Materials and methods for preventing and treating microbe-mediated epithelial disorders

Abstract

The present invention provides pharmaceutical compositions in the form of relatively high molecular weight biocompatible polymers such as polyethylene glycol, optionally supplemented with a protective polymer such ad dextran and/or essential pathogen nutrients such as L-glutantine. Also provided are methods for preventing or treating gut-derived sepsis attributable to intestinal pathogens such as Pseudomonas aeruginosa by administering high molecular weight polyethylene glycol as well as methods for monitoring the administration of high molecular weight polyethylene glycol, such as in methods of preventing, ameliorating or treating microbe-induced epithelial disorders, as exemplified by gut-derived sepsis. Frequently, gut-derived sepsis arises as a complication in mammals recovering from surgical intervention or suffering from a disease or disorder, providing indications of suitable animals to receive preventative treatment. Finally, the invention provides a composition comprising infant formula and polyethylene glycol and methods for using that composition.

Description

FIELD OF INVENTION [0001] The present invention relates to materials and methods for preventing or treating microbe-mediated epithelial disorders, such as gut-derived sepsis. BACKGROUND [0002] Microbe-mediated epithelial disorders, or abnormal conditions, present a significant threat to the health of man and animals, imposing a burden on healthcare systems worldwide. One example of such disorders, gut-derived sepsis, is a major cause of mortality among organisms, such as human patients, that suffer from any of a variety of diseases, disorders or afflictions, such as bum injuries, neonatal enterocolitis, severe neutropenia, inflammatory bowel disease, and organ rejection following transplantation. The intestinal tract reservoir has long been recognized to be a potentially lethal focus of bacterial-mediated sepsis in, e.g., critically ill, hospitalized patients. The ability of microbial pathogens such as the Pseudomonads (e.g., Pseudomonas aeruginosa) to perturb the regulatory functio...

AI Technical Summary

Benefits of technology

[0007] The present invention satisfies the aforementioned need in the art by providing a high molecular weight (HMW) polyethylene glycol composition that provides effective protection against an abnormal condition characterized by an epithelial surface at risk of developing a microbe-mediated disorder. Exemplary abnormal conditions include gut-derived sepsis, and other intestinal disorders / diseases associated with intestinal flora, due to intestinal pathogens including, but not limited to, P. aeruginosa. The HMW PEG inhibits or prevents contact of such pathogens as P. aeruginosa with the intestinal epithelial surface. In addition, high molecular weight PEG suppresses virulence expression in these pathogens (e.g., P. aeruginosa) responsive to a variety of signals that may involve quorum sensing signaling networks. The ability of HMW PEGs to interdict at the infectious interface between the intestinal pathogen and the intestinal epithelium provides an alternative approach to preventing or treating gut-derived sepsis, e.g., following catabolic stress. Importantly, treatments with HMW PEGs would be cost effective and relatively simple to perform on human patients as well as a variety of other organisms such as agriculturally significant livestock (e.g., cattle, pigs, sheep, goats, horses, chickens, turkeys, ducks, geese, and the like), pets, and zoo animals.

Problems solved by technology

Microbe-mediated epithelial disorders, or abnormal conditions, present a significant threat to the health of man and animals, imposing a burden on healthcare systems worldwide.

Conventional therapeutic approaches to the prevention or treatment of microbe-mediated epithelial disorders such as gut-derived sepsis have met with incomplete success.

Antibiotic-based approaches are compromised by the difficulty in tailoring antibiotics to the intestinal pathogen in a manner that does not impact the remaining intestinal flora.

In addition, many of the intestinal pathogens, as typified by P. aeruginosa, often become resistant to antibiotic challenges, resulting in a costly, ongoing and incompletely successful approach to prevention or treatment.

Problems also plague immunotherapeutic approaches.

Particularly, many intestinal pathogens such as P. aeruginosa, are immunoevasive, rendering sucn approaches minimally effective.

Also, solutions of low molecular weight PEG can lose their efficacy in attenuating the virulence capacity of certain organisms, despite preserving them.

Consequently, LMW PEG treatments of the intestine produce significant changes in the physiology of the treated organisms, with unpredictable, and thus potentially deleterious, longer-term consequences for the health and well-being of the treated organism.

Moreover, such treatments provoke physically demanding reactions in the form of massive intestinal voiding in critically ill organisms such as hospitalized human patients.

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