Methods and compositions for treatment of microbiome-associated disorders
Inventors
Cutcliffe, Colleen • Eid, John S. • Altman, Tomer • Kolterman, Orville G. • Bullard, James H.
Assignees
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Publication Number
US-11583558-B2
Publication Date
2023-02-21
Expiration Date
Abstract
Disclosed herein are methods and compositions for treatment of a microbiome associated disorder. Further, disclosed herein are methods and compositions for modulating short chain fatty acid production in a subject.
Core Innovation
The invention relates to pharmaceutical compositions and methods that treat a disorder in a subject by administering a therapeutically effective microbial composition. The microbial composition is configured to increase production of butyrate in the subject and is used to treat hyperalgesia, anxiety, or both. In the disclosed approach, the microbial composition includes two primary fermenter microbes and three secondary fermenter microbes.
The microbial composition is described as capable of modulating a gut-brain neural circuit in the subject. The disclosed compositions are characterized using isolated and/or purified microbes defined by high-identity rRNA sequences, including 16S rRNA and 23S rRNA, and are linked to butyrate pathway enzyme sequences and short-chain fatty acids (SCFAs).
Broad formulation concepts and delivery considerations are also described, including enteric-coated delivery to the ileum and colon and concepts involving prebiotic/probiotic/synbiotic formulations and spore forms. In some embodiments, the fermenter microbes include obligate anaerobes as primary fermenter microbes and secondary fermenter microbes, and specific primary and secondary fermenter microbes are stated, including Akkermansia muciniphila and Bifidobacterium infantis as primary fermenters, and Eubacterium hallii, Clostridium beijerinckii, and Clostridium butyricum as secondary fermenters.
Claims Coverage
The independent claim is directed to treating hyperalgesia, anxiety, or both by administering a therapeutically effective microbial composition that increases butyrate production. The independent claim specifies five fermenter microbes in a defined primary/secondary structure, and dependent features include modulation of a gut-brain neural circuit, obligate anaerobe fermenter microbes, prebiotic selection, and specified microbe selections.
Treating hyperalgesia, anxiety, or both by administering a butyrate-increasing microbial composition
A method of treating a disorder in a subject with hyperalgesia, anxiety, or both by administering a therapeutically effective amount of a microbial composition, wherein the microbial composition increases production of butyrate in the subject.
Two primary fermenter microbes and three secondary fermenter microbes
The microbial composition comprises two primary fermenter microbes and three secondary fermenter microbes that increase production of butyrate in the subject.
Gut-brain neural circuit modulation
The microbial composition modulates a gut-brain neural circuit in the subject.
Obligate anaerobe fermenter constraint
Primary fermenter microbes and secondary fermenter microbes are obligate anaerobes.
Prebiotic selection for the microbial composition
Including a prebiotic in the microbial composition, selected from a defined group or from any combination of the defined prebiotics.
Specified primary and secondary microbes as primary fermenters and secondary fermenters
Including Akkermansia muciniphila and Bifidobacterium infantis as primary fermenters, and Eubacterium hallii, Clostridium beijerinckii, and Clostridium butyricum as secondary fermenters.
Additional microbe selection from a listed group
Including at least one specified microbe selected from a listed group, with any combination thereof.
The claim coverage centers on administration of a therapeutically effective microbial composition that increases butyrate production in a subject to treat hyperalgesia, anxiety, or both, with the microbial composition structured as two primary fermenter microbes and three secondary fermenter microbes and further characterized by gut-brain neural circuit modulation, obligate anaerobes, prebiotic selection, and specified microbe selections.
Stated Advantages
Treatment of hyperalgesia, anxiety, or both by administering a microbial composition that increases production of butyrate.
Modulation of the gut-brain axis and nervous system effects, including enteric, central, and autonomic pathways.
Associations with modulation of GPCR-related targets, including free fatty acid receptors/GPR41, GLP-1 and PYY, neurotransmitters including serotonin, dopamine, and GABA, and neuroactive metabolites including indole-3-propionate.
Associations with modulation of inflammatory and endocrine-related pathways, including cytokine/inflammatory mediators and steroid hormones cortisol and corticosterone.
Associations with modulation of thyroid homeostasis and pathways involving NF-kB, HDAC, and nuclear receptors including PXR.
Modulating a gut-brain neural circuit in the subject.
Using fermenter microbes that are obligate anaerobes.
Documented Applications
Companion diagnostic and sequencing concepts for identifying or supporting use in relation to microbiome-based treatment of hyperalgesia, anxiety, or both.
Delivery concepts including an enteric-coated oral pill and delivery to ileum and colon for administering the microbial composition.
Treatment of hyperalgesia, anxiety, or both in a subject using a therapeutically effective microbial composition.
Modulating a gut-brain neural circuit in the subject as part of the treatment approach.
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