What are probiotics?

Probiotics are described as being living micro-organisms which, upon ingestion, affect the body in a beneficial manner. The human bowel contains a complex population of bacteria of several hundred different species and thousands of subspecies. These bacteria, and the chemicals they produce, can have a negative or a positive effect on the human body within which they live. The ‘good’ bacteria found in the human bowel are known as normal flora. This normal human flora is considered beneficial to the body as these bacteria aid in the breakdown of proteins and fats in food and help with the metabolism of vitamins, minerals and amino acids. They control infective bacteria from implanting via a number of mechanisms, and in addition, the good bacteria appear to boost the immune system and protect us from pathogenic (bad) bacteria penetrating the bowel wall and infecting the host, the human body. In fact they can stimulate immune responses beyond the gut positively improving skin and respiratory tract immunity, for example.

Problems arise if pathogenic or bad bacteria implant or live among the good human flora. This can cause an imbalance which can have a debilitating and toxic effect on the bowel or even the entire body. Probiotics can include normal human flora which are introduced into the body to increase their dominance in the bowel, thereby reversing the damage and associated problems caused by bad bacteria. Although transient passage of cultured probiotics can improve symptoms it should be noted that oral probiotics commercially available are incapable of implanting permanently into the gut flora as they have lost their capability to adhere to epithelial cells through the process of culturing in the commercial laboratory. It is only fresh human probiotics from another human being that retain that capability and hence can be implanted to reverse damage and side effects and then stay in the bowel to protect in the future.

What is FMT?

FMT (Faecal Microbial Transplant) uses normal ‘healthy’ human flora introduced into the patients bowel to ‘kill’ the bad bacteria.

The use of healthy human flora appears to be the most effective probiotic treatment available today. Healthy human flora acts as a ‘broad spectrum antibiotic’ against pathogens with the added benefit of being able to implant missing bacteria.

FMT therapy involves the infusion of healthy human donor flora bacteria into the bowel of the patient. The infusion is repeated for at least 5 days or longer. The therapy includes a special low fibre diet prior to infusion and a course of antibiotics to kill off as many bad bacteria as possible before infusion.

Killing off ‘bad’ bacteria before infusion gives the newly introduced ‘good’ bacteria a better chance of re-establishing dominance. Preparation also includes a bowel washout prior to infusion.

Infusions can be done via:

• Enema – this is a simpler method of infusing as a liquid flora mixture in saline through the rectum

What is FMT Used For?

Clostridium difficile infection

Clostridium difficile is a spore-forming bacterium which is probably most commonly ‘caught’ through the mouth often in hospitals, especially after the use of antibiotics. It can result in syndromes of varying severity including transient diarrhoea, a carrier status, a mild colitis-like illness, pseudomembranous colitis, and even toxic megacolon with possible mortality.

Most affected patients can respond to medical therapy including discontinuation of the responsible antibiotic. It is not the antibiotic that causes the infection but rather the antibiotic use weakens the defence of the bowel bacteria so permitting C. difficile to implant in the bowel. Treatment with metronidazole (Flagyl), vancomycin, rifampicin, teicoplanin or bacitracin can be successful in clearing up the symptoms. However, despite a seemingly successful initial treatment around 25% or more patients may have a recurrence of diarrhoea following withdrawal of these specific antibiotics. This is thought to occur because the normal flora may not at this time, possess the power to eradicate the persisting Clostridial spores. In many patients the C. difficile spores remain and a chronic, relapsing disease can continue. Treatment of this recurrent C. difficile diarrhoea can be particularly difficult, mainly because we do not have the tools to kill spores. Various approaches to therapy have included resins such as cholestyramine (Questran) and colestid (Colestipol) granules, specific probiotics such as Lactobacillus GG, Saccharomyces boulardii and intravenous immunoglobulin.5 Ultimately, if all medical therapies fail, re-colonisation of the colon using human faecal origin probiotics has been used and reported to be successful in eradicating spores.

FMT can be used to treat chronically ill patients who have had recurrent C. difficile diarrhoea, colitis or previous pseudomembranous colitis. The focus is particularly on those cases where other therapies have failed. In such patients we may initially use a combination therapy with vancomycin, rifampicin and metronidazole together combined with Lactobacillus GG. If all pharmacological therapies fail, faecal microbiota transplantation (FMT) is used to terminate the C. difficile infection since human faecal flora bacteria appear to have the capability to permanently eradicate C. difficile spores – a treatment not able to be matched by any other currently known therapy. Using FMT, the cure rate approaches 90-95%.

Diarrhoea-predominant IBS

Diarrhoea-predominant IBS is a common disorder of the gastrointestinal tract that can present with cramping pain, diarrhoea, bloating, explosive stools, urgency, incontinence and rectal bleeding if the stools are very frequent.

Although the cause of IBS is unknown it has been termed “a functional disorder” because there is no sign of any disease when the bowels are examined (normal structure) and it is presumed that only the function has changed. The condition can cause a great deal of discomfort with some patients eventually knowing where every toilet/bathroom is located between home and work. Some patients have episodes of incontinence and yet, the disease continues to be explained by psychogenic factors, with visceral hypersensitivity, neurotransmitter imbalance and stress or fibre deficiency. Recently, infection and inflammation has been obliquely alluded to as a possible cause.

Observations showing that many patients develop diarrhoea-predominant IBS following a gastrointestinal infection or the use of antibiotics, that metronidazole and other antibiotics can transiently suppress the symptoms, and that symptoms can be totally reversed by FMT in many patients, have led to the suggestion that diarrhoea-predominant IBS is also a chronic infection that has not been detected by standard stool tests. It needs to be remembered that the majority of chronic diarrhoeal infections are caused by agents yet to be defined by scientific endeavour. This concept can be more easily understood by the fact that for over 70 years the cause of chronic peptic ulcer disease was blamed on stress and high acid output while at the same time Helicobacter pylori was visible under the microscope but not recognised as the cause of ulcer disease. Chronic IBS is also likely to be shown to be caused by a number of infective agents since all clinical and pathologic findings point to this very fact. Indeed, in retrospect, it is much easier to imagine IBS to be caused by infections of the bowel flora than it was to believe that peptic ulcers could be caused by a chronic gastric infection.

However, patients with diarrhoea-predominant IBS need first to be investigated for known infective pathogens, especially parasites and C. difficile. This is best achieved by obtaining a sample of stool at initial colonoscopy rather than using a normal stool sample. In this way a ‘purged’ specimen is obtained in a very fresh state and immediately placed in the appropriate fixative to maximise detection of the offending bugs. Patients are first investigated via colonoscopy and aspirated fluid from the caecum is collected. Particular attention is given to collection of stool specimens in SAF (sodium acetate, acetic acid, and formalin) fixative especially for diagnosis of Dientamoeba fragilis, Blastocystis hominis, Entamoeba histolytica, other rare parasites, C. difficile and its toxin, Aeromonas hydrophilia, C. jejuni and other pathogens. The bacteria are cultured from unfixed specimen. Once parasitic diseases have been cured and no other pathology is seen such as chronic colitis, polyps, cancer or Crohn’s disease, the patient will be ready for probiotic infusion originating from a human source (FMT). In diarrhoea-predominant IBS it is hypothesised that a yet undescribed or undetectable bacterial species causing chronic infection – also probably a clostridium-type bacterium – is secreting toxins that influence the bowel enteric nerves in several ways. They can induce water secretion from the bowel causing the diarrhoea, stimulate pain fibres resulting in cramping pain and the bacteria can manufacture gas causing excessive flatulence. Lavage or purging of the bowel prior to infusion of normal flora from another human being allows for removal of the majority of pathogenic bacteria while allowing the incoming human flora to act as a powerful antibiotic to combat the remaining pathogens and also to bring in any missing components of the flora to implant in the bowel wall of the recipient who has been suffering with IBS. It should be noted that commercially available oral probiotics are incapable of implanting permanently in the gut flora as they have lost their capability to adhere to epithelial cells through the process of culturing in the commercial laboratory. It is only fresh human probiotic from another human being that retain that capability and hence can be implanted long term.

UC & Crohn’s

Colitis is inflammation of the bowel that can be acute or chronic. Acute inflammatory changes are usually self-resolving and are caused by specific infections such as shigella, salmonella, amoebae or Campylobacter jejuni to give few examples. These do not require any treatment with human probiotics since they are self-limiting or can be treated with specific antibiotics. Chronic inflammation can also be caused by chronic infections eg C difficile, Dientamoeba fragilis, and E. histolytica.

In patients with chronic colitis of unknown origin various subdivisions of the condition have been made. Patients can have a microscopic colitis, which presents as chronic diarrhoea and cramping but colonoscopically there are no areas of inflammation until one takes a biopsy and then typical inflammatory cells are visible under the microscope. Other patients have classic distal where colonoscopically inflammatory changes begin at the rectum and can extend to a variable distance up the bowel. In some patients the entire bowel is involved in colitis and this is called pan-colitis. Crohn’s and collagenous colitis make up other subdivisions.

The treatment of colitis has been generally standardised throughout the world and usually requires anti-inflammatory drugs such as corticosteroids (eg. prednisone), 5-aminosalicylic acid (5-ASA) compounds (eg. sulfasalazine, olsalazine, mesalazine), azathioprine, 6-mercaptopurine, cyclosporin, and antibiotics such as metronidazole, ciprofloxacin and vancomycin. Most of these agents, except for prednisone, also have anti-microbial actions, which points to the fact that colitis is almost certainly a chronic infection with a hitherto undescribed pathogen or pathogens. Among theories on causation of colitis it is generally thought that a passing bowel infection initiates an ongoing autoimmune response. The basis for this is – in part – the observation that we cannot find a pathogenic organism that causes colitis, and that it appears to respond to immunity-modifying drugs. Yet colitis may also follow an acute bowel infection-like episode. Other chronic infections such as Helicobacter pylori, hepatitis B or C, bronchiectasis, or fungal infections of the skin do not set up an ongoing ‘autoimmune’ condition. Hence, from the observation of other infections in the body it is highly unlikely that colitis is anything more than a chronic infection causing chronic inflammation and the infection has simply not been found. A similar situation has been operating in Crohn’s disease where an immune reaction to an unknown pathogen has been invoked as the mechanism. It is now unlikely that this is the mechanism operating but rather that Mycobacterium avium ssp. paratuberculosis (Map) is the ongoing infection that starts up and maintains the inflammation. ( www.crohns.org )

From these simple observations it is likely that ulcerative colitis, along with microscopic colitis, represents the visible effects of a chronic infection of the gut flora which science has not yet identified. It is likely that this infection through the release of various cytokines produces the clinical picture we call colitis. Although FMT has been successful in reversing colitis this treatment is less successful in colitis than it is in C. difficile diarrhoea and pseudomembranous colitis. The reason for this is unclear but we may be dealing with a pathogen or pathogens which are not as easily destroyed by the influx of normal human bacterial flora. Furthermore, in C. difficile diarrhoea and in patients with diarrhoea-predominant IBS the bowel is generally not inflamed and this may allow for easier implantation of a new bacteria onto the bowel mucosa than it is in colitis. In chronic colitis the implantation of the flora may be less likely on the inflamed tissues. We have noticed that if patients are given standard anti-inflammatory therapy until their bowel wall is completely healed, FMT can achieve long term reversal of colitis in more than 50% of patients in our experience, but the result is still unpredictable in the individual case. In addition if C. difficile co-exists in patients with chronic ulcerative colitis FMT can eradicate C. difficile and reduce the severity of the condition in such patients. Furthermore, the removal of associated parasites, especially D. fragilis which in itself can cause colitis, can also reduce the severity of colitis. There are patients who have had co-existing D. fragilis, Blastocystis hominis and C. difficile and whose severity of ulcerative colitis could be dramatically improved simply by removing the co-existing pathogens by either specific anti-parasitic agents or by FMT. C. difficile is typically ‘impossible’ to remove by the use of vancomycin, metronidazole or rifampicin in patients with chronic colitis.

Donors

All donors must be regularly screened according to published TGA guidelines with the following tests.

1. Serology testing for the following:
   1. HIV-1 / HIV-2 
   2. HBV
   3. HCV
   4. HTLV-1 / HTLV-2
   5. Strongyloides stercoralis 
   6. Syphilis (Treponema pallidum)
   7. HAV testing
   8. NAT for HIV-1, HBV and HCV
   9. Rheumatoid factor, ANA, ANCA, anti-thyroid Ab
   10. FBE, LFT, U&E, TSH, iron studies

Donor stool samples 

Stool samples from all potential donors must be screened and shown to not contain a list of specified microorganisms that impact the quality and safety of the stool and include:

a. Clostridioides difficile

b. Salmonella spp.

c. Shigella spp.

d. Campylobacter spp.

e. Giardia, D fragilis, B hominus

f. Cryptosporidium spp. Microsporidia

g. Entamoeba histolytica

h. Norovirus

i. Rotavirus

j. Enterovirus

k. MDROs including vancomycin-resistant enterococci (VRE), extended-spectrum β-lactamase (ESBL), and carbapenem-resistant enterobacteriaceae (CRE)