Technological Trends Involving Probiotics in the Treatment of Diabetic
Neuropathy: A Patent Review (2009-2022)

Sthefane      Silva  Santos; Mariana   Bastos   de Souza; Pedro   Santana   Sales  Lauria; Paulo   José   Lima  Juiz; Cristiane      Flora  Villarreal; Max   Denisson   Maurício  Viana
Abstract

Background: Diabetic neuropathy (DN) causes neuropathic pain, and current treatments are unsatisfactory. Recently studies have demonstrated an assertive correlation between gut microbiota and pain modulation.
Objective: Considering the emerging search for new therapies for the control of DN and the growing commercial interest in the probiotics market, this study aimed to provide patents on the use of probiotics in the control of DN.
Methods: This is a patent prospection performed in the Espacenet Patent database, using the association of keywords and IPC related to probiotics in medical preparations and foods, from 2009 to December 2022.
Results: Results have shown that in 2020, there was a boom in patent filing in the area. Asian countries accounted for more than 50% of all 48 inventions (n = 48), with Japan as the only applicant in 2021. Products being developed in recent years point to effects that may represent an advancement in DN treatment, such as reduced concentration of pro-inflammatory mediators, metabolites and neurotransmitters release, and hypoglycemic potential. All effects were more related to the Lactobacillus and Bifidobacterium genera, associated with more than one property mentioned.
Conclusion: The mechanisms attributed to the microorganisms suggest the therapeutic potential of probiotics in the non-pharmacological treatment of pain. New applications for probiotics have resulted from great research interest by academia, but also reflect commercial interests despite the paucity of clinical trials. Thus, the present work supports the evolution of research to explore the benefits of probiotics and their clinical use in DN.
Keywords: Neuropathic pain, gut microbiota, diabetic complications, pathophysiology, probiotics market, reactive oxygen species.
[1]
Sun H, Saeedi P, Karuranga S, et al. IDF Diabetes Atlas: Global, regional and country-level diabetes prevalence estimates for 2021 and projections for 2045. Diabetes Res Clin Pract  2022; 183: 109119.
 [http://dx.doi.org/10.1016/j.diabres.2021.109119] [PMID: 34879977]

[2]
Albers JW, Pop-Busui R. Diabetic neuropathy: Mechanisms, emerging treatments, and subtypes. Curr Neurol Neurosci Rep  2014; 14(8): 473.
 [http://dx.doi.org/10.1007/s11910-014-0473-5] [PMID: 24954624]

[3]
Akter N. Diabetic peripheral neuropathy: Epidemiology, physiopathology, diagnosis and treatment. Delta Med College J  2019; 7(1): 35-48.
 [http://dx.doi.org/10.3329/dmcj.v7i1.40619]

[4]
do Nascimento OJM, Pupe CCB, Cavalcanti EBU. Diabetic neuropathy. Rev Dor  2016; 17: 46-51.

[5]
Waldfogel JM, Nesbit SA, Dy SM, et al. Pharmacotherapy for diabetic peripheral neuropathy pain and quality of life. Neurology  2017; 88(20): 1958-67.
 [http://dx.doi.org/10.1212/WNL.0000000000003882] [PMID: 28341643]

[6]
Ardeleanu V, Toma A, Pafili K, et al. Current pharmacological treatment of painful diabetic neuropathy: A narrative review. Medicina  2020; 56(1): 25.
 [http://dx.doi.org/10.3390/medicina56010025] [PMID: 31936646]

[7]
Lin B, Wang Y, Zhang P, Yuan Y, Zhang Y, Chen G. Gut microbiota regulates neuropathic pain: Potential mechanisms and therapeutic strategy. J Headache Pain  2020; 21(1): 103.
 [http://dx.doi.org/10.1186/s10194-020-01170-x] [PMID: 32807072]

[8]
Franca GM, da Cruz GS, Morais RP, Dias AKC, Araujo ME da S, Moreira LM, et al. The immunomodulatory effect of the intestinal microbiota, the consequences of its imbalance and probiotic prophylaxis. Ibero-American J Human. Sci Educ  2021; 7(9): 151-75.

