Lactobacillus Probiotics Enhance GLP-1 Receptor Expression
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Solution Overview
Problem
Type 2 diabetes patients often fail to achieve adequate glycemic control with GLP-1-based therapies due to impaired GLP-1 sensitivity and responsiveness, which can be attributed to gut microbiota dysbiosis and other multifactorial origins, leading to reduced efficacy of GLP-1 receptor agonists and DPP4 inhibitors.
Innovation Solution
The use of specific Lactobacillus probiotic strains in combination with incretin-based drugs, such as GLP-1 receptor agonists, DPP4 inhibitors, or dual GLP-1/GIP receptor agonists, to restore the incretin effect by modulating the gut microbiota and enhancing GLP-1 receptor expression and nitric oxide production, thereby improving glycemic control in type 2 diabetes patients.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If GLP-1-based therapies are used to treat type 2 diabetes, then glycemic control is improved, but efficacy is reduced in patients with impaired GLP-1 sensitivity
Solution Approach 1:
The patent introduces probiotic bacteria (Lactobacillus and Bifidobacterium strains) as intermediary agents that modify the gut microbiota composition. These probiotics act as mediators between the host and the GLP-1-based therapy, restoring GLP-1 sensitivity by modulating the gut microbiota environment, thereby enhancing the effectiveness of incretin-based drugs in patients who previously showed impaired response
Solution Approach 2:
The patent applies parameter changes by altering the gut microbiota composition through probiotic administration. Specifically, it increases the abundance of beneficial bacteria (Lactobacillus and Bifidobacterium) and decreases harmful bacteria, thereby changing the physiological parameters of GLP-1 sensitivity and responsiveness in the host, which in turn improves the efficacy of GLP-1-based therapies
2Reliability
If probiotic strains are administered to restore incretin effect, then GLP-1 receptor expression is enhanced, but treatment complexity increases
Solution Approach 1:
The patent merges two therapeutic approaches into a single integrated treatment regimen: probiotic administration and incretin-based drug therapy. By combining these treatments, the patent aims to achieve synergistic effects where the probiotics prepare the gut environment to enhance the efficacy of the incretin-based drugs, thereby restoring the incretin effect more effectively than either treatment alone
Solution Approach 2:
The patent employs self-service by utilizing naturally occurring probiotic bacteria that can colonize the gut and exert their beneficial effects autonomously. The probiotic strains (Lactobacillus and Bifidobacterium) are administered orally and self-regulate within the gut microbiota ecosystem, modulating the environment to enhance GLP-1 sensitivity without requiring complex external control mechanisms
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 combination of Lactobacillus probiotics with incretin-based drugs enhances the therapeutic efficacy of GLP-1-based therapies by improving GLP-1 receptor expression and nitric oxide production, leading to better glycemic control and insulin secretion in type 2 diabetes patients, particularly those who do not respond adequately to incretin-based treatments alone.
Implementation Method 1
The use of specific Lactobacillus probiotic strains in combination with incretin-based drugs, such as GLP-1 receptor agonists, DPP4 inhibitors, or dual GLP-1/GIP receptor agonists, to restore the incretin effect by modulating the gut microbiota
Implementation Method 2
Through the triggering of the gut-brain-periphery axis the enteric hormonal signal is transmitted to the brain. The latter organ then redistributes the neuro-hormonal message to peripheral tissues that engages numerous physiological functions involve in the control of glucose homeostasis
Implementation Method 3
G proteins, adenylate cyclase, cAMP, EPAC, PKA, CREB, PKC, Akt, ERK, nitric oxide (NO), and NO synthase (NOS) are the main signaling molecules responsible for GLP-1 intracellular signaling and action
Implementation Method 4
G proteins, adenylate cyclase, cAMP, EPAC, PKA, CREB, PKC, Akt, ERK, nitric oxide (NO), and NO synthase (NOS) are the main signaling molecules responsible for GLP-1 intracellular signaling and action
Implementation Method 5
The active peptide GLP-1 7-37 is rapidly degraded by the dipeptidyl peptidase 4 (DPP4), an amino-terminal peptidase largely distributed throughout the gut, into an inactive GLP-1 9-37 peptide. For the second one DPP4 inhibitors have been developed
Implementation Method 6
G proteins, adenylate cyclase, cAMP, EPAC, PKA, CREB, PKC, Akt, ERK, nitric oxide (NO), and NO synthase (NOS) are the main signaling molecules responsible for GLP-1 intracellular signaling and action
Data Source
Figure 1A~1B
Figure 1C~2A
Figure 2B
AI summary
The present invention relates to methods of enhancing the potency of incretin-based drugs in subjects in need thereof. Through different animal models, the inventors identified that a specific gut microbiota signature impairs GLP-1-activated gut-brain axis which could be transferred to germ free mice. The dysbiotic gut microbiota induces enteric neuropathy, reduces GLP-1 receptor and nNOS mRNA concentration, GLP-1 -induced nitric oxide production for the control of insulin secretion and gastric emptying. The frequency of Lactobacilli in the ileum microbiota was tightly correlated with nMOS mRNA concentration, which is a mode of action of GLP-1, of the enteric nervous system opening a novel route for the improvement of GLP-1 based therapies in type 2 diabetic patients. In particular, the present invention relates to a method of enhancing the potency of an incretin-based drug administered to a diabetic subject as part of a treatment regimen.