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The composition of human gut flora changes over time, when the diet changes, and as overall health changes.<ref name=Quigley2013rev/><ref name=Shen2016rev/>
The composition of human gut flora changes over time, when the diet changes, and as overall health changes.<ref name=Quigley2013rev/><ref name=Shen2016rev/>

==Enteric nervous system==
The [[enteric nervous system]] is one of the main divisions of the [[nervous system]] and consists of a mesh-like system of [[neuron]]s that governs the function of the [[gastrointestinal system]]; it has been described as a "second brain" for several reasons. The enteric nervous system can operate autonomously. It normally communicates with the [[central nervous system]] (CNS) through the [[parasympathetic nervous system|parasympathetic]] (e.g., via the [[vagus nerve]]) and [[sympathetic nervous system|sympathetic]] (e.g., via the [[prevertebral ganglia]]) nervous systems. However, [[vertebrate]] studies show that when the [[vagus nerve]] is severed, the enteric nervous system continues to function.<ref name="amjphysgastro">{{cite journal | url=http://ajpgi.physiology.org/content/285/3/G461.full | title=Musings on the Wanderer: What's New in Our Understanding of Vago-Vagal Reflexes? V. Remodeling of vagus and enteric neural circuitry after vagal injury |author1=Li,Ying |author2=Owyang,Chung | journal=American Journal of Physiology. Gastrointestinal and Liver Physiology |date=September 2003 | volume=285 | issue=3 | pages=G461-9 | doi=10.1152/ajpgi.00119.2003}}</ref>
In vertebrates, the enteric nervous system includes [[efferent neurons]], [[afferent neuron]]s, and [[interneurons]], all of which make the enteric nervous system capable of carrying reflexes and acting as an [[integrating center]] in the absence of CNS input. The sensory neurons report on mechanical and chemical conditions. Through intestinal muscles, the motor neurons control [[peristalsis]] and churning of intestinal contents. Other neurons control the secretion of [[enzymes]]. The enteric nervous system also makes use of more than 30 [[neurotransmitters]], most of which are identical to the ones found in CNS, such as [[acetylcholine]], [[dopamine]], and [[serotonin]]. More than 90% of the body's serotonin lies in the gut, as well as about 50% of the body's dopamine and the dual function of these neurotransmitters is an active part of gut-brain research.<ref>{{cite web|last=Pasricha|first=Pankaj Jay|title=Stanford Hospital: Brain in the Gut - Your Health|url=http://www.youtube.com/watch?v=UXx4WTVU34Y}}</ref><ref>Martinucci I et al. Genetics and pharmacogenetics of aminergic transmitter pathways in functional gastrointestinal disorders. Pharmacogenomics. 2015;16(5):523-39. Review. PMID 25916523</ref><ref>Smitka K, et al. The role of "mixed" orexigenic and anorexigenic signals and autoantibodies reacting with appetite-regulating neuropeptides and peptides of the adipose tissue-gut-brain axis: relevance to food intake and nutritional status in patients with anorexia nervosa and bulimia nervosa. Int J Endocrinol. 2013;2013:483145. Review. PMID 24106499 [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3782835/ Free full text PMC 3782835]</ref>


==Brain function==
==Brain function==

Revision as of 05:35, 20 June 2016

Not to be confused with Neuraxis.
The gut-brain axis is the relationship between the GI tract and the gut flora that reside there, and brain function and development

The gut–brain axis refers to the biochemical signaling taking place between the gastrointestinal tract and the nervous system, often involving intestinal microbiota, which have been shown to play an important role in healthy brain function.[1][2]

The gut microbiota communicates with the central nervous system through different pathways (neural, immune and endocrine) and influences the brain, more specifically its function and its behavior. Several studies have shown that the gut microbiota is involved in the regulation of anxiety, pain, cognition and mood. These studies used germ-free animals compared to normal animals, which were later exposed to pathogenic bacterial infections, probiotic bacteria and antibiotic drugs. The gut-brain axis is an emerging concept that could be helpful for developing new therapeutic strategies for complex central nervous system disorders by modifying the gut microbiota.[2]

