- Email: [email protected]
Harnessing the microbiome in glaucoma and uveitis
Medical Hypotheses xxx (2015) xxx–xxx
Contents lists available at ScienceDirect
Medical Hypotheses journal homepage: www.elsevier.com/locate/mehy
Correspondence Harnessing the microbiome in glaucoma and uveitis
In the last few years there has been a flurry of research into the human microbiome and links have been made to several human diseases [1]. The largest population of microbes is found in the GI tract (approximately 1014 micro-organisms from at least 1000 distinct microbial species), however populations also exist in other areas within the human body such as the nasal passage, oral cavity, otic cavity, skin surface and the urogenital tract [2]. Unfortunately in Ophthalmology there has been limited work in this exciting field. I feel there is great potential to harness the human microbiome in the treatment of glaucoma and uveitis and I hope to present here some tentative links between them that could prove to be fruitful avenues for research in the future. Glaucoma is the leading cause of irreversible blindness worldwide [3]. Its pathophysiological feature is the gradual degeneration of retinal ganglion cells (RGC) [4]. It is due to this neuronal degeneration that glaucoma has been linked to a number of other neurodegenerative diseases such as Alzheimer’s Disease [4]. Cell death mechanisms in such diseases have shown great similarity to glaucoma [5]. One possible mechanism by which the microbiome could aid the management of glaucoma is by modulating brainderived neurotrophic factor (BDNF) levels. It has been shown that BDNF levels in the hippocampus of mice are affected by its microbiota profile and reductions in BDNF levels can be rescued by probiotic treatment [6]. BDNF has been shown to have a potent effect on the survival of RGCs [4], thus if we can modify BDNF levels through the microbiome this could have therapeutic benefit in glaucoma. Modifying BDNF levels through the microbiome could potentially be more efficient and widely clinically applicable than other methods, such as gene therapy, which have shown promise experimentally in increasing BDNF levels [7]. It is however yet to be shown if retinal BDNF levels are affected by microbiome load or type. Encouragingly recent work has shown a link between the oral microbiome and glaucoma pathophysiology [8]. Harnessing the microbiome could have an impact in the management of uveitis. Expression of the human transgene HLA-B27 has shown to be affected by the microbiome and there is a strong link between HLA-B27 and uveitis [9]. Other immune modulatory roles of the microbiome have been elucidated such as an impact on regulatory T cells (Tregs) [10]. An associating between Tregs and uveitis has been made [11]; thus modifying Tregs through the microbiome could have therapeutic benefit. Interestingly there is evidence for a link between the microbiome and spondyloarthritis (SpA) [12] and evidence exists for a link between SpA and uveitis mediated by HLA-B27 [13]. The microbiome has shown central nervous system effects via a number of routes, not discussed here, that may prove beneficial in
http://dx.doi.org/10.1016/j.mehy.2015.07.015 0306-9877/Ó 2015 Elsevier Ltd. All rights reserved.
glaucoma and uveitis: the autonomic nervous system, the enteric nervous system, and the neuroendocrine system [14]. It can be seen that there are promising theoretical links between the microbiome and glaucoma and uveitis. Future work needs to characterise the organisms of the microbiome in further detail and link these findings to the pathophysiology of these disease processes. It is only then we can begin to examine, and understand, the potential exciting benefits of harnessing the microbiome via techniques such as diet modification, increased antimicrobial stewardship, prebiotics, probiotics, faecal transplants and other novel strategies such as altering physical activity and stress levels [15]. Sources of support or financial assistance None. Conflict of interest statement No conflicts of interest declared. References [1] Wagner Mackenzie B, Waite DW, Taylor MW. Evaluating variation in human gut microbiota profiles due to DNA extraction method and inter-subject differences. Front Microbiol 2015;6:130. [2] Hill JM, Bhattacharjee S, Pogue AI, Lukiw WJ. The gastrointestinal tract microbiome and potential link to Alzheimer’s disease. Front Neurol 2014;5:43. [3] Quigley HA, Broman A. The number of persons with glaucoma worldwide in 2010 and 2020. Br J Ophthalmol 2006;90:151–6. [4] Almasieh M, Wilson AM, Morquette B, Cueva Vargas JL, Di Polo A. The molecular basis of retinal ganglion cell death in glaucoma. Prog Retin Eye Res 2012;31(2):152–81. [5] Di Matteo V, Esposito E. Biochemical and therapeutic effects of antioxidants in the treatment of Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis. Curr Drug Targets CNS Neurol Disord 2003;2(2):95–107. [6] Foster JA, McVey