Methods of enhancing the potency of incretin-based drugs in subjects in need thereof

Abstract

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.

1 . (canceled) 
     
     
         2 . A method of treating type 1 diabetes or type 2 diabetes or one or more complications thereof in a subject in need thereof comprising administering to the subject a therapeutically effective combination of at least one  Lactobacillus  probiotic strain and an incretin-based drug, wherein administration of the combination results in enhanced therapeutic efficacy relative to the administration of the incretin-based drug alone. 
     
     
         3 . The method of  claim 1  wherein the incretin-based drug is a GLP-1 receptor agonist or a DDP-4 inhibitor. 
     
     
         4 . The method of  claim 2  wherein the one or more complications of diabetes include cardiometabolic complications, metabolic complications, hepatic complications, respiratory complications, renal complications, nervous system complications and inflammation complications. 
     
     
         5 . The method of  claim 3  which further comprises administering to the subject a therapeutically effective amount of a drug selected from the group consisting of sulfonylurea drugs, biguanides, alpha-glucosidase inhibitors, thiazolidinediones, and meglitinides. 
     
     
         6 . The method of  claim 1  wherein the probiotic  Lactobacillus  strain is administered to the subject by ingestion and the incretin-based drug is administered to the subject subcutaneously. 
     
     
         7 . The method of  claim 1  wherein the probiotic  Lactobacillus  strain is selected from the group consisting of  Lactobacillus acetotolerans, Lactobacillus acidipiscis, Lactobacillus acidophilus, Lactobacillus agilis, Lactobacillus algidus, Lactobacillus alimentarius, Lactobacillus amylolyticus, Lactobacillus amylophilus, Lactobacillus amylovorus, Lactobacillus animalis, Lactobacillus arizonensis, Lactobacillus aviarius, Lactobacillus bifermentans, Lactobacillus brevis, Lactobacillus buchneri, Lactobacillus casei, Lactobacillus coelohominis, Lactobacillus collinoides, Lactobacillus coryniformis  subsp.  coryniformis, Lactobacillus coryniformis  subsp.  torquens, Lactobacillus  crispatus,  Lactobacillus curvatus, Lactobacillus cypricasei, Lactobacillus delbrueckii  subsp.  bulgaricus, Lactobacillus delbrueckii  subsp  delbrueckii, Lactobacillus delbrueckii  subsp.  lactis, Lactobacillus durianus, Lactobacillus equi, Lactobacillus farciminis, Lactobacillus ferintoshensis, Lactobacillus fermentum, Lactobacillus formicalis, Lactobacillus fructivorans, Lactobacillus frumenti, Lactobacillus fuchuensis, Lactobacillus gallinarum, Lactobacillus gasseri, Lactobacillus graminis, Lactobacillus hamsteri, Lactobacillus helveticus, Lactobacillus helveticus  subsp.  jugurti, Lactobacillus heterohiochii, Lactobacillus hilgardii, Lactobacillus homohiochii, Lactobacillus intestinalis, Lactobacillus japonicus, Lactobacillus jensenii, Lactobacillus johnsonii, Lactobacillus kefiri, Lactobacillus kimchii, Lactobacillus kunkeei, Lactobacillus leichmannii, Lactobacillus letivazi, Lactobacillus lindneri, Lactobacillus malefermentans, Lactobacillus mali, Lactobacillus maltaromicus, Lactobacillus manihotivorans, Lactobacillus mindensis, Lactobacillus mucosae, Lactobacillus murinus, Lactobacillus nagelii, Lactobacillus oris, Lactobacillus panis, Lactobacillus pantheri, Lactobacillus parabuchneri, Lactobacillus paracasei  subsp.  paracasei, Lactobacillus paracasei  subsp.  pseudoplantarum, Lactobacillus paracasei  subsp.  tolerans, Lactobacillus parakefiri, Lactobacillus paralimentarius, Lactobacillus paraplantarum, Lactobacillus pentosus, Lactobacillus perolens, Lactobacillus plantarum, Lactobacillus pontis, Lactobacillus psittaci, Lactobacillus reuteri, Lactobacillus rhamnosus, Lactobacillus ruminis, Lactobacillus sakei, Lactobacillus salivarius, Lactobacillus salivarius  subsp.  salicinius, Lactobacillus salivarius  subsp.  salivarius, Lactobacillus sanfranciscensis, Lactobacillus sharpeae, Lactobacillus suebicus, Lactobacillus thermophilus, Lactobacillus thermotolerans, Lactobacillus vaccinostercus, Lactobacillus vaginalis, Lactobacillus versmoldensis, Lactobacillus vitulinus, Lactobacillus vermiforme , and  Lactobacillus zeae    
     
     
         8 . The method of  claim 2  wherein the probiotic  Lactobacillus  strain is a food grade bacteria. 
     
     
         9 . The method of  claim 2  wherein the probiotic  Lactobacillus  strain is encapsulated in order to be protected against the stomach. 
     
     
         10 . The method of  claim 2  wherein the probiotic  Lactobacillus  strain is administered to the subject in the form of a food composition. 
     
     
         11 . A pharmaceutical composition comprising at least one probiotic  Lactobacillus  strain and at least one incretin-based drug. 
     
     
         12 . A method of i) restoring the incretin effect of GLP-1 and/or ii) preventing glucose intolerance and/or iii) improving glycemic management in a subject in need thereof comprising administering to the subject an effective amount of at least one  Lactobacillus  probiotic strain. 
     
     
         13 - 14 . (canceled) 
     
     
         15 . A method for predicting the response of a patient to a GLP-1 receptor agonist, said method comprising:
 i) determining the  Lactobacillus  genus frequency in the gut of said patient;   ii) comparing the value obtained at step i) with a predetermined reference value;   iii) concluding that the patient will develop a resistance to a GLP-1 receptor agonist when the value determined at step i) is lower than the predetermined reference value or concluding that the patient will not develop a resistance to a GLP-1 receptor agonist when the value determined at step i) is higher than the predetermined reference value.