The gut-brain axis includes the central nervous system, neuroendocrine and neuroimmune systems, sympathetic and parasympathetic arms of the autonomic nervous system, enteric nervous system, and the gut microbiota. All of these interact to create a network that establishes the signal from the brain to the gut and the gut to the brain. A lot more work has to be done to understand which aspects influence what, but the vagus nerve has been established as having a key role in communication between the gut and the brain.[3][4]

Bifidobacterium adolescentis Gram
Lactobacillus sp 01

Gut flora

Main article: Gut flora

The gut flora is the complex community of microorganisms that live in the digestive tracts of humans and other animals, as well as insects. The gut metagenome is the aggregate of all the genomes of gut microbiota.[5] The gut is one niche that human microbiota inhabit.[6]

In humans, the gut microbiota has the largest numbers of bacteria and the greatest number of species compared to other areas of the body.[7] In humans the gut flora is established at one to two years after birth, and by that time the intestinal epithelium and the intestinal mucosal barrier that it secretes have co-developed in a way that is tolerant to, and even supportive of, the gut flora and that also provides a barrier to pathogenic organisms.[8][9]

The relationship between gut flora and humans is not merely commensal (a non-harmful coexistence), but rather a mutualistic relationship.[6]: 700  Human gut microorganisms benefit the host by collecting the energy from the fermentation of undigested carbohydrates and the subsequent absorption of short-chain fatty acids (SCFAs), acetate, butyrate, and propionate.[7][10] Intestinal bacteria also play a role in synthesizing vitamin B and vitamin K as well as metabolizing bile acids, sterols, and xenobiotics.[6][10] The systemic importance of the SCFAs and other compounds they produce are like hormones and the gut flora itself appears to function like an endocrine organ,[10] and dysregulation of the gut flora has been correlated with a host of inflammatory and autoimmune conditions.[7][11]

The composition of human gut flora changes over time, when the diet changes, and as overall health changes.[7][11]

Enteric nervous system

The enteric nervous system is one of the main divisions of the nervous system and consists of a mesh-like system of neurons that governs the function of the gastrointestinal system; it has been described as a "second brain" for several reasons. The enteric nervous system can operate autonomously. It normally communicates with the central nervous system (CNS) through the parasympathetic (e.g., via the vagus nerve) and sympathetic (e.g., via the prevertebral ganglia) nervous systems. However, vertebrate studies show that when the vagus nerve is severed, the enteric nervous system continues to function.[12]

In vertebrates, the enteric nervous system includes efferent neurons, afferent neurons, and interneurons, all of which make the enteric nervous system capable of carrying reflexes and acting as an integrating center in the absence of CNS input. The sensory neurons report on mechanical and chemical conditions. Through intestinal muscles, the motor neurons control peristalsis and churning of intestinal contents. Other neurons control the secretion of enzymes. The enteric nervous system also makes use of more than 30 neurotransmitters, most of which are identical to the ones found in CNS, such as acetylcholine, dopamine, and serotonin. More than 90% of the body's serotonin lies in the gut, as well as about 50% of the body's dopamine and the dual function of these neurotransmitters is an active part of gut-brain research.[13][14][15]

Brain function

Researchers found noticeable improvements in the ability of rats to cope with stressful activity (such as swimming) when diets are supplemented by specific gut microbiota.

Research suggests that there is a gut–brain axis, a bidirectional neurohumoral communication system in the human body that functions as a pathway for the gut microbiota to modulate brain function of its host. This signaling is important for maintaining homeostasis and this is regulated through the central and enteric nervous systems and the neural, endocrine, immune, and metabolic pathways.[16]

Multiple studies have established that there is a direct connection between gut microbiota and the regulation of mood, cognition, and visceral pain. For example mice whose diets are supplemented with Bifidobacterium breve show elevated concentrations of fatty acids in the brain, including arachidonic acid and docosahexaenoic acid, which are known to play important roles in neurodevelopmental processes, including neurogenesis.The c-Fos activation in the paraventricular nucleus was rapidly induced by the inoculation of Bifidobacterium infantis. Tryptophan metabolism was modulated by B. infantis, suggesting that the normal gut microbiota can influence the precursor pool for serotonin, which is correlated to neurophysiological behavior. Anxiety-like behavior and central neurochemical changes were relieved in GF mice compared with specific pathogen free (SPF) mice.[17]

