Pass the POO/Medicine

As many will know if they read the reviews I compile, I have an over 20 year interest in the role of the mucosal immune system (mainly in the gut) and its effects on human health, beyond the local tissues and organs.

The gastrointestinal tract is rooted in what is gently chided by the dedicated science/medical community as ‘folk medicine’, and for thousands of years healers, shaman and other practitioners have applied their best efforts to securing the gut as the seat of all disease.

In Asian medicine the abdomen is recognised as the seat of the soul the “Honoured Middle” (onaka) and the centre of spiritual and physical strength (Hara) is how the Japanese describe the intestine. [1] Yet for many Europeans and North Americans it is largely a tube which simply has to function albeit increasingly less efficiently.

Whilst it is true that this is an overly simplistic notion, it is becoming clear that the exchange that takes place between the bacteria in the gut; genetic, molecular and functional has profound influences on human health. How we manage this information and apply it in clinical practice has spun out numerous strategies, none more challenging to the average clinician and patient than the idea of faecal transfer. Variously called Faecal Bacteriotherapy or Faecal Transplantation it is in essence the transfer of one healthy human’s bacterial colonies found in their stool sample to another unhealthy human for the purpose of mitigating an active disease.

Recent findings demonstrate that it is possible to engraft new microbiota from a donor source, resulting in the restoration of gut functionality and improvement in health. This builds upon decades of case reports and series in which faecal transfers were used to successfully treat refractory and recurrent Clostridium difficile infection.

History

Back in 1958 – over 50 years ago the idea that faecal transplantation may mitigate or resolve the condition called pseudomembranous colitis, caused by a pathogen (we now know this to be Clostridium Difficile [2] ) growing unopposed on antibiotic treated gastric tissues was explored and written about.[3] A follow up paper in 1960 gave further insights into its potential as a simple restorative treatment.[4]

In 1958, 4 patients with non-recovering pseudomembranous colitis despite what are described as ‘heroic’ efforts including hydration, vasopressors, hydrocortisone, antibiotics and L. acidophilus were in desperation treated with faecal retention enemas using faeces collected from healthy donors with no antibiotic exposure. All 4 recovered in days and were discharged. The authors noted:

“We hope that more complete evaluation of this simple therapeutic measure can be given further clinical trial by others.” They further commented that once “more precise” microorganisms are identified, their administration in “enteric-coated capsules might be both more aesthetic and more effective.”

C. Difficile is now the equivalent killer of patients in the USA to those lost to HIV infection (15~20,000).[5] This simple effective intervention is achieving a greater recognition as a mechanism changer in the host of the infected patient. Yet the standard of practice in hospitals for this condition once it has achieved fulminant status is emergent resection of the colon – which apart from the clinical burden in terms of therapy and cost has seen little improvement in outcome figures from that achieved in 1958 at just ~50%.[6] This relapse and loss rate may be improved by using relevant lab markers but patients still suffer from a high rate of mortality.[7]

Over the interceding decades since the 1958 paper over 200 cases of CD being treated with faecal transfer using either enemas or nasogastric tube administration have been recorded with a quite remarkable successful outcome of ~90% and no apparent ill effects.[8],[9],[10],[11]

Current use

So why one may ask is this simple inexpensive and effective strategy still not a standard of care in hospitals? Maybe in the absence of much science (i.e. appropriate RCT comfort inducers), the idea probably cannot yet overcome the instinctive avoidance of something seemingly repulsive by many clinicians and their patients.

Yet there is no shortage of workable data, just shortage of randomised clinical studies. Albeit that the risk to benefit ratio is heavily in favour of this against its most dramatic options, there is a degree of uncertainty about the safety of this innocuous transplantation, albeit that studies in the microflora and its role in human health are literally filling journals on a weekly basis.[12]

Borody et al reported positive outcomes in a small trial using faecal transplantation therapy to treat ulcerative colitis (UC). A group of 6 patients with “severe, recurrent symptoms and UC confirmed on colonoscopy and histology were administered retention enemas and repeated this daily for 5 days. A very impressive and complete reversal of symptoms was achieved in all patients by 4 months and all other medication was discontinued. On follow up at 1 and 13 years there was no clinical, colonoscopic, or histologic evidence of UC in any patient.[13]

Novel ideas

Whilst it would seem quite logical that this is an area of investigation for inflammatory bowel diseases as these are associated with an altered microbial mix in the gastrointestinal tract and subsequent immune discord.[14] The idea that it may alter a generalised condition such as metabolic syndrome and obesity[15], ..