[9]
Zheng D, Liwinski T, Elinav E. Interaction between microbiota and immunity in health and disease. Cell Res  2020; 30(6): 492-506.
 [http://dx.doi.org/10.1038/s41422-020-0332-7] [PMID: 32433595]

[10]
Guo R, Chen LH, Xing C, Liu T. Pain regulation by gut microbiota: Molecular mechanisms and therapeutic potential. Br J Anaesth  2019; 123(5): 637-54.
 [http://dx.doi.org/10.1016/j.bja.2019.07.026] [PMID: 31551115]

[11]
 Probiotics Market Size | Industry Report, 2021 -2030. Available From: grandviewresearch.com/industry-analysis/probiotics-market [Accessed on: Apr 15, 2022].

[12]
Dixit Y, Wagle A, Vakil B. Patents in the field of probiotics, prebiotics, synbiotics: A review. J Food Microbiol Saf Hyg  2016; 01: 02.

[13]
Milner E, Stevens B, An M, et al. Utilizing probiotics for the prevention and treatment of gastrointestinal diseases. Front Microbiol  2021; 12: 689958.
 [http://dx.doi.org/10.3389/fmicb.2021.689958] [PMID: 34434175]

[14]
Sorokulova I. Preclinical testing in the development of probiotics: A regulatory perspective with Bacillus strains as an example. Clin Infect Dis  2008; 46 (Suppl. 2): S92-5.
 [http://dx.doi.org/10.1086/523334] [PMID: 18181731]

[15]
 Global innovation index 2020: Who will finance innovation? 2020. Available From: wipo.int/global_innovation_index/en/2020/index.html [Accessed on : Apr 15, 2022].

[16]
 Global Innovation Index 2021: Which are the most innovative countries? 2021. Available From: wipo.int/global_innovation_index/en/2021/index.html?gclid=Cj0KCQiA2NaNBhDvARIsAEw55hhjx9i-8FcypiOCvDsXGphJNpyAFIIP5V261BxKofxLFWUk00gKdhQaAsPEALw_wcB [Accessed on: Apr 15, 2022].

[17]
Koirala S, Anal AK. Probiotics-based foods and beverages as future foods and their overall safety and regulatory claims. Future Foods  2021; 3: 100013.
 [http://dx.doi.org/10.1016/j.fufo.2021.100013]

[18]
 Evelo Biosciences. 2021. Available From: evelobio.com [Accessed on: Apr 15, 2022].

[19]
 Probiotics and Synbiotics products. Available From: probiotical.com/index.php?lingua=en [Accessed on: Apr 15, 2022].

[20]
 4D Pharma plc - developing science, delivering therapies. Available From: 4dpharmaplc.com/en [Accessed on: Apr 15, 2022].

[21]
Baral KC, Bajracharya R, Lee SH, Han HK. Advancements in the pharmaceutical applications of probiotics: Dosage forms and formulation technology. Int J Nanomedicine  2021; 16: 7535-56. Available from:
 [http://dx.doi.org/10.2147/IJN.S337427] [PMID: 34795482]

[22]
de Oliveira Júnior JO, Portella CSA. Junior, Cohen CP. Inflammatory mediators of neuropathic pain. Rev Dor  2016; 17.

[23]
Ding LN, Ding WY, Ning J, Wang Y, Yan Y, Wang ZB. Effects of probiotic supplementation on inflammatory markers and glucose homeostasis in adults with type 2 diabetes mellitus: A systematic review and meta-analysis. Front Pharmacol  2021; 12: 770861.
 [http://dx.doi.org/10.3389/fphar.2021.770861] [PMID: 34955840]

[24]
Cristofori F, Dargenio VN, Dargenio C, Miniello VL, Barone M, Francavilla R. Anti-inflammatory and immunomodulatory effects of probiotics in gut inflammation: A door to the body. Front Immunol  2021; 12: 578386.
 [http://dx.doi.org/10.3389/fimmu.2021.578386] [PMID: 33717063]

[25]
Boakye PA, Tang SJ, Smith PA. Mediators of neuropathic pain; focus on spinal microglia, CSF-1, BDNF, CCL21, TNF-α Wnt ligands, and interleukin 1β. Front Pain Res  2021; 2: 698157.