Behavioral phenotype

During birth, the microbial colonization contributes to the development of epithelial barrier function, gut homeostasis, angiogenesis, innate adaptive immune function, and common neuro-developmental disorders (autism, schizophrenia). Compared to the SPF mice, the GF mice illustrated increased motor activity, reduced anxiety-like behavior, altered expression of synaptic plasticity-related genes, elevated noradrenaline, dopamine, and 5-hydroxytryptamine turnover in the striatum (The striate nucleus is part of the cerebrum of the brain and is involved in a number of different cognitive processes). When SPF mice are exposed to antibiotics, gastrointestinal infections and stress, sharp changes in diet, the gut homeostasis and the central nervous system becomes imbalanced, therefore antibiotic drugs suggest a role for the gut microbiota in the regulation of anxiety, mood, cognition and pain.

Disorder Microbiome Alterations[16]
Anxiety/Irritable Bowel Syndrome Less Lactobacilli and Bifidobacteria; More Firmicutes:Bacteroidetes Ratio
Depression Less Bacteroidetes, Proteobacteria, and Actinobacteria
Autism Less Bacteroidetes:Firmicutes Ratio
Parkinson's Disease Less Prevotellaceae

Visceral pain

Visceral pain can happen in the gut because of gastrointestinal disorders, such as irritable bowel syndrome (IBS).[2] The perception of visceral pain involves sensory nerves on a peripheral sensitization and cortical and sub-cortical pathways on a central level. In addition, there is substantial overlap in the brain areas underlying visceral pain and those that are involved in the processing of psychological stress. Imaging studies in humans with IBS have shown increased activation of the same brain area.[18] Lactobacilli and Bifidobacteria can reduce visceral pain induced by stress and IBS, in humans and mice, and many different probiotics have been shown to have beneficial effects in humans with abdominal pain.[19][20]

Stress

Some probiotics can apparently help reduce anxiety, stress, and mood of patients with IBS and chronic fatigue, but the mechanisms of action of such effects currently remain unclear and may involve a combination of neural, immune and endocrine effects. Lactobacillus reuteri, probiotic, is known to modulate the immune system, decrease anxiety, and reduce the stress-induced increase of corticosterone. Other probiotics can lower inflammatory cytokines, decrease oxidative stress, and improve nutritional status.[21]

Lab mouse mg 3135

Physical and psychological stressors can cause a lot of issues for both the human host and gut microbiome, such as anxiety-like behavior. A lot of animal studies have shown the influence that stress can have on individuals and their microbiome. The influence of stress can begin early in life and affect individuals through adulthood. For example, studies looking at maternal separation for rats shows neonatal stress leads to long-term changes in the gut microbiota such as its diversity and composition, which also lead to stress and anxiety-like behavior.[1]

There have been some treatments for anxiety-like behavior in mice using the transfer of healthier gut microbiota or ingestion of probiotics. One study found that the transfer of microbiota to germ-free mice from mice with anxiety-like behavior produced timid behavior. The opposite was also found to be true- when anxious mice had non-anxious mice microbiota transferred they started behaving more like their donors.[22] Probiotics shown to decrease anxiety and stress are Lactobacillus helveticus, Bifodobacterium longum, and Lactobacillus rhamnosus.[22]

Irritable bowel syndrome

A physical symptom of stress is irritable bowel syndrome, which is the most common gastrointestinal disorder. Irritable bowel syndrome results in abdominal pain, changes in bowel movements, and an increase in proinflammatory cytokines. Overall, studies have found that the luminal and mucosal microbiota are changed in irritable bowel syndrome individuals, and these changes can relate to the type of irritation such as diarrhea or constipation. Also, there is a decrease in the diversity of the microbiome with low levels of fecal Lactobacilli and Bifidobacteria, high levels of facultative anaerobic bacteria such as Escherichia coli, and increased ratios of Firmicutes:Bacteroidetes.[16]

Obesity

Microbiomes are under selective pressures just like the human host, and there is evidence to show microbes will manipulate host behavior to increase their own fitness against the host and other microbes. The metagenomics conflict between a host and its microbes can be seen in an evolutionary genetic conflict view, which includes other genomes such as the microbes, that influences the physiology and behavior of the host.[22] There is evidence that microbiota influence eating behaviors based on the preferences of the microbiota, which can lead to the host consuming more food eventually resulting in obesity. It has generally been observed that with higher gut microbiome diversity, the microbiota will spend energy and resources on competing with other microbiota and less on manipulating the host. The opposite is seen with lower gut microbiome diversity, and these microbiotas will work together for to create host food cravings.[22]

