Treatment methods and compositions
Inventors
Assignees
US Department of Veterans Affairs • UNM Rainforest Innovations
Publication Number
US-11986501-B2
Publication Date
2024-05-21
Expiration Date
2039-07-16
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Abstract
This disclosure describes compositions and methods involving amounts of probiotic bacteria effective to decrease intestinal permeability or intestinal epithelial tight junction permeability in a subject having or at risk of having defective intestinal barrier, increased intestinal permeability and/or intestinal epithelial tight junction permeability compared to a normal subject. The probiotic bacteria can include a Lactobacillus spp. and/or a Bifidobacterium spp.
Core Innovation
This disclosure describes compositions and methods involving amounts of probiotic bacteria effective to decrease intestinal permeability or intestinal epithelial tight junction permeability in subjects having or at risk of having defective intestinal barrier or increased permeability compared to normal subjects. The probiotic bacteria include Lactobacillus spp. and/or Bifidobacterium spp., specifically strains such as Lactobacillus acidophilus strain ATCC 4356 and Bifidobacterium bifidum strain ATCC 35914.
The invention addresses the problem that defective intestinal epithelial tight junction barrier is a pathogenic factor of inflammatory conditions of the gut, such as inflammatory bowel disease (IBD), and also in inflammatory conditions extending beyond the gut including alcoholic liver disease. Defective tight junction barriers increase intestinal penetration of bacterial antigens and promote inflammation. Currently, there are no therapeutic agents that target the intestinal tight junction barrier directly, and the mechanisms that enhance this barrier are poorly understood.
The probiotic strains described enhance intestinal epithelial tight junction barrier function by interacting with the apical membrane TLR2 receptor complex, causing increased aggregation, expression, and activity of TLR2, cytoplasmic-to-apical membrane translocation of Nod1, and activation of signaling pathways such as p38 kinase. This leads to activation of occludin gene expression and increased occludin protein levels, strengthening the tight junction barrier. The probiotics also suppress NF-κB activation, a pro-inflammatory mediator, thereby reducing inflammation. The two strains together have a synergistic effect enhancing the intestinal epithelial barrier more than either alone.
Claims Coverage
The patent includes eight independent claims focusing on methods involving administration of a combination of Lactobacillus acidophilus strain ATCC 4356 and Bifidobacterium bifidum to subjects with or at risk of increased intestinal permeability or inflammation.
Inhibition or suppression of NF-κB activation
Administering a composition comprising Lactobacillus acidophilus strain ATCC 4356 and Bifidobacterium bifidum in an amount effective to induce inhibition or suppression of NF-κB activation in intestinal epithelial cells of a subject having or at risk of defective intestinal barrier or increased permeability.
Induction of cytoplasmic to apical membrane translocation or activation of Nod1
Administering a composition comprising the combination of strains in an amount effective to induce cytoplasmic to apical membrane translocation of Nod1 or activation of Nod1 signal transduction pathway in intestinal epithelial cells of a subject having or at risk of increased intestinal permeability or inflammation.
Increase in occludin expression in intestinal epithelial cells
Administering a composition comprising the combination of Lactobacillus acidophilus strain ATCC 4356 and Bifidobacterium bifidum in an amount effective to induce an increase in occludin expression in intestinal epithelial cells of a subject having or at risk of increased intestinal permeability or inflammation.
Amelioration of symptoms or clinical signs of inflammatory gut conditions
Administering the composition in an amount effective to ameliorate at least one symptom or clinical sign of an inflammatory condition of the gut in subjects having or at risk of increased epithelial tight junction permeability.
Amelioration of symptoms or clinical signs of inflammatory conditions of organs
Administering the composition in an amount effective to ameliorate at least one symptom or clinical sign of an inflammatory condition of an organ, particularly the liver, in subjects having or at risk of increased intestinal permeability or epithelial tight junction permeability.
Enhancement of intestinal barrier function and decrease in intestinal permeability and inflammation
Administering the composition in an amount effective to increase intestinal barrier function, decrease intestinal permeability or epithelial tight junction permeability, and/or decrease intestinal inflammation in subjects having or at risk of defective intestinal barrier, increased permeability, or inflammation.
Prophylactic administration before symptom manifestation
The composition is administered before the subject exhibits a symptom or clinical sign resulting from increased intestinal or epithelial tight junction permeability.
Synergistic efficacy of combination composition
The composition comprising the combination of Lactobacillus acidophilus strain ATCC 4356 and Bifidobacterium bifidum is more effective than compositions comprising either strain alone.
The independent claims cover methods of administering a defined combination of two probiotic strains to reduce intestinal permeability, inhibit pro-inflammatory signaling pathways, increase tight junction protein expression, and ameliorate inflammatory symptoms in gastrointestinal and related systemic conditions. The claims emphasize the combination's enhanced efficacy and prophylactic applications.
Stated Advantages
The compositions comprising Lactobacillus acidophilus and Bifidobacterium bifidum strains enhance intestinal epithelial tight junction barrier function to decrease intestinal permeability.
The probiotic strains synergistically increase barrier function more effectively in combination than individually.
The compositions suppress NF-κB activation, reducing pro-inflammatory responses in intestinal epithelial cells.
They induce signaling through TLR2 and Nod1 pathways leading to increased occludin expression, strengthening tight junctions.
Administration ameliorates symptoms and signs of inflammatory conditions of the gut and liver, including models of inflammatory bowel disease and alcoholic liver disease.
The probiotic strains have no known safety concerns, facilitating advancement to clinical trials.
Documented Applications
Treatment or prophylaxis of defective intestinal barrier or increased intestinal permeability disorders including inflammatory bowel disease such as Crohn's disease, ulcerative colitis, necrotizing enterocolitis, coeliac disease, and irritable bowel syndrome.
Treatment or prophylaxis of inflammatory conditions of the liver including alcoholic liver disease, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, and metabolic syndrome.
Therapeutic use in animal models to inhibit DSS-induced colitis and alcohol-consumption-induced liver inflammation and fatty liver disease.
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