[26]
Berger AA, Liu Y, Possoit H, et al. Dorsal Root Ganglion (DRG) and Chronic Pain. Anesth Pain Med  2021; 11(2): e113020.
 [http://dx.doi.org/10.5812/aapm.113020] [PMID: 34336621]

[27]
El Sheikh WM, Alahmar IE, Salem GM, El-Sheikh MA. Tumor necrosis factor alpha in peripheral neuropathy in type 2 diabetes mellitus. Egypt J Neurol Psychiat Neurosurg  2019; 55(1): 37.
 [http://dx.doi.org/10.1186/s41983-019-0080-0]

[28]
Hung AL, Lim M, Doshi TL. Targeting cytokines for treatment of neuropathic pain. Scand J Pain  2017; 17(1): 287-93.
 [http://dx.doi.org/10.1016/j.sjpain.2017.08.002] [PMID: 29229214]

[29]
Tsuda M, Masuda T, Kitano J, Shimoyama H, Tozaki-Saitoh H, Inoue K. IFN-γ receptor signaling mediates spinal microglia activation driving neuropathic pain. Proc Natl Acad Sci USA  2009; 106(19): 8032-7.
 [http://dx.doi.org/10.1073/pnas.0810420106] [PMID: 19380717]

[30]
Sanz HY, Gauffin CP, Santacruz YA, Moya PÁ, Laparra LM. Bacteroides cect 7771 and the use thereof in the prevention and treatment of excess weight, obesity and metabolic and immunological alterations. Patent EP2889371A1, 2015.

[31]
Goodman B, Ponichi T, Itano A, Comac T, Kravitz V, Gabrish E, et al. Compositions and methods for treating diseases using the blautia strain. Patent JP2021502964A, 2021.

[32]
Goodman B, Ponichi T, Itano A, Bodmer M, Comac T, Baez-Jang G, et al. Compositions and methods for treating immune disorders using the immunomodulatory lactococcus bacterial strain. Patent JP2021502970A, 2021.

[33]
Sanz HY, Arlette SY, Gauffin P. Bifidobacterium CECT 7765 and use thereof in the prevention and/or treatment of excess weight, obesity and related pathologies. Patent AU2011340460A1, 2013.

[34]
Hillman M, Ahrné S, Önning G. Lactobacillus compositions and uses thereof. Patent WO2020245350A1, 2020.

[35]
Huang H-Y, Chen Y-H, Hsieh FC. Composition and use of Lactobacillus reuteri GMNL-89 in treating type 2 diabetes. Patent GB2524474A, 2015.

[36]
Kubow S, Sheppard J. Use of soy kefir powder for reducing pain, blood pressure and inflammation. Patent US2009221469A1, 2009.

[37]
Yuil S, Rayhart N, Reed S, et al. Composition containing bacterial strain. Patent JP2021522160A, 2021.

[38]
Savignac HM, Murder IE. Composition containing bacterial strain. Patent JP2020520928A, 2020.

[39]
Murder IE, Etol A, Ahmed S, Fotiado P, Ursia JRI, Savignac H. Composition containing bacterial strain. Patent JP2020523316A, 2020.

[40]
Murder IE, Etol A, Ahmed S, Fotiado P, Yuil S, Savignac H. Composition containing bacterial strain. Patent JP2020523341A, 2020.

[41]
Dean F, Adam BF, Vincent MI, Jonathan WK, David R, Paul FM, et al. Bacteria for the treatment of disorders. Patent JP2020525012A, 2020.

[42]
Savignac H, Murder IE, Stevenson AJ. Composition containing bacterial strain. Patent JP2020520911A, 2020.

[43]
Choi Y, Kim J, Lee J-C, Ko GP, Nam T-W, Kim J-H, et al. Lactobacillus plantarum Kbl396 strain and use thereof. Patent EP3747988A1, 2020.

[44]
Altaf S, Bodmer M, Lu J, Maslin D, Mchale D, Zhang C. Compositions and methods of treating inflammation using prevotella histicola. Patent WO2022187064A1, 2022.

[45]
Srinivasan D, Yen JH, Joseph DJ, Friedman W. Cell type-specific interleukin-1beta signaling in the CNS. J Neurosci  2004; 24(29): 6482-8. Available from:
 [http://dx.doi.org/10.1523/JNEUROSCI.5712-03.2004] [PMID: 15269258]

[46]
Recasens M, Almolda B, Pérez-Clausell J, Campbell IL, González B, Castellano B. Chronic exposure to IL-6 induces a desensitized phenotype of the microglia. J Neuroinflammation  2021; 18(1): 31. Available from:
 [http://dx.doi.org/10.1186/s12974-020-02063-1] [PMID: 33482848]

[47]
Neumann M, Naumann M. Beyond IκBs: Alternative regulation of NF‐KB activity. FASEB J  2007; 21(11): 2642-54. Available from:
 [http://dx.doi.org/10.1096/fj.06-7615rev] [PMID: 17431096]