Depression

Depression is the most common mental disorder and depressive episodes are connected to the dysregulation of the hypothalamic-pituitary-adrenal axis.[16][1] The hypothalamic-pituitary-adrenal axis can be influenced by both psychological and physical stressors.[3] Depressive episodes are normally characterized by factors such as a down mood and not gaining pleasure from life, with biological aspects such as changes in appetite, sleep, and sex drive of the individual. Biologically, individuals with more severe forms of depression tend to secrete a higher amount of cortisol.[16] As shown, a disruption in any of the physiological balances in the body can have negative consequences on the host. Because of this, depressive episodes can be fixed by the normalization of the hypothalamic-pituitary-adrenal axis.[16][1]

Other disorders

Schizophrenia

Schizophrenia is a rare and debilitating disorder that mostly affects young people. It is characterized by disrupted thought processes, such as delusions and hallucinations, and the deterioration in cognitive function that gets worse over time in chronic cases. A study found that certain drugs, such as phencyclidine (PCP), when given to rodents, produces schizophrenia-like behavior and cognitive and motor dysfunction. Once the drug was taken, the rodents gut microbiome significantly changed. Once given the antibiotic ampicillin, the gut microbiome changed again and the schizophrenia PCP symptoms were no longer present. This suggests there might be a connection between gut microbiota and the cognitive effects found in schizophrenic patients[16]

Autism

Autism is a neurodevelopmental disorder with individuals experiencing problems in language acquisition and reduced sociability. About 70% of individuals with autism also experience gastrointestinal issues, indicating there may be a connection between autism and the gut-brain axis. To explore this, a study looked at the behavior of germ-free mice compared to house mice. They found that the germ-free mice were more likely to spend time with an object than with mice they are more familiar with, indicating abnormal animal sociable behavior. The injection of house mice gut microbiota showed a partial normalization in behavior for the germ-free mice.[16] Another study found differences in fecal microbiota between autistic children and those not on the spectrum. The fecal microbiota of autistic children showed lower levels in Bacteroidetes:Firmicutes ratio and an increase in Lactobacillus spp. There was also an increase in Desulfovibrio spp., which also correlated with the severity of autistic behaviors.[16] In addition, organisms from the bacterial genus Clostridium were found at an elevated level in the stools of children with autism compared to the stools of the children without.[21]

Parkinson's disease

Parkinson’s disease (PD) is a chronic disorder where individuals experience a malfunction in nerve cells in the brain creating involuntary movement, which worsens over time. The gut microbiota of Parkinson’s disease patients was compared to those without the disorder. They found that there was a reduction of Prevotellaceae in those with the disease and levels of Enterobacteriaceae was positively correlated with the severity of posture instability and walking difficulty. The authors suggest further study and the injection of the microbiota of healthy individuals into those with the disorder.[16]

Gut–brain–liver axis

The liver plays a dominant role in blood glucose homeostasis by maintaining a balance between the uptake and storage of glucose through the metabolic pathways of glycogenesis and gluconeogenesis. In recent studies, it is illustrated that intestinal lipids regulate glucose homeostasis involving a gut-brain-liver axis. The direct administration of lipids into the upper intestine increases the long chain fatty acyl-coenzyme A (LCFA-CoA) levels in the upper intestines and suppresses glucose production even under sub diaphragmatic vagotomy or gut vagal deafferentation. This interrupts the neural connection between the brain and the gut and blocks the upper intestinal lipids’ ability to inhibit glucose production. The gut-brain-liver axis and gut microbiota composition can regulate the glucose homeostasis in the liver and provide potential therapeutic methods to treat obesity and diabetes.[21]

Psychobiotics

Psychobiotics are defined by Dinan et al.[23] as those living organisms that on sufficient ingestion produces a health benefit in those patients with psychiatric, or neurological, illnesses.[24][25][26][27][28][29] Research to understand the mechanisms of psychobiotics on the gut–brain axis and enteric nervous system is currently under way. Preliminary evidence suggests modulation of neuroimmunologic, neuroinflammatory, and neurohormonal pathways. Other possible mechanisms identified include modulation of the hypothalamic–pituitary–adrenal axis, the vagus nerve, microglia, myelination, and prefrontal cortex gene expression.[30]

