EFTA01178505.pdf

Atnyotrophic Lateral Sclerosis and Frontotemporal Degeneration, 2013; 14: 482-485 informa healthcare ALS-UNTANGLED ALS Untangled No. 21: Fecal transplants The ALSUntangled Group Fecal microbiota transplantation (FMT) is a tech- New England Journal of Medicine used duodenal nique whereby stool from a healthy donor is deliv- infusion of donor feces for recurrent C. difficile ered into the GI tract of a sick patient. On behalf of diarrhea. The study was stopped at interim analysis 0 PALS who requested it, we herein review the evi- after only 43 patients had been randomized, because VI ri dence for using FMT to treat ALS almost all of the patients in the control groups had ct recurrence, whereas FMT was effective in 81% after 41; li Rationale a single infusion, and two out of the three other =s patients after a subsequent infusion (7). The human intestinal tract contains between 1 X The goal of FMT is restoration of normal 05 1013-1 X 1014 microorganisms, belonging to over healthy gut flora homeostasis. The composition of 7000 different strains, and containing over 3 million the gut microbiome is presumably influenced by tk unique genes (1,2). Thus, gut microbes outnumber our environment, thus spouses or other cohabitat- our own cells by an order of magnitude and could ing family members are preferred as stool donors. 00 possess 150 times more genes than the entire human The donors are screened for stool and blood-born E genome. Modern sequencing and metagenomic §ig techniques have enabled characterization of the pathogens, a stool sample is obtained, homogenized complex human `fecal microbiome'. Humans can be in a blender, filtered, re-suspended, then delivered either by nasogastric tube, enema, or colonoscopy 3e divided into three distinct 'enterotypes', based on the • relative profiles of gut microorganisms. Disruption into the recipient (8). pL of the normal microbial homeostasis has been directly Patients with neurodegenerative and neuroim- rn A implicated in the pathogenesis of ulcerative colitis, munologic disorders often suffer from chronic con- Crohn's disease, celiac disease, diabetes, obesity, and stipation. As the use of FMT to treat recalcitrant E certain allergies (reviewed in (2)). Both animal and constipation has expanded, case reports have accu- human studies have also shown that the gut micro- mulated in which patients with neurologic and g a2 biome is altered in obesity, and germ-free mice are autoimmune disorders have seen marked improve- resistant to diet induced obesity (3,4). Recognizing ments in their non-GI symptoms with FMT (6). E 69 the potential importance of this rapidly expanding These have inspired further investigations into the field, the National Institutes of Health have estab- potential role of a 'brain-gut axis' employing bidi- 8 lished the Human Microbiome Project to study the rectional communication via neuronal, hormonal, complexity of the gut microflora and its roles in immunologic and toxic signaling. Proposed mecha- health and disease (http://commonfund.nih.gov/ nisms include direct communication through the hmp/). vagus nerve, changes in tryptophan and norepi- FMT, also called fecal bacteriotherapy, has been nephrine metabolism, production and absorption of reported in dozens of publications, mostly for treat- neuroactive metabolites, immune activation through ing patients with recurrent Clostridium difficile diar- molecular mimicry, and the direct production of rhea, for which it has had unanimously excellent neurotoxins (6,9-11). results. FMT was first reported as an effective ther- FMT is generally considered most effective in apy for pseudomembranous colitis by Eisenman treating constipation caused by chronic clostridial et al. in 1958 (5), although donor stool transplanta- infections. Interestingly, several pathogenic clostrid- tion as a treatment for diarrhea was documented as ial strains are well known to cause neuromuscular far back as 4th century China (reviewed in (6)). disease, such as C. botulinum and C. tetani — which A recent randomized clinical trial published in the produce neurotoxins that can infect lower motor ISSN 2167-8421 print/ISSN 2167-9223 online 4 2013 Informa Healthcare DOI: 10.3109/21678421.2013.814981 RIGHTS LINK.> EFTA01178505  ALSUntangled Update 21 483 neurons, and in the case of tetanus, utilize retro- Relevant human data grade signaling to the CNS. Given the well charac- There are no published clinical trials or even case terized pathogenicity of these clostridial strains, the reports of FMT use in PALS. Only a single PALS frequency of constipation in many chronic neuro- has reported trying FMT on PatientsLikeMe, with logic disorders, and published case reports in which a one-time dose, 'slight' perceived effectiveness, and FMT and/or antibiotic regimens targeting clostrid- no side-effects. An informal poll of ALSUntangled ial infections appeared to serendipitously attenuate providers and FMT experts resulted in only a single neurologic symptoms, some researchers have pos- anecdotal report of a patient with ALS who was tulated that neurotoxins produced by related spe- treated with repeated FMT for chronic constipation cies may be neuro-pathogenic. Longstreth et al. and saw his ALS symptoms improve.The patient was specifically hypothesized that ALS may be caused a professional athlete and the stool donor a 'fan'. He by an as-yet-unidentified motor neuron toxin pro- reportedly "got out of the wheel chair and was said duced by a clostridial species in susceptible patients to be able to dance" with his wife, though later (12). Unlike recurrent C. difficile diarrhea, in which declined. No neurologic evaluation, ALSFRS-R, the normal fecal microbiome has been severely pulmonary spirometry, nor other data are available, altered, it is possible that a pathogenic microbial and the case has not been published. composition in neurologic diseases such as ALS Borody et al. in Australia at the Centre for Diges- might be more resilient to change and thus antibi- tive Diseases (vnvw.cdd.com.au) and Probiotic otics/probiotics previously trialed may not be effec- Therapy Research Centre (www.probiotictherapy. tive (10). com.au) have used FMT and/or antibiotic regimens designed to treat constipation, ulcerative colitis, and Relevant animal data other bowel disorders, and noted serendipitous There are no published animal data investigating improvements in several extra-intestinal conditions. FMT as a treatment for ALS. There are limited ani- These have included case reports and small case mal data on alterations in the gut microbiome in series of patients with Parkinson's disease, multiple other neurologic disorders. For example, studies sclerosis, and myoclonus dystonia (10,17-19). There with germ-free animals or animals given specific gut are also case reports suggesting improvement in infections iatrogenically have implicated the fecal chronic fatigue syndrome, Alzheimer's disease, and microbiome in certain mood disorders, cognition, autism (2,10), and the intestinal microbiota is altered and pain syndromes (reviewed in (9)). Experimental in children with autism compared to healthy controls autoimmune encephalomyelitis (EAE), an animal (20). A patient with both myasthenia gravis and model for multiple sclerosis, does not develop in ulcerative colitis (UC) received a proctocolectomy germ-free mice, and subsequent colonization with for her UC, after which she experienced complete fecal microbiota causes them to develop demyelina- remission of her myasthenia; at a three-year follow tion (13,14). The colonic microbiome is also altered up, she was asymptomatic and had a normal EMG in a mouse model of Alzheimer's disease, evaluated (21). by fatty acid methyl ester analysis (15). In ALS, constipation is common and presumed There are animal data demonstrating that multifactorial — related to dehydration, lack of clostridia! toxins, such as tetanus toxin, can be dietary fiber intake, and decreased physical activity transported to the CNS despite an intact blood- (22). However, a study using radio-opaque markers brain barrier and without invoking an immune found that ALS patients have substantially delayed mechanism. For example, the non-toxic C frag- gastric emptying and colonic transit times compared ment of tetanus toxin is known to be transported to healthy controls even if they did not complain of in a retrograde fashion to the CNS, and thus has GI symptoms; this abnormal colonic motility did not been studied as a potential vehicle to target thera- correlate with bulbar involvement or disease dura- pies for neurodegenerative disorders. In one study, tion (23). Recent studies have also suggested a rela- naked DNA encoding the non-toxic C fragment of tionship between prediagnostic body fat and ALS tetanus toxin was injected intramuscularly into risk (24), interesting in the light of recent human and SOD1-G93A mice, and was transported retrograde animal data on the role of the fecal microbiome in and trans-synaptically back to the spinal cord obesity. (confirmed by Western blot), and surprisingly had therapeutic benefits in the ALS mice (16). The Costs and potential side-effects authors hypothesized that the therapeutic benefit may be related to intrinsic neuroprotective proper- Risks appear minimal with FMT if the donor has ties of this non-toxic fragment, which were also been properly screened for infectious organisms. demonstrated in vitro, possibly due to similarities Colonoscope insertion has a small risk of perfora- between the tetanus toxin and certain endogenous tion. Some patients may develop transient GI com- growth factors that utilize transynaptic transport plaints or altered bowel habits for several days after pathways. FMT (personal communication, Olga Aroniadis, RIGHTS LINK.> EFTA01178506  484 The ALSUntangled Group Montefiore Medical Center). In a 2012 multicenter Robertson, Larry Phillips, Michael Benatar, Eric long-term follow-up study on FMT for recurrent C. Sorenson, Christen Shoesmith, Steven Nash, difficile, four patients developed an autoimmune dis- Nicholas Maragakis, Dan Moore, James Caress, ease at some time after FMT, but there was no clear Kevin Boylan, Carmel Armon, Megan Grosso, relation to the FMT (25). If carried out by one's self Bonnie Gerecke, Jim Wymer, Bjorn Oskarsson, at home, the cost for 10 consecutive treatments with Robert Bowser, Vivian Drory, Jeremy Shefner, Noah FMT is about $800, which includes laboratory tests Lechtzin, Melanie Leitner, Robert Miller, Hiroshi to screen the donor, the cost of a blender, a strainer, Mitsumoto, Todd Levine, James Russell, IChema enema bags/bottles, and miscellaneous items (per- Sharma, David Saperstein, Leo McClusky, Daniel sonal communication, Mark Davis, Director, Bright MacGowan, Jonathan Licht, Ashok Verma, Michael Medicine Clinic). In the Bright Medicine Clinic, Strong, Catherine Lomen-Hoerth, Rup Tandan, Davis maintains a `donor bank' and charges -$4000 Michael Rivner, Steve Kolb, Meraida Polak, Stacy for 10 days of treatment. Rudnicki, Pamela Kittrell, Muddasir Quereshi, George Sachs, Gary Pattee, Michael Weiss, John Kissel, Jonathan Goldstein, Jeffrey Rothstein, Conclusions Dan Pastula, Gleb Levitsky, Mieko Ogino, Jeffrey There is rapidly expanding evidence implicating Rosenfeld, Efrat Carmi, Craig Oster, Christina • alterations in the fecal microbiome in wide-ranging Fournier, Paul Barkhaus, Eric Valor, Brett Morrison. 43 human diseases, including potential contributions Note: this paper represents a consensus of those cc via a gut-brain signaling axis in neurodegenerative weighing in. The opinions expressed in this paper are eL and neuroimmunologic disorders. Proposed mecha- not necessarily shared by every investigator in this L. 1112 nisms such as immune modulation and the produc- group. ,,i tion of neurotoxins by clostridia or other microbiota could bypass an intact blood-brain barrier. To date, there are no data directly implicating the fecal micro- Declaration of interest: ALSUntangled is spon- tk g biome in ALS, nor published case reports of FMT sored by the Packard Center and the Motor being tried in PALS. Data in other neurodegenera- Neurone Disease Association. ?.; 4 tive and neuroimmunologic disorders are largely cir- Ead cumstantial, comprising a handful of published case References §i reports. Therefore, ALSUntangled does not recom- 1. NIH Human Microbiome Project Website [Internet]. E as Bethesda: National Institutes of Health. (updated 2013 May mend FMT as a treatment for ALS at this time. 3e However, it is plausible that the fecal microbiome 2013, cited 2013 Jun 51. Available from: wv.w.commonfund. nih.gmihmpt. plays a role in some neurologic disorders, including 2. de Vos WM, de Vos EA. Role of the intestinal microbiome in .54 ALS Given the lack of effective therapies and the health and disease: from correlation to causation. Nutrition cch' relatively low cost and low risk of FMT - if per- Reviews. 2012;70:S45-56. formed by experienced clinical centers we support 3. Ley RE. Obesity and the human microbiome. Current Opin- further investigations in this developing field. A rea- ion in Gastroenterology. 2010;26. 4. Backhed F, Manchester JK, Semenkovich CF, Gordon JI. sonable next step would be a detailed molecular Mechanisms underlying the resistance to diet-induced obes- E analysis of gut bacteria in ALS patients; certainly ity in germ-free mice. Proceedings of the National Academy o these are the types of studies being advocated by the of Sciences. 2007;104:979-84. NIH Human Microbiome Project. If alterations are 5. Eisman B, Silen W, Bascom G, Auvar AJ. Fecal Enema As An Adjunct in the Treatment of Pscudomembranous Ente- 8 detected in the gut microbiome of ALS patients, a rocolitis. Surgery. 