[48]
Liu YW, Su YW, Ong WK, Cheng TH, Tsai YC. Oral administration of Lactobacillus plantarum K68 ameliorates DSS-induced ulcerative colitis in BALB/c mice via the anti-inflammatory and immunomodulatory activities. Int Immunopharmacol  2011; 11(12): 2159-66. Available from:
 [http://dx.doi.org/10.1016/j.intimp.2011.09.013] [PMID: 21996541]

[49]
Miller WR, Murray BE, Rice LB, Arias CA. Resistance in vancomycin-resistant enterococci. Infect Dis Clin North Am  2020; 34(4): 751-71. Available from:
 [http://dx.doi.org/10.1016/j.idc.2020.08.004] [PMID: 33131572]

[50]
Clark AK, Old EA, Malcangio M. Neuropathic pain and cytokines: Current perspectives. J Pain Res  2013; 6(Nov): 803-14.
 [PMID: 24294006]

[51]
Shao Q, Li Y, Wang Q, Zhao J. IL-10 and IL-1β mediate neuropathic-pain like behavior in the ventrolateral orbital cortex. Neurochem Res  2015; 40(4): 733-9.
 [http://dx.doi.org/10.1007/s11064-015-1521-5] [PMID: 25617163]

[52]
Yanik BM, Dauch JR, Cheng HT. Interleukin-10 reduces neurogenic inflammation and pain behavior in a mouse model of type 2 diabetes. J Pain Res  2020; 13: 3499-512.
 [http://dx.doi.org/10.2147/JPR.S264136] [PMID: 33402846]

[53]
Lantero A, Tramullas M, Pílar-Cuellar F, et al. TGF-β and opioid receptor signaling crosstalk results in improvement of endogenous and exogenous opioid analgesia under pathological pain conditions. J Neurosci  2014; 34(15): 5385-95.
 [http://dx.doi.org/10.1523/JNEUROSCI.4405-13.2014] [PMID: 24719115]

[54]
Falb D, Kotula JW, Isabella VM, Miller PF, Fisher AB, Millet Y, et al. Bacteria engineered to detoxify deleterious molecules. Patent WO2017123610A2, 2017.

[55]
Falb D, Miller PF, Kotula JW, Isabella VM, Fisher AB, Millet Y, et al. Bacteria engineered to treat diseases associated with tryptophan metabolism. Patent WO2017136795A1, 2017.

[56]
Brown S, Zarrinpar A, Snyder J. Engineered commensal bacteria and methods of use. Patent CN110709093A, 2020.

[57]
Liu YW, Liong MT, Tsai YC. New perspectives of Lactobacillus plantarum as a probiotic: The gut-heart-brain axis. J Microbiol  2018; 56(9): 601-13.
 [http://dx.doi.org/10.1007/s12275-018-8079-2] [PMID: 30141154]

[58]
Moya-Pérez A, Neef A, Sanz Y. Bifidobacterium pseudocatenulatum CECT 7765 Reduces Obesity-Associated Inflammation by Restoring the Lymphocyte-Macrophage Balance and Gut Microbiota Structure in High-Fat Diet-Fed Mice. PLoS One  2015; 10(7): e0126976. Available from:
 [http://dx.doi.org/10.1371/journal.pone.0126976] [PMID: 26161548]

[59]
Bethea JR, Fischer R. Role of peripheral immune cells for development and recovery of chronic pain. Front Immunol  2021; 12: 641588.
 [http://dx.doi.org/10.3389/fimmu.2021.641588] [PMID: 33692810]

[60]
Pang L, Lian X, Liu H, et al. Understanding diabetic neuropathy: Focus on oxidative stress. Oxid Med Cell Longev  2020; 2020: 9524635. Available from:
 [http://dx.doi.org/10.1155/2020/9524635] [PMID: 32832011]

[61]
Walton DM, Minton SD, Cook AD. The potential of transdermal nitric oxide treatment for diabetic peripheral neuropathy and diabetic foot ulcers. Diabetes Metab Syndr  2019; 13(5): 3053-6. Available from:
 [http://dx.doi.org/10.1016/j.dsx.2018.07.003] [PMID: 30030157]

[62]
Stamler JS. Compositions and methods of modulating gasotransmitter signaling. Patent WO2020172288A1, 2020.

[63]
Whitlock DR, Weiss L, Ambrogio LN. Ammonia oxidizing microorganisms for use and delivery to the gastrointestinal system. Patent US2019247446A1, 2019.

