Lactococcus lactis Transformant for Weight Loss via Oxyntomodulin Expression
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Solution Overview
Problem
Current weight loss medications, including chemical and herbal remedies, often come with adverse side effects and production challenges, such as high costs and inconvenience, while existing bacterial expression systems for oxyntomodulin introduce antibiotic resistance genes, posing safety concerns.
Innovation Solution
A transformant strain of Lactococcus lactis is engineered to express human oxyntomodulin through homologous recombination, eliminating antibiotic resistance genes and enabling oral administration in the form of probiotics for weight loss and lipid reduction, utilizing codon-optimized human oxyntomodulin gene insertion into the thyA gene for constitutive expression.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If chemical weight loss medications are used to suppress appetite, then weight loss effect is achieved, but side effects such as serotonin syndrome, hypertension and angina pectoris occur
Solution Approach 1:
The patent uses a probiotic bacteria system that naturally degrades after completing its weight loss function in the gastrointestinal tract, eliminating the need for long-term medication and reducing cumulative side effects. The bacteria are consumed and excreted naturally, providing a temporary but effective intervention without persistent harmful effects.
Solution Approach 2:
The patent introduces oxyntomodulin-expressing bacteria as an intermediary that mediates weight loss through natural physiological pathways rather than directly suppressing appetite with chemical drugs. The bacteria produce oxyntomodulin peptide locally in the gut, which acts on GLP-1 receptors to reduce appetite and increase fat mobilization, avoiding the systemic side effects of traditional appetite suppressants.
2Productivity
If antibiotic resistance genes are included in bacterial expression systems, then gene expression is achieved, but safety concerns arise due to potential allergen introduction and drug resistance
Solution Approach 1:
The patent removes antibiotic resistance genes from the bacterial expression system, extracting only the essential components needed for oxyntomodulin production. The bacteria use native promoter sequences and ribosome binding sites from safe probiotic strains, eliminating the harmful antibiotic resistance element while maintaining gene expression capability through alternative regulatory mechanisms.
Solution Approach 2:
The patent converts the potential harm of antibiotic resistance into a benefit by using the bacteria's natural probiotic properties and safe degradation characteristics. The bacteria are designed to be transient and harmless, turning what would be a safety risk (live bacteria in humans) into a beneficial temporary therapeutic agent that naturally eliminates itself after use.
3Ease of operation
If oxyntomodulin is produced by chemical synthesis or bioengineering, then the peptide can be administered, but production costs are high and in vivo half-life is short
Solution Approach 1:
The patent enables the bacteria to self-produce oxyntomodulin through their own metabolic machinery, eliminating the need for expensive external chemical synthesis or complex bioengineering production facilities. The bacteria serve as living factories that continuously produce the peptide in the gastrointestinal tract, reducing production costs and enabling sustained local availability.
Solution Approach 2:
The patent establishes continuous production of oxyntomodulin by the probiotic bacteria throughout their residence in the gastrointestinal tract, rather than relying on short-lived injected peptides. The bacteria continuously synthesize and secrete oxyntomodulin, maintaining therapeutic levels over an extended period and effectively increasing the in vivo half-life through sustained local production.
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 Lactococcus lactis transformant achieves significant weight loss and lipid reduction in obese mice with improved safety and reduced production costs, outperforming previous bacterial expression systems by enhancing weight loss efficacy and minimizing side effects, while maintaining environmental safety.
Implementation Method 1
A transformant strain of Lactococcus lactis is engineered to express human oxyntomodulin through homologous recombination
Implementation Method 2
the L. lactis thyA (thymidylate synthase, thyA) gene with the codon-optimized human oxyntomodulin gene through homologous recombination
Implementation Method 3
OXM directly acts on GLP-1 receptor of the gastrointestinal mucosa epithelial cell to inhibit the absorption of glucose and lipid
Implementation Method 4
OXM acts on the vagus nerve to down-regulate the secretion of ghrelin and suppress the appetite
Implementation Method 5
OXM stimulates the synthesis and secretion of thyroid hormone to increase the energy consumption and fat mobilization
Data Source
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AI summary
The present invention discloses a transformant for weight loss and lipid reduction, which is obtained by recombining and substituting human oxyntomodulin gene into thymidylate synthase gene of L.lactis genome. Wherein the recombinant substitution is homologous recombination by artificially synthesizing gene sequences, making the sequence flanking the human oxyntomodulin gene derived from the homologous sequences of thymidylate synthase gene in the L.lactis genome, then the gene fragments are electroporated into L.lactis, to carry out homologous recombination. The transformant in the invention is to constitutively express oxyntomodulin, which does not contain antibiotic resistance gene. The transformant can achieve the effects of weight loss, blood lipid reduction, and blood glucose reduction. Thus it can be used for the preparation of drugs for the treatment of obesity, diabetes, and dyslipidemia.