Lean donor faecal infusion improves hepatic and peripheral insulin resistance as well as fasting lipid levels in obese individuals with the metabolic syndrome underscoring the potential role of gut microbiota in the disturbances of glucose and lipid metabolism in obesity. Our data could provide pathophysiological insight in the metabolic deviations in obese subjects and a rationale for therapeutic intervention.[16]

…or a complex but expanding area of diseases referred to as autoimmunity and allergy is less immediately obvious has been attracting attract serious discussion for a few years now.[17],[18],[19]

One of the leading researchers into the potential role of bacterial transfer therapy Dr Borody from Australia is currently recruiting for patients suffering from Parkinson ’s disease after he found one of his patients made a recovery after transplantation.

IBS a very common functional disorder has no direct studies on its effects from receiving faecal transplantation but represents an interesting area of possibility.[20]

Probiotics

To date the most appreciated and clinically utilised manner for influencing the gastric microbial balance or populations has been through the ingestion of probiotics and prebiotics based on the turn of the 20^th century’s great immunologist Metchnikoff.[21]

However, there is inconsistent evidence of their use as a single therapy in the treatment of conditions such as those described above and consistent outcomes remain difficult to achieve. In part this is due to the unravelling of the role of single strain organisms and their effects on humans as well as the complex logistics of influencing the microbial community in the gut. Human originating bacteria may well confer additional immune benefits than those derived from the dairy industry but both originating organisms are capable of activating microbial associated molecular patterns on dendritic cells and so confer an immunological message to the adaptive immune cells.[22]

Difficult issues

It is a formidable task – over100 trillion bacteria reside in the colon as well as other organisms and viruses. In addition these cohabitants are uniquely adapted to the gastrointestinal tract and occupy niches in complex communities that resist easy manipulation by medication as well as probiotics. The result of this has been a gradual understanding of the modest – albeit useful contribution that a probiotic infusion may make to the bacterial relationships in our inner tube of life. The result has been the somewhat enshrined notion that once established the ‘fingerprint’ of our bacterial cousins will remain unchanged despite antibiotics and probiotics. This seems to be a compelling concept, especially in terms of the core microbiome and its longevity of occupation, but a recent paper looking at the impact of faecal transplantation suggests that this may need a review.[23]

What did the study show?

A small group of ten patients undergoing “faecal bacteriotherapy,” or “faecal transplantation”  first had their gastrointestinal tract treated with antibiotics and then faecal suspensions collected from healthy donors were administered daily. In this study the first infusion was administered through a colonoscope and subsequent doses were given over a 60-minute period through a nasal jejunal tube or via enemas suggesting options for clinical settings. The participant’s microbial concentrations were analysed at 4, 8, and 24 weeks post-initial infusion and then compared with the initial infused donor faecal suspension to determine whether the donor flora had become a stable microbiota of the faeces of the recipients.

Key findings

The samples revealed that the recipients faecal flora now reflected those of the donor indicating the possibility of providing a degree of permanence to the new colonies of bacteria.

The authors stated:

This study demonstrates a durable beneficial change in the patients’ bacterial populations of the colon to represent those of the healthy donor’s microbiota. Manipulation of the colonic microbiota to improve its protective and beneficial role represents a promising field of new therapeutic strategies for the treatment of gastrointestinal conditions.

Where now

Virtually all of this therapy for the purpose of writing it up has been undertaken in hospital settings and cautions have been issued regarding the unknown bacterial composition of the donor stool. The application has either been via naso-gastric tube – out of the reach of most practitioners operating from private clinics, or by retention enemas, a long understood mechanism for the introduction of fluids and medications into the colon.

On the basis that the risks to benefits are heavily stacked in the benefits section one study explored the practicality of administering the enemas at home using stool samples collected from healthy family members. 7 patients with C.Diff were sent home to administer the transplant and at 14 months follow up revealed a100% success in restoring the GIT to health after a single administration.[24]

What did they do?

This is included for intellectual observation only – not as a recommendation for spontaneous utilisation without suitable medical support.

All patients (recipients) underwent a full history and physical examination. Potential family member faecal donors were selected by the patients and were questioned for any of the following contraindications for donation:

1.      any history of gastrointestinal illness including peptic ulcer disease, gastroesophageal reflux, irritable bowel syndrome, inflammatory bowel disease, or polyps;

2.      any malignancy; and

3.      antibiotic use or hospitalization within the past 3 months.