Neufeld KA. Gut–brain axis: how the microbiome influences anxiety and depression. Trends Neurosci 2013;36(5):305–12. [7] Martin KR, Quigley HA, Zack DJ, et al. Gene therapy with brain-derived neurotrophic factor as a protection: retinal ganglion cells in a rat glaucoma model. Invest Ophthalmol Vis Sci 2003;44(10):4357–65. [8] Astafurov K, Elhawy E, Ren L, et al. Oral microbiome link to neurodegeneration in glaucoma. PLoS One 2014;9(9). [9] Lin P, Bach M, Asquith M, Lee AY, et al. HLA B27 and human Î22-microglobulin affect the gut microbiota of transgenic rats. PLoS One 2014;9(8). [10] Hoeppli RE, Wu D, Cook L, Levings MK. The environment of regulatory T cell biology: cytokines, metabolites, and the microbiome. Front Immunol 2015;6:61. [11] Zou W, Wu Z, Xiang X, Sun S, Zhang J. The expression and significance of T helper cell subsets and regulatory T cells CD4+CD25+ in peripheral blood of patients with human leukocyte antigen B27-positive acute anterior uveitis. Graefes Arch Clin Exp Ophthalmol 2014;252(4):665–72. [12] Manasson J, Scher JU. Spondyloarthritis and the microbiome: new insights from an ancient hypothesis. Curr Rheumatol Rep 2015;17(2):10. [13] Haroon M, O’Rourke M, Ramasamy P, Murphy CC, FitzGerald O. A novel evidence-based detection of undiagnosed spondyloarthritis in patients presenting with acute anterior uveitis: the DUET (Dublin Uveitis Evaluation Tool). Ann Rheum Dis 2014.
2
Correspondence / Medical Hypotheses xxx (2015) xxx–xxx
[14] Bhattacharjee S, Lukiw WJ. Alzheimer’s disease and the microbiome. Front Cell Neurosci 2013;7:153. [15] Hansen TH, GÃbel RJ, Hansen T, Pedersen O. The gut microbiome in cardiometabolic health. Genome Med 2015;7(1):33.
Ankur Gupta Queen’s Medical Centre, Nottingham, UK E-mail addresses: [email protected], [email protected] Available online xxxx
Contents lists available at ScienceDirect
Medical Hypotheses journal homepage: www.elsevier.com/locate/mehy
Correspondence Harnessing the microbiome in glaucoma and uveitis
In the last few years there has been a flurry of research into the human microbiome and links have been made to several human diseases [1]. The largest population of microbes is found in the GI tract (approximately 1014 micro-organisms from at least 1000 distinct microbial species), however populations also exist in other areas within the human body such as the nasal passage, oral cavity, otic cavity, skin surface and the urogenital tract [2]. Unfortunately in Ophthalmology there has been limited work in this exciting field. I feel there is great potential to harness the human microbiome in the treatment of glaucoma and uveitis and I hope to present here some tentative links between them that could prove to be fruitful avenues for research in the future. Glaucoma is the leading cause of irreversible blindness worldwide [3]. Its pathophysiological feature is the gradual degeneration of retinal ganglion cells (RGC) [4]. It is due to this neuronal degeneration that glaucoma has been linked to a number of other neurodegenerative diseases such as Alzheimer’s Disease [4]. Cell death mechanisms in such diseases have shown great similarity to glaucoma [5]. One possible mechanism by which the microbiome could aid the management of glaucoma is by modulating brainderived neurotrophic factor (BDNF) levels. It has been shown that BDNF levels in the hippocampus of mice are affected by its microbiota profile and reductions in BDNF levels can be rescued by probiotic treatment [6]. BDNF has been shown to have a potent effect on the survival of RGCs [4], thus if we can modify BDNF levels through the microbiome this could have therapeutic benefit in glaucoma. Modifying BDNF levels through the microbiome could potentially be more efficient and widely clinically applicable than other methods, such as gene therapy, which have shown promise experimentally in increasing BDNF levels [7]. It is however yet to be shown if retinal BDNF levels are affected by microbiome load or type. Encouragingly recent work has shown a link between the oral microbiome and glaucoma pathophysiology [8]. Harnessing the microbiome could have an impact in the management of uveitis. Expression of the human transgene HLA-B27 has shown to be affected by the microbiome and there is a strong link between HLA-B27 and uveitis [9]. Other immune modulatory roles of the microbiome have been elucidated such as an impact on regulatory T cells (Tregs) [10]. An associating between Tregs and uveitis has been made [11]; thus modifying Tregs through the microbiome could have therapeutic benefit. Interestingly there is evidence for a link between the microbiome and spondyloarthritis (SpA) [12] and evidence exists for a link between SpA and uveitis mediated by HLA-B27 [13]. The microbiome has shown central nervous system effects via a number of routes, not discussed here, that may prove beneficial in
http://dx.doi.org/10.1016/j.mehy.2015.07.015 0306-9877/Ó 2015 Elsevier Ltd. All rights reserved.