1958;44:854-9. following step would be properly controlled studies 6. Aroniadis OC, Brandt LJ. Fecal microbiota transplantation: in animal models, such as ALS mice. These studies past, present and future. Current Opinion in Gastroentero- could employ the same germ-free, and/or probiotic logy. 2013;29:79-84. treatment regimens published in mouse models of 7. van Nood E, Vrieze A, Nieuwdorp M, Fuentes S, Zoetendal EAE, Alzheimer's disease, and obesity. EG, de Vos WM, et al. Duodenal Infusion of Donor Feces for Recurrent Clostridium difficile. N Engl J Med. The ALSUntangled Group currently consists of 2013;368:407-15. the following members: Lyle Ostrow, Richard 8. Aas J, Gesscrt CE, Bakken JS. Recurrent Clostridium difft- Bedlack, Orla Hardiman, Terry Heiman-Patterson, cik Colitis: Case Series Involving 18 Patients Treated with Laurie Gutmann, Mark Bromberg, Gregory Carter, Donor Stool Administered via a Nasogastric Tube. Clinical Edor Kabashi, Tulio Bertorini, Tahseen Mozaffar, Infectious Diseases. 2003;36:580-5. 9. Cryan JF, Dinan TG. Mind-altering microorganisms: the Peter Andersen, Jeff Dietz, Josep Gamez, Mazen impact of the gut microbiota on brain and behaviour. Nat Dimachkie, Yunxia Wang, Paul Wicks, James Rev Neurosci. 2012;13:701-12. Heywood, Steven Novella, L.P. Rowland, Erik Pioro, 10. Borody TJ, Khoruts A. Fecal microbiota transplantation and Lisa Kinsley, Kathy Mitchell, Jonathan Glass, Sith emerging applications. Nat Rev Gastroenterol Hepatol. Sathornsumetee, Hubert Kwiecinski, Jon Baker, 2012;9:88-96. 11. Break H, Rub U, Gai WP, Del Tredici K Idiopathic Nazem Atassi, Dallas Forshew, John Ravits, Robin Parkinson's disease: possible routes by which vulnerable Commit, Carlayne Jackson, Alex Sherman, Kate neuronal types may be subject to ncuro-invasion by an Dalton, Katherine Tindall, Ginna Gonzalez, Janice unknown pathogen. J Neural Transm. 7 - 1 fi RIGHTS LINK.> EFTA01178507  ALSUntattgled Update 21 485 12. Longstreth J, Meschke JS, Davidson SIC, Smoot LM, Smoot 19. Borody T, Torres M, Campbell J, Hills L, Ketheeswaran S. JC, Koepsell TD. Hypothesis: A motor neuron toxin pro- Treatment of Severe Constipation Improves Parkinson's duced by a clostridia! species residing in gut causes ALS. Disease (PD) Symptoms. American Journal of Gastroenter- Medical Hypotheses. 2005;64:1153-6. ology. 2009;104:$367. 13. Berer K, Mues M, Koutrolos M, Rasbi ZA, Boxiki M, Johncr 20. Fincgold SM, Dowd SE, Gontcharova V, Liu C, Henley KE, C, et al. Commensal microbiota and myelin autoantigen Wolcott RID, et al. Pyrosequencing study of fecal microflora cooperate to trigger autoimmune demyelination. Nature. of autistic and control children. Anaerobe. 2010;16: 2011;479:538-41. 444-53. 14. LeeYK, Menczes JS, Umesald Y, Mazmanian SK. Proinflam- 21. Gower Rousseau C, Reumaux D, Bellard M, Delecourt L, matory T-cell responses to gut microbiota promote experimen- Ribet M, Colombel JF. Remission of myasthenia gravis tal autoimmune encephalomyelitis. Proceedings of the National after proctocolectomy in a patient with ulcerative colitis. Academy of Sciences. 2011;108 (Suppl l):4615-22. The American Journal of Gastroenterology. 1993;88: IS. Karri S, Acosta-Martinez V, Coimbatore G. Effect of dilly- 1136-8. drotcstosterone on gastrointestinal tract of male Alzheimer's 22. Forshew A, Bromberg B. A survey of clinicians' practice in disease transgenic mice. Indian Journal of Experimental the symptomatic treatment of ALS. Amyotroph Lateral Biology. 2010;48:453. Scler. 2003;4:258-63. 16. Moreno-Igoa M, Cahro A, Penas C, Manzano R, ()Evan S, 23. lbepfer CF. Gastrointestinal dysfunction in amyotrophic Munoz M, et al. Fragment C of tetanus toxin, more than a lateral sclerosis. Amyotroph Lateral Scler. 2000;I:15-9. carrier. Novel perspectives in non-viral ALS gene therapy. 24. Gallo V, Wark PA, Jenab M, Pearce N, Brayne C, J Mol Med. 2010;88:297-308. Vermeulen R, et al. Prediagnostic body fat and risk of death 17. Borody T, Leis S, Campbell J, Torres M, Nowak A. Fecal from amyotrophic lateral sclerosis. The EPIC cohort. Neu- Microbial., Transplantation (FM1) in Multiple Sclerosis rology. 2013;80:829-38. ri (MS). American Journal of Gastroenterology. 2011;106:S352. 25. Brandt LI, Aroniadis OC, Mellow M, Kanatzar A, Kelly C, IS. Borody T, Rosen D, TOMS M, Campbell J, Nowak A. Park T, et al. Long-Term Follow-Up of Colonoscopic Fecal e Myoclonus-dystonia Affected by GI Microbiota? American Microbiota Transplant for Recurrent Clostridium difficile : the Journal of Gastroenterology. 2011;106:$351-2. Infection. Am J Gastrocnterol. 2012;107:1079—87. •u: pia .!to.= 67. 8.°9 E>. u... 3§ g.N yC 88 9;8 E o 8 RIGHTS LINK, EFTA01178508