo approaches. BX001 safety and tolerability was confirmed in a double-blind, randomized, vehicle-controlled cosmetic trial in which it was administered to subjects with mild to moderate acne vulgaris.
Orally administered BX002 in first-in-human study was shown to be safe and well-tolerated in healthy adults. PK analysis showed high levels of viable phage in stool at sufficient levels to interact with target bacteria after passage through gastrointestinal tract.
Phage have high intrinsic safety and specificity and offer a promising treatment strategy to target Fusobacterium nucleatum associated with colorectal cancer. Here we demonstrate the ability to express a eukaryotic protein in an unconventional bacterial host using a sequence designed by computational tools.
S. aureus contributes to atopic dermatitis pathogenesis through the release of virulence factors that affect the keratinocytes and immune cells. A broad host range cocktail of natural phages targeting S. aureus was effective in reducing bacterial burden in-vitro and holds the potential to offer a novel therapeutic approach for atopic dermatitis.
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