Method for selection of agents influencing intestinal motility disorders and pain
Inventors
Connolly, Eamonn • Kunze, Wolfgang • Bienenstock, John
Assignees
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Publication Number
US-9816150-B2
Publication Date
2017-11-14
Expiration Date
Abstract
A method is provided for evaluating agents for the treatment of different intestinal motility disorders, using distinct methodological parts related to musculature and nerves of the GI tract which communicate with the brain. In particular, the present invention provides a method for the selection of an agent effective for the treatment of an intestinal motility disorder, comprising: a) a step of spatiotemporal (ST) mapping carried out on a gastrointestinal segment to analyze the effect of the agent on gastrointestinal motility; and b) a step of ex vivo nerve bundle recording carried out on a gastrointestinal segment to analyze the effect of the agent on mesenteric afferent nerve firing. Bacterial strains selected by the methods of the invention and the use of the bacterial strains in the treatment of intestinal motility disorders are also provided.
Core Innovation
The invention provides a two-step ex vivo agent-selection method for intestinal motility disorders and associated pain. It uses spatiotemporal (ST) mapping of GI segments together with intraluminal pressure to quantify migrating motor complex (MMC) frequency and MMC velocity and to measure intraluminal peak pressure (PPr). Agent effects are differentiated at least by intestinal region and by target, including muscle versus nerve.
In the second step, ex vivo extracellular mesenteric afferent nerve bundle recording is used to quantify spontaneous firing frequency as a pain signaling readout. This framework distinguishes agent effects on mesenteric afferent nerve firing while also relating those effects to the quantified MMC and intraluminal pressure measures obtained in the first step.
Selection criteria are linked to desired motility direction and pain outcome. Agents are selected to increase or decrease MMC frequency, MMC velocity and/or intraluminal peak pressure according to the intended intestinal motility disorder context, while also selecting for decreased mesenteric afferent nerve firing to reduce pain signaling. The disclosure also includes two deposited Lactobacillus gasseri strains, LG345A and LG621A, with corresponding motility and pain-signaling profiles.
Claims Coverage
The provided independent claims cover two specific Lactobacillus gasseri strains defined by direction of effects on migrating motor complex (MMC) parameters and mesenteric afferent nerve firing, plus two independent composition claims pairing each strain with an additional therapeutic or nutritional agent. In total, 4 independent claims are identified.
Strain increases MMC frequency, MMC velocity and intraluminal peak pressure while decreasing mesenteric afferent nerve firing (LG345A/DSM 27123)
A bacterial strain that increases migrating motor complex (MMC) frequency, MMC velocity and intraluminal peak pressure, and decreases mesenteric afferent nerve firing, wherein the bacterial strain is Lactobacillus gasseri 345A (LG345A) having been deposited under DSMZ Accession No. DSM 27123.
Strain decreases MMC velocity and decreases mesenteric afferent nerve firing (LG621A/DSM-27126)
A bacterial strain that decreases MMC velocity and decreases mesenteric afferent nerve firing, wherein the bacterial strain is Lactobacillus gasseri 621A (LG621A) having been deposited under DSMZ Accession No. DSM-27126.
Composition with LG345A and a further therapeutic or nutritional agent
A composition comprising the bacterial strain Lactobacillus gasseri 345A and a further therapeutic or nutritional agent.
Composition with LG621A and a further therapeutic or nutritional agent
A composition comprising the bacterial strain Lactobacillus gasseri 621A and a further therapeutic or nutritional agent.
Across the independent claims, the core coverage is for two deposited Lactobacillus gasseri strains characterized by directional effects on MMC parameters and mesenteric afferent nerve firing, together with compositions that include either strain combined with a further therapeutic or nutritional agent.
Stated Advantages
Increases migrating motor complex (MMC) frequency, MMC velocity and intraluminal peak pressure.
Decreases mesenteric afferent nerve firing.
Decreases MMC velocity.
Provides compositions that include the specified bacterial strains with a further therapeutic or nutritional agent.
Documented Applications
Treating or reducing the risk of constipation or colic by decreasing the transit time of material through a subject’s intestine.
Treating or reducing the risk of developing irritable bowel syndrome in a subject by increasing the transit time of material through the subject’s intestine.
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