[64]
Vermeiren J, Van de Wiele T, Verstraete W, Boeckx P, Boon N. Nitric oxide production by the human intestinal microbiota by dissimilatory nitrate reduction to ammonium. J Biomed Biotechnol  2009; 2009: 284718. Available from:
 [http://dx.doi.org/10.1155/2009/284718] [PMID: 19888436]

[65]
Lundberg JO, Weitzberg E, Gladwin MT. The nitrate–nitrite–nitric oxide pathway in physiology and therapeutics. Nat Rev Drug Discov  2008; 7(2): 156-67. Available from:
 [http://dx.doi.org/10.1038/nrd2466] [PMID: 18167491]

[66]
Cinelli MA, Do HT, Miley GP, Silverman RB. Inducible nitric oxide synthase: Regulation, structure, and inhibition. Med Res Rev  2020; 40(1): 158-89.
 [http://dx.doi.org/10.1002/med.21599] [PMID: 31192483]

[67]
Barbosa JHP, Oliveira SL, Seara LT. The role of advanced glycation end products (AGEs) in triggering the vascular complications of diabetes. Arq Bras Endocrinol Metabol  2008; 52(6): 940-50. Available from:
 [http://dx.doi.org/10.1590/S0004-27302008000600005] [PMID: 18820805]

[68]
Nowotny K, Jung T, Höhn A, Weber D, Grune T. Advanced glycation end products and oxidative stress in type 2 diabetes mellitus. Biomolecules  2015; 5(1): 194-222.
 [http://dx.doi.org/10.3390/biom5010194] [PMID: 25786107]

[69]
Förstermann U. Nitric oxide and oxidative stress in vascular disease. Pflugers Arch  2010; 459(6): 923-39.
 [http://dx.doi.org/10.1007/s00424-010-0808-2] [PMID: 20306272]

[70]
Dewanjee S, Das S, Das AK, et al. Molecular mechanism of diabetic neuropathy and its pharmacotherapeutic targets. Eur J Pharmacol  2018; 833: 472-523. Available from:
 [http://dx.doi.org/10.1016/j.ejphar.2018.06.034] [PMID: 29966615]

[71]
Shi X, Chen Y, Nadeem L, Xu G. Beneficial effect of TNF-α inhibition on diabetic peripheral neuropathy. J Neuroinflammation  2013; 10(1): 836. Available from:
 [http://dx.doi.org/10.1186/1742-2094-10-69] [PMID: 23735240]

[72]
Park HY, Kim YS, Oh MJ, Lee SH, Ha SK, Choi SY, et al. Composition for inhibiting non-fluorescent advanced glycation end products and use of the same. Patent KR20200052016A, 2020.

[73]
Park HY, Kim YS, Lee SH, Ha SK. Novel Bacillus subtilis strain having advanced glycation end product inhibitory activity effects and use of the same. Patent KR101841023B1, 2018.

[74]
Park HY, Kim YS, Lee SH, Ha SK. Novel Lactobacillus paracasei strain having advanced glycation end products inhibitory activity effects and use of the same. Patent KR101869740B1, 2018.

[75]
Park HY, Kim YS, Lee SH, Ha SK. Novel Lactobacillus pentosus strain having advanced glycation end products inhibitory activity effects and use of the same. Patent KR101869739B1, 2018.

[76]
Park HY, Kim YS, Lee SH, Ha SK. Novel Lactococcus lactis strain having advanced glycation end products inhibitory activity effects and use of the same. Patent KR101841021B1, 2018.

[77]
Park HY, Kim YS, Lee SH, Ha SK. Novel strain having activity of reducing advanced glycation end products and use thereof. Patent WO2018186710A1, 2018.

[78]
Majeed M, Majeed S, Nagabhushanam K, Lawrence L, Arumugam S, Mundkur L. Skin protective activity of lactosporin-the extracellular metabolite from Bacillus coagulans MTCC 5856. Cosmetics  2020; 7(4): 76.
 [http://dx.doi.org/10.3390/cosmetics7040076]

[79]
Martin-Gallausiaux C, Marinelli L, Blottière HM, Larraufie P, Lapaque N. SCFA: Mechanisms and functional importance in the gut. Proc Nutr Soc  2021; 80(1): 37-49.
 [http://dx.doi.org/10.1017/S0029665120006916] [PMID: 32238208]

[80]
Zhang L, Chu J, Hao W, et al. Gut microbiota and type 2 diabetes mellitus: Association, mechanism, and translational applications. Mediators Inflamm  2021; 2021: 1-12.
 [http://dx.doi.org/10.1155/2021/5110276] [PMID: 34447287]