Additionally, research has correlated the oral microbiome to cognitive function.[31]

Psychobiotics can also be defined as microbes that have negative neurological interactions. Recently it was shown microbes may play a role in the formation of amyloid-β.[32]

See also

References

  1. ^ a b c d Foster, J.A.; McVey Neufelt, K.A. (2013). "Gut-brain axis: how the microbiome influences anxiety and depression". Trends in Neurosciences. 36: 305–312. PMID 23384445.
  2. ^ a b c Cryan, J. F.; Dinan, T. G. (2012). "Mind-altering microorganisms: The impact of the gut microbiota on brain and behaviour". Nature Reviews Neuroscience. 13 (10): 701–712. doi:10.1038/nrn3346. PMID 22968153.
  3. ^ a b Dinan, T.G.; Cryan, J.F. (2012). "Regulation of stress response by the gut microbiota:Implications for psychoneuroendocrinology". Psychoneuroendocrinology. 37: 1369–1378. PMID 22483040.
  4. ^ Cryan, J.F.; Dinan, T.G. (2015). "More than a Gut Feeling: the Microbiota Regulates Neurodevelopment and Brain Behavior". Neuropsychopharmacology Reviews. 40: 241–242. PMC 4262908. PMID 25482171.
  5. ^ Saxena, R.; Sharma, V.K (2016). "A Metagenomic Insight Into the Human Microbiome: Its Implications in Health and Disease". In D. Kumar; S. Antonarakis (eds.). Medical and Health Genomics. Elsevier Science. p. 117. doi:10.1016/B978-0-12-420196-5.00009-5. ISBN 978-0-12-799922-7.
  6. ^ a b c Sherwood, Linda; Willey, Joanne; Woolverton, Christopher (2013). Prescott's Microbiology (9th ed.). New York: McGraw Hill. pp. 713–721. ISBN 9780073402406. OCLC 886600661.
  7. ^ a b c d Quigley EM Gut bacteria in health and disease. Gastroenterol Hepatol (N Y). 2013 Sep;9(9):560-9. PMID 24729765 Free full text PMC 3983973
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  9. ^ Faderl M et al. Keeping bugs in check: The mucus layer as a critical component in maintaining intestinal homeostasis. IUBMB Life. 2015 Apr;67(4):275-85. PMID 25914114
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  11. ^ a b Shen S, Wong CH. Bugging inflammation: role of the gut microbiota. Clin Transl Immunology. 2016 Apr 15;5(4):e72. Review. PMID: 27195115 Free full text PMC 4855262
  12. ^ Li,Ying; Owyang,Chung (September 2003). "Musings on the Wanderer: What's New in Our Understanding of Vago-Vagal Reflexes? V. Remodeling of vagus and enteric neural circuitry after vagal injury". American Journal of Physiology. Gastrointestinal and Liver Physiology. 285 (3): G461-9. doi:10.1152/ajpgi.00119.2003.
  13. ^ Pasricha, Pankaj Jay. "Stanford Hospital: Brain in the Gut - Your Health".
  14. ^ Martinucci I et al. Genetics and pharmacogenetics of aminergic transmitter pathways in functional gastrointestinal disorders. Pharmacogenomics. 2015;16(5):523-39. Review. PMID 25916523
  15. ^ Smitka K, et al. The role of "mixed" orexigenic and anorexigenic signals and autoantibodies reacting with appetite-regulating neuropeptides and peptides of the adipose tissue-gut-brain axis: relevance to food intake and nutritional status in patients with anorexia nervosa and bulimia nervosa. Int J Endocrinol. 2013;2013:483145. Review. PMID 24106499 Free full text PMC 3782835
  16. ^ a b c d e f g h i j Dinan, T.G; Cryan, 2015 (2015). "The impact of gut microbiota on brain and behavior: implications for psychiatry". Curr Opin Clin Nutr Metab Care. 18: 552–558. PMID 21303428. {{cite journal}}: |first2= has numeric name (help)
  17. ^ Innis, S. M. (2007). "Dietary (n-3) fatty acids and brain development". J. Nutr. 137: 855–859. PMID 17374644.
