Engineered Bacteria Metabolizing Bile Acids for Diarrhea Treatment
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Solution Overview
Problem
Current treatments for bile acid diarrhea, such as bile acid sequestrants, have limitations including poor patient compliance and interference with medication absorption, highlighting the need for effective therapies to manage diseases associated with bile acids and bile salts.
Innovation Solution
Modified bacteria, engineered to metabolize bile acids and bile salts using transgenes encoding hydroxysteroid dehydrogenases, are introduced to the gut to efficiently metabolize bile acids, altering their bioactivity and bioavailability, thereby treating associated disorders.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If bile acid sequestrants are used to treat bile acid diarrhea, then diarrhea symptoms are managed, but patient compliance deteriorates due to poor palatability and adverse events
Solution Approach 1:
The engineered bacteria autonomously metabolize excess bile acids in the gut without requiring patient intervention beyond initial administration. The bacteria self-regulate bile acid levels through their metabolic pathways, eliminating the need for continuous patient compliance with medication regimens while maintaining treatment efficacy.
Solution Approach 2:
Engineered bacteria serve as a biological intermediary that mediates the treatment of bile acid diarrhea. Instead of using chemical sequestrants that directly bind bile acids, the bacteria metabolize bile acids through enzymatic pathways (7α-dehydrogenase, 3α-hydroxysteroid dehydrogenase), providing a more palatable and better-tolerated treatment option.
2Reliability
If bile acid sequestrants are used to treat bile acid diarrhea, then diarrhea symptoms are managed, but absorption of other medications deteriorates
Solution Approach 1:
The bacteria act as a selective intermediary that metabolizes bile acids through specific enzymatic pathways without interfering with the absorption of other medications. Unlike non-specific chemical sequestrants that bind multiple substances, the bacterial enzymes (7α-dehydrogenase, 3α-hydroxysteroid dehydrogenase) specifically target bile acid structures, leaving other medications unaffected and maintainable in the system.
Solution Approach 2:
The treatment effect is localized to bile acid metabolism within the gut environment. The engineered bacteria express specific metabolic enzymes that act locally on bile acids without creating systemic effects that would interfere with medication absorption elsewhere in the body, thus maintaining medication compatibility while treating diarrhea.
3Reliability
If modified bacteria are introduced to metabolize bile acids, then bile acid levels are reduced and therapeutic products are produced, but treatment complexity increases
Solution Approach 1:
The engineered bacteria perform multiple therapeutic functions simultaneously: they metabolize excess bile acids through 7α-dehydrogenase and 3α-hydroxysteroid dehydrogenase pathways, produce therapeutic metabolites (such as ursodeoxycholic acid), and modulate gut microbiota composition. This multi-functionality consolidates multiple treatment mechanisms into a single biological agent, reducing overall treatment complexity despite the sophisticated metabolic capabilities.
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The modified bacteria effectively metabolize bile acids, reducing their levels and altering their properties to produce therapeutic products, providing a more effective and compliant treatment option for bile acid-related disorders.
Implementation Method 1
Modified bacteria, engineered to metabolize bile acids and bile salts using transgenes encoding hydroxysteroid dehydrogenases
Implementation Method 2
Throughout the gastrointestinal tract (GIT), bile acids encounter gut bacteria, which are capable of metabolizing bile acids to numerous products with altered bioactivity and bioavailability
Data Source
AI summary
The disclosure relates generally to bacteria that have been modified to metabolize a bile acid, pharmaceutical compositions including the bacteria, and methods of using the bacteria and pharmaceutical compositions to treat disorders associated with an elevated amount of bile acid, e.g., bile acid diarrhea.