Laboratory Testing of Donors and Recipients

• All donors underwent screening serology for human immunodeficiency virus (HIV), human T-lymphotropic virus I/II, syphilis enzyme immunoassay, hepatitis A immunoglobulin M, hepatitis B surface antigen, hepatitis C antibody, and Helicobacter pylori antibody.
• Recipients had blood testing for: complete blood count, sequential multi-channel analysis with computer-20 (Chem-20), serum protein electrophoresis, serum immunoglobulin’s, HIV,
• and antigliadin antibodies.
• Stools from both donors and recipients were obtained for culture and sensitivity, ova, and parasites (3 separate specimens), cryptosporidia, microspora and Clostridium difficile toxin.
• Stool specimens were obtained from recipients prior to faecal transplantation and sent to the reference laboratory for culture and typing of C difficile.

Transplantation Protocol

Recipients were initiated on maintenance therapy with oral Saccharomyces Boulardii (Florastor; Biocodex Inc,) 500 mg orally twice per day, plus metronidazole 500 mg orally 3 times per day or vancomycin 125 mg orally 4 times per day, to ensure they were asymptomatic until 24–48 hours prior to the procedure. All patients were asked to return to clinic for follow-up 2 weeks post procedure.[25]

Instructions to Recipients and Donors

Recipients and donors were given the following instructions.

• Equipment needed: (1) bottle of normal saline (200 mL); (2) standard 2 quart enema bag kit available at a drug store (Life Brand Hot Water Bottle and Syringe kit; Shoppers Drug Mart, Toronto, ON, Canada); and (3) standard kitchen blender (1 L capacity) with markings for volume on side, available at any department store.
• Stop vancomycin/metronidazole 24–48 hours before procedure.
• Continue S Boulardii during transplant and for 60 days afterwards.
• Add 50 mL of stool (volume occupied by solid stool) from donor obtained immediately prior to administration (less than 30 minutes) to 200 mL normal saline in the blender.
• Mix in the blender until liquefied to “milkshake” consistency.
• Pour mixture (approximately 250 mL) into the enema bag.
• Administer enema to patient using instructions provided with enema bag kit. Patient should hold the infusate as long as possible and lie still as long as possible on his or her left side so that the urge to defecate is prevented. Ideally perform the procedure after the first bowel movement of the day (usually in the morning).
• If diarrhoea recurs within 1 hour, the procedure may be immediately repeated.

Comment

The author’s state:

In this case series faecal transplantation was both well tolerated and efficacious in a group of highly motivated outpatients. No patient required a repeat procedure, and there were no treatment failures despite 3 patients receiving antibiotics in the post-transplant period.

The 100% efficacy in this group of 7 highly refractory patients, suggests that this protocol is very promising. Nevertheless, a larger study would be required to more accurately determine efficacy.

Whilst unfamiliar to many clinicians there are many therapists who have been using enemas as part of their treatment protocol for many years. It is unclear whether the same level of pre preparation is required for a second transplant if required, but this should probably represent the minimum level of investigation when transplanting from an ostensibly healthy patient into one experiencing both functional or pathological GI and systemic illness.

References

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[1] Yu F, Takahashi T, Moriya J, Kawaura K, Yamakawa J, Kusaka K, Itoh T, Morimoto S, Yamaguchi N, Kanda T. Traditional Chinese medicine and Kampo: a review from the distant past for the future. J Int Med Res. 2006 May-Jun;34(3):231-9. Review. View Abstract

[2] Viswanathan VK, Mallozzi MJ, Vedantam G. Clostridium difficile infection: An overview of the disease and its pathogenesis, epidemiology and interventions. Gut Microbes. 2010 Jul;1(4):234-242. Epub 2010 Jun 16. View Abstract

[3] Eiseman, B., Silen, W., Bascom, G.S. & Kauvar, A.J. Fecal enema as an adjunct in the treatment of pseudomembranous enterocolitis. Surgery 44, 854–859 (1958). No abstract available

[4] Collins, DC. Pseudomembranous enterocolitis. Further observations on the value of donor fecal enemata as an adjunct in the treatment of pseudomembranous enterocolitis. Am J Proctol. 1960 Oct;2:389-91. No abstract available.