[81]
Takahashi D, Hoshina N, Kabumoto Y, et al. Microbiota-derived butyrate limits the autoimmune response by promoting the differentiation of follicular regulatory T cells. EBioMedicine  2020; 58: 102913.
 [http://dx.doi.org/10.1016/j.ebiom.2020.102913] [PMID: 32711255]

[82]
Kukkar A, Singh N, Jaggi AS. Attenuation of neuropathic pain by sodium butyrate in an experimental model of chronic constriction injury in rats. J Formos Med Assoc  2014; 113(12): 921-8. Available from:
 [http://dx.doi.org/10.1016/j.jfma.2013.05.013] [PMID: 23870713]

[83]
Tochiki KK, Cunningham J, Hunt SP, Géranton SM. The expression of spinal methyl-cpg-binding protein 2, DNA methyltransferases and histone deacetylases is modulated in persistent pain states. Mol Pain  2012; 8: 14.

[84]
Segal E, Elinav E. Bacterial populations for promoting health. Patent CN107847531A, 2018.

[85]
De PC, Pflugfelder S, Britton R. Commensal bacteria as novel treatment for dry eye and sjogren syndrome. Patent WO2018194889A1, 2018.

[86]
Cutcliffe C, Eid JS, Bullard JH, Schicklberger MF. Methods and compositions relating to microbial treatment and diagnosis of disorders. Patent US10675312B2, 2020.

[87]
Biffi A, Rossi R, Fiore W, Guglielmetti SD. Use of a composition comprising microorganisms to increase the intestinal production of butyric acid, folic acid or niacin and/or decrease the intestinal production of succinic acid. Patent EP3041489A1, 2016.

[88]
Cutcliff C, Eid JSA, Colterman OGB. Methods and compositions for the treatment of microbiome-related disorders. Patent JP2020532515A, 2020.

[89]
Santiago M, Roerovs K. Compositions and methods for maintaining and restoring a healthy intestinal barrier. JP2020530424A, 2020.

[90]
Rivière A, Selak M, Lantin D, Leroy F, De Vuyst L. Bifidobacteria and butyrate-producing colon bacteria: Importance and strategies for their stimulation in the human gut. Front Microbiol  2016; 7: 979. Available from:
 [http://dx.doi.org/10.3389/fmicb.2016.00979] [PMID: 27446020]

[91]
Shionoya H, Yajima M, Kitamura K, Suzuki T, Terato K. Digestive tract blocking lps production-enhancing composition consisting of antibody, and analgesic composition. Patent JP2018062483A, 2018.

[92]
Wang X, Sun J, Wang Y, Liu C, Wang Q, Cheng A, et al. Probiotic low glycemic index homogenate diet. Patent CN109527543A, 2019.

[93]
Yang NJ, Chiu IM. Bacterial signaling to the nervous system through toxins and metabolites. J Mol Biol  2017; 429(5): 587-605. Available from:
 [http://dx.doi.org/10.1016/j.jmb.2016.12.023] [PMID: 28065740]

[94]
Ghosh SS, Wang J, Yannie PJ, Ghosh S. Intestinal barrier dysfunction, LPS translocation, and disease development. J Endocr Soc  2020; 4(2): bvz039.
 [http://dx.doi.org/10.1210/jendso/bvz039] [PMID: 32099951]

[95]
Zamyatina A, Heine H. Lipopolysaccharide recognition in the crossroads of TLR4 and caspase-4/11 mediated inflammatory pathways. Front Immunol  2020; 11: 585146. Available from:
 [http://dx.doi.org/10.3389/fimmu.2020.585146] [PMID: 33329561]

[96]
Xue T, Zhang X, Xing Y, et al. Advances about immunoinflammatory pathogenesis and treatment in diabetic peripheral neuropathy. Front Pharmacol  2021; 12: 748193. Available from:
 [http://dx.doi.org/10.3389/fphar.2021.748193] [PMID: 34671261]

[97]
Sharma M, Li Y, Stoll ML, Tollefsbol TO. The epigenetic connection between the gut microbiome in obesity and diabetes. Front Genet  2020; 10: 1329. Available from:
 [http://dx.doi.org/10.3389/fgene.2019.01329] [PMID: 32010189]

[98]
Lundh M, Galbo T, Poulsen SS, Mandrup-Poulsen T. Histone deacetylase 3 inhibition improves glycaemia and insulin secretion in obese diabetic rats. Diabetes Obes Metab  2015; 17(7): 703-7. Available from:
 [http://dx.doi.org/10.1111/dom.12470] [PMID: 25846481]

[99]
Vitetta L, Palacios T. Diagnostic and therapeutic methods for type 2 diabetes. Patent AU2018361704A1, 2020.