  18. ^ Mayer, E. A.; et al. (2008). "Functional GI disorders: from animal models to drug development". Gut. 57: 384–404. PMC 4130737. PMID 17965064.
  19. ^ Bercik, P.; Collins, S. M.; Verdu, E. F. (2012). "Microbes and the gut–brain axis". Neurogastroenterol. Motil. 24: 405–413. PMID 22404222.
  20. ^ Clarke, G.; Cryan, J. F.; Dinan, T. G.; Quigley, E. M. (2012). "Review article: probiotics for the treatment of irritable bowel syndrome — focus on lactic acid bacteria". Aliment. Pharmacol. Ther. 35: 403–413. PMID 22225517.
  21. ^ a b c Chen, X; D'Souza, R; Hong, ST (2013). "The role of gut microbiota in the gut-brain axis: current challenges and perspectives". Protein & Cell. 4 (6): 403–14. doi:10.1007/s13238-013-3017-x. PMID 23686721.
  22. ^ a b c d Alcock, J.; Maley, C.C.; Aktipis, C.A. (2014). "Is eating behavior manipulated by gastrointestinal microbiota? Evolutionary pressures and potential mechanisms". Bioessays. 36: 940–949. PMC 4270213. PMID 5103109.
  23. ^ Dinan TG, Stanton C, Cryan JF (2013). "Psychobiotics: a novel class of psychotropic". Biol Psychiatry. 74 (10): 720–6. doi:10.1016/j.biopsych.2013.05.001. PMID 23759244.
  24. ^ Zhou L, Foster JA (2015). "Psychobiotics and the gut-brain axis: in the pursuit of happiness". Neuropsychiatr Dis Treat. 11: 715–23. doi:10.2147/NDT.S61997. PMC 4370913. PMID 25834446.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  25. ^ Gnanavel S (2015). "Psychobiotics: the latest psychotropics". Indian J Psychol Med. 37 (1): 110. doi:10.4103/0253-7176.150862. PMC 4341301. PMID 25722529.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  26. ^ Evrensel A, Ceylan ME (2015). "The Gut-Brain Axis: The Missing Link in Depression". Clin Psychopharmacol Neurosci. 13 (3): 239–244. doi:10.9758/cpn.2015.13.3.239. PMC 4662178. PMID 26598580.
  27. ^ Kelly JR, Kennedy PJ, Cryan JF, Dinan TG, Clarke G, Hyland NP (2015). "Breaking down the barriers: the gut microbiome, intestinal permeability and stress-related psychiatric disorders". Front Cell Neurosci. 9: 392. doi:10.3389/fncel.2015.00392. PMC 4604320. PMID 26528128.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  28. ^ Smythies LE, Smythies JR (2014). "Microbiota, the immune system, black moods and the brain-melancholia updated". Front Hum Neurosci. 8: 720. doi:10.3389/fnhum.2014.00720. PMC 4163975. PMID 25309394.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  29. ^ Selhub EM, Logan AC, Bested AC (2014). "Fermented foods, microbiota, and mental health: ancient practice meets nutritional psychiatry". J Physiol Anthropol. 33: 2. doi:10.1186/1880-6805-33-2. PMC 3904694. PMID 24422720.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  30. ^ Hoban AE; Stilling RM; Ryan FJ; Shanahan F; Dinan TG; Claesson MJ; et al. (2016). "Regulation of prefrontal cortex myelination by the microbiota". Transl Psychiatry. 6: e774. doi:10.1038/tp.2016.42. PMID 27045844.
  31. ^ Noble JM, Scarmeas N, Papapanou PN (2013). "Poor oral health as a chronic, potentially modifiable dementia risk factor: review of the literature". Curr Neurol Neurosci Rep. 13 (10): 384. doi:10.1007/s11910-013-0384-x. PMID 23963608.
  32. ^ Kumar DK, Choi SH, Washicosky KJ, Eimer WA, Tucker S, Ghofrani J; et al. (2016). "Amyloid-β peptide protects against microbial infection in mouse and worm models of Alzheimer's disease". Sci Transl Med. 8 (340): 340ra72. doi:10.1126/scitranslmed.aaf1059. PMID 27225182.{{cite journal}}: CS1 maint: multiple names: authors list (link)

Further reading

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