[5] Rupnik, M., Wilcox, M.H. & Gerding, D.N. Clostridium difficile infection: new developments in epidemiology and pathogenesis. Nat. Rev. Microbiol. 7, 526–536 (2009). View Abstract

[6] Lamontagne, F. et al. Impact of emergency colectomy on survival of patients with fulminant Clostridium difficile colitis during an epidemic caused by a hypervirulent strain. Ann. Surg. 245, 267–272 (2007). View Abstract

[7] Pepin J, Vo TT, Boutros M, Marcotte E, Dial S, Dubé S, Vasilevsky CA, McFadden N, Patino C, Labbé AC. Risk factors for mortality following emergency colectomy for fulminant Clostridium difficile infection. Dis Colon Rectum. 2009 Mar;52(3):400-5. View Abstract

[8] van Nood, E., Speelman, P., Kuijper, E.J. & Keller, J.J. Struggling with recurrent Clostridium difficile infections: is donor faeces the solution? Eur. Surveill. 14 (2009). View Abstract

[9] Rohlke, F., Surawicz, C.M. & Stollman, N. Fecal flora reconstitution for recurrent Clostridium difficile infection: results and methodology. J. Clin. Gastroenterol. 44, 567–570 (2010). View Abstract

[10] Yoon SS, Brandt LJ. Treatment of refractory/recurrent C. difficile-associated disease by donated stool transplanted via colonoscopy: a case series of 12 patients. J Clin Gastroenterol. 2010 Sep;44(8):562-6. View Abstract

[11] MacConnachie AA, Fox R, Kennedy DR, Seaton RA. Faecal transplant for recurrent Clostridium difficile-associated diarrhoea: a UK case series. QJM. 2009 Nov;102(11):781-4. Epub 2009 Sep 2. View Abstract

[12] Backhed, F., Ley, R.E., Sonnenburg, J.L., Peterson, D.A. & Gordon, J.I. Host-bacterial mutualism in the human intestine. Science 307, 1915–1920 (2005) View Abstract

[13] Borody TJ, Warren EF, Leis S, Surace R, Ashman O. Treatment of ulcerative colitis using fecal bacteriotherapy. J Clin Gastroenterol. 2003;37(1):42-47. View Abstract

[14] Garrett, W.S., Gordon, J.I. & Glimcher, L.H. Homeostasis and inflammation in the intestine. Cell 140, 859–870 (2010) View Abstract

[15] Ley, R.E., Turnbaugh, P.J., Klein, S. & Gordon, J.I. Microbial ecology: human gut microbes associated with obesity. Nature 444, 1022–1023 (2006). View Abstract

[16] Vrieze A, et al. Metabolic effects of transplanting gut microbiota from lean donors to subjects with metabolic syndrome. European Association for the Study of Diabetes. EASD 2010; Abstract 90. View Abstract

[17] Wen, L. et al. Innate immunity and intestinal microbiota in the development of type 1 diabetes. Nature 455, 1109–1113 (2008). View Abstract

[18] Noverr, M.C. & Huffnagle, G.B. Does the microbiota regulate immune responses outside the gut? Trends Microbiol. 12, 562–568 (2004). View Abstract

[19] Kunisawa J, Kiyono H. Aberrant interaction of the gut immune system with environmental factors in the development of food allergies. Curr Allergy Asthma Rep. 2010 May;10(3):215-21. Review. View Abstract

[20] Bazzocchi G, Gionchetti P, Almerigi PF, Amadini C, Campieri M. Intestinal microflora and oral bacteriotherapy in irritable bowel syndrome. Dig Liver Dis. 2002 Sep;34 Suppl 2:S48-53. View Abstract

[21] Metchnikoff, E. The Prolongation of Life: Optimistic Studies, Arno Press, New York, (1977) , 343 pp.

[22] Rhee SH. Basic and translational understandings of microbial recognition by toll-like receptors in the intestine. J Neurogastroenterol Motil. 2011 Jan;17(1):28-34. Epub 2011 Jan 26. View Abstract

[23] Grehan MJ, Borody TJ, Leis SM, Campbell J, Mitchell H, Wettstein A. Durable alteration of the colonic microbiota by the administration of donor fecal flora. J Clin Gastroenterol. 2010;44(8):551-561.

[24] Silverman MS, Davis I, Pillai DR. Success of self-administered home fecal transplantation for chronic Clostridium difficile infection. Clin Gastroenterol Hepatol. 2010 May;8(5):471-3. Epub 2010 Feb 1. View Abstract

[25] Pillai A, Nelson RL. Probiotics for treatment of Clostridium difficile- associated colitis in adults. Cochrane Database of Systemic Reviews 2008:CD004611. View Abstract