[100]
Kawanami D, Matoba K, Sango K, Utsunomiya K. Incretin-based therapies for diabetic complications: Basic mechanisms and clinical evidence. Int J Mol Sci  2016; 17(8): 1223. Available from:
 [http://dx.doi.org/10.3390/ijms17081223] [PMID: 27483245]

[101]
Zhang D, Lv G. Therapeutic potential of spinal GLP-1 receptor signaling. Peptides  2018; 101: 89-94. Available from:
 [http://dx.doi.org/10.1016/j.peptides.2018.01.003] [PMID: 29329976]

[102]
Srivastava S, Singh PR. Oral administration of Lactobacillus casei and Bifidobacterium bifidum improves glucagon like peptide-1(GLP-1) and glucose-dependent insulinotropic polypeptide (gip) level in streptozotocin induced diabetic rats. Curr Res Nutr Food Sci  2021; 9(2): 431-40.
 [http://dx.doi.org/10.12944/CRNFSJ.9.2.07]

[103]
Yan F, Li N, Yue Y, et al. Screening for potential novel probiotics with dipeptidyl peptidase IV-inhibiting activity for type 2 diabetes attenuation in vitro and in vivo. Front Microbiol  2020; 10: 2855.
 [http://dx.doi.org/10.3389/fmicb.2019.02855] [PMID: 31998245]

[104]
Yu Q, Xu Y, Zhang Y, Liu X, Ning X. Application of probiotics combined with dendrobium officinale, Phyllanthus emblica and extracts in improvement of diabetes and metabolic syndrome. Patent CN110604790A, 2019.

[105]
Xu Y, Zhang Y, Yu Q, Liu X, Ning X. Application of dendrobium officinale and extract thereof to improvement of diabetes and metabolic syndrome in combination with probiotics. Patent CN110604789A, 2019.

[106]
Zhang Y, Yu Q, Xu Y, Liu X, Ning X. Application of probiotics combined with Phyllanthus emblica extract to improvement of diabetes and metabolic syndrome. Patent CN110604748A, 2019.

[107]
Ji Q, Wang X, Ming J, Xu X, Xia Y. Effect of combination of Bifidobacterium and berberine on pre-diabetes and type 2 diabetes. Patent WO2020015622A1, 2020.

[108]
Burcelin R, Terce F, Grasset E, Christensen J, Collet X. Methods of enhancing the potency of incretin-based drugs in subjects in need thereof. Patent US2019388486A1, 2019.

[109]
Vitetta L, Palacios T. Modulation of intestinal microbiota in pre-diabetes and type 2 diabetes. Patent AU2018359009A1, 2020.

[110]
Alagiakrishnan K, Halverson T. Holistic perspective of the role of gut microbes in diabetes mellitus and its management. World J Diabetes  2021; 12(9): 1463-78.
 [http://dx.doi.org/10.4239/wjd.v12.i9.1463] [PMID: 34630900]

[111]
Han AW, Raja BB, Kawana S, Yamamoto ML, Dabbagh K, Desantis TZ. Gemella sanguinis as a biotherapeutics. Patent CN111132684A, 2020.

[112]
Sun Z, Sun Y, Hai K. Selenium and probiotics combination and application thereof. Patent CN105030844A, 2015.

[113]
Shan B, Wang J, Ren B, Liu H, Jian Y, Liu Z, et al. Hypoglycemic probiotic preparation and its preparation method. Patent CN105039217A, 2015.

[114]
Jewett BE, Sharma S. Physiology, GABA StatPearls. Treasure Island, FL: StatPearls Publishing 2022.

[115]
Kraychete DC, Gozzani JL, Kraychete AC. Dor neuropática: Aspectos neuroquímicos. Rev Bras Anestesiol  2008; 58(5): 492-505. Available from:
 [http://dx.doi.org/10.1590/S0034-70942008000500008] [PMID: 19382409]

[116]
Sommer C. Serotonin in pain and analgesia: Actions in the periphery. Mol Neurobiol  2004; 30(2): 117-26. Available from:
 [http://dx.doi.org/10.1385/MN:30:2:117] [PMID: 15475622]

[117]
Cortes-Altamirano JL, Olmos-Hernandez A, Jaime HB, et al. Review: 5-HT1, 5-HT2, 5-HT3 and 5-HT7 receptors and their role in the modulation of pain response in the central nervous system. Curr Neuropharmacol  2018; 16(2): 210-21.
 [PMID: 28901281]

[118]
Van Steenwinckel J, Noghero A, Thibault K, Brisorgueil MJ, Fischer J, Conrath M. The 5-HT2A receptor is mainly expressed in nociceptive sensory neurons in rat lumbar dorsal root ganglia. Neuroscience  2009; 161(3): 838-46.
 [http://dx.doi.org/10.1016/j.neuroscience.2009.03.087] [PMID: 19362128]

[119]
Strandwitz P, Lewis K. Modulation of the gut microbiome to treat mental disorders or diseases of the central nervous system. Patent CN109715177A, 2019.

[120]
Skolnick S, Strandwitz P. Methods and compositions for treating and preventing cns disorders and other conditions caused by gut microbial dysbiosis. Patent WO2020160183A1, 2020.

[121]
Marco P, Angela A, Mirta F, Angela M, Giovanna F, Antonio DC. Compositions for use in the treatment and / or amelioration of sleep and mood disorders. Patent JP2021506856A, 2021.

[122]
Park SJ, Kim DH, Kang HJ, et al. Enhanced production of γ-aminobutyric acid (GABA) using Lactobacillus plantarum EJ2014 with simple medium composition. Lebensm Wiss Technol  2021; 137: 110443. Available from:
 [http://dx.doi.org/10.1016/j.lwt.2020.110443]

[123]
Bravo JA, Forsythe P, Chew M. Ingestion of Lactobacillus strain regulates emotional behavior and central GABA receptor expression in a mouse via the vagus nerve. Proc Natl Acad Sci USA  108(38): 16050-5.

[124]
Cani PD, Knauf C. How gut microbes talk to organs: The role of endocrine and nervous routes. Mol Metab  2016; 5(9): 743-52. Available from:
 [http://dx.doi.org/10.1016/j.molmet.2016.05.011] [PMID: 27617197]

[125]
Sharma R, Gupta D, Mehrotra R, Mago P. Psychobiotics: The Next-Generation Probiotics for the Brain. Curr Microbiol  2021; 78(2): 449-63. Available from:
 [http://dx.doi.org/10.1007/s00284-020-02289-5] [PMID: 33394083]

[126]
Tian P, Chen Y, Zhu H, et al. Bifidobacterium breve CCFM1025 attenuates major depression disorder via regulating gut microbiome and tryptophan metabolism: A randomized clinical trial. Brain Behav Immun  2022; 100: 233-41. Available from:
 [http://dx.doi.org/10.1016/j.bbi.2021.11.023] [PMID: 34875345]

[127]
Chang YW, Chen DZ, Huang MH. Do extraordinary science and technology scientists balance their publishing and patenting activities? PLoS One  2021; 16(11): e0259453. Available from:
 [http://dx.doi.org/10.1371/journal.pone.0259453] [PMID: 34735508]

[128]
Krauß J, Kuttenkeuler D. When to file for a patent? The scientist’s perspective. N Biotechnol  2021; 60: 124-9. Available from:
 [http://dx.doi.org/10.1016/j.nbt.2020.10.006] [PMID: 33091617]

[129]
Blind K, Pohlisch J, Zi A. Publishing, patenting, and standardization: Motives and barriers of scientists. Res Policy  2018; 47(7): 1185-97. Available from:
 [http://dx.doi.org/10.1016/j.respol.2018.03.011]

[130]
Moore TJ, Heyward J, Anderson G, Alexander GC. Variation in the estimated costs of pivotal clinical benefit trials supporting the US approval of new therapeutic agents, 2015–2017: A cross-sectional study. BMJ Open  2020; 10(6): e038863. Available from:
 [http://dx.doi.org/10.1136/bmjopen-2020-038863] [PMID: 32532786]

[131]
Brüssow H. Probiotics and prebiotics in clinical tests: An update. F1000 Res  2019; 8: 1157. Available from:
 [http://dx.doi.org/10.12688/f1000research.19043.1] [PMID: 31354938]
Cite As
Current Diabetes Reviews

Technological Trends Involving Probiotics in the Treatment of Diabetic Neuropathy: A Patent Review (2009-2022)

Abstract