glaucoma and uveitis: the autonomic nervous system, the enteric nervous system, and the neuroendocrine system [14]. It can be seen that there are promising theoretical links between the microbiome and glaucoma and uveitis. Future work needs to characterise the organisms of the microbiome in further detail and link these findings to the pathophysiology of these disease processes. It is only then we can begin to examine, and understand, the potential exciting benefits of harnessing the microbiome via techniques such as diet modification, increased antimicrobial stewardship, prebiotics, probiotics, faecal transplants and other novel strategies such as altering physical activity and stress levels [15]. Sources of support or financial assistance None. Conflict of interest statement No conflicts of interest declared. References [1] Wagner Mackenzie B, Waite DW, Taylor MW. Evaluating variation in human gut microbiota profiles due to DNA extraction method and inter-subject differences. Front Microbiol 2015;6:130. [2] Hill JM, Bhattacharjee S, Pogue AI, Lukiw WJ. The gastrointestinal tract microbiome and potential link to Alzheimer’s disease. Front Neurol 2014;5:43. [3] Quigley HA, Broman A. The number of persons with glaucoma worldwide in 2010 and 2020. Br J Ophthalmol 2006;90:151–6. [4] Almasieh M, Wilson AM, Morquette B, Cueva Vargas JL, Di Polo A. The molecular basis of retinal ganglion cell death in glaucoma. Prog Retin Eye Res 2012;31(2):152–81. [5] Di Matteo V, Esposito E. Biochemical and therapeutic effects of antioxidants in the treatment of Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis. Curr Drug Targets CNS Neurol Disord 2003;2(2):95–107. [6] Foster JA, McVey Neufeld KA. Gut–brain axis: how the microbiome influences anxiety and depression. Trends Neurosci 2013;36(5):305–12. [7] Martin KR, Quigley HA, Zack DJ, et al. Gene therapy with brain-derived neurotrophic factor as a protection: retinal ganglion cells in a rat glaucoma model. Invest Ophthalmol Vis Sci 2003;44(10):4357–65. [8] Astafurov K, Elhawy E, Ren L, et al. Oral microbiome link to neurodegeneration in glaucoma. PLoS One 2014;9(9). [9] Lin P, Bach M, Asquith M, Lee AY, et al. HLA B27 and human Î22-microglobulin affect the gut microbiota of transgenic rats. PLoS One 2014;9(8). [10] Hoeppli RE, Wu D, Cook L, Levings MK. The environment of regulatory T cell biology: cytokines, metabolites, and the microbiome. Front Immunol 2015;6:61. [11] Zou W, Wu Z, Xiang X, Sun S, Zhang J. The expression and significance of T helper cell subsets and regulatory T cells CD4+CD25+ in peripheral blood of patients with human leukocyte antigen B27-positive acute anterior uveitis. Graefes Arch Clin Exp Ophthalmol 2014;252(4):665–72. [12] Manasson J, Scher JU. Spondyloarthritis and the microbiome: new insights from an ancient hypothesis. Curr Rheumatol Rep 2015;17(2):10. [13] Haroon M, O’Rourke M, Ramasamy P, Murphy CC, FitzGerald O. A novel evidence-based detection of undiagnosed spondyloarthritis in patients presenting with acute anterior uveitis: the DUET (Dublin Uveitis Evaluation Tool). Ann Rheum Dis 2014.
2
Correspondence / Medical Hypotheses xxx (2015) xxx–xxx
[14] Bhattacharjee S, Lukiw WJ. Alzheimer’s disease and the microbiome. Front Cell Neurosci 2013;7:153. [15] Hansen TH, GÃbel RJ, Hansen T, Pedersen O. The gut microbiome in cardiometabolic health. Genome Med 2015;7(1):33.
Ankur Gupta Queen’s Medical Centre, Nottingham, UK E-mail addresses: [email protected], [email protected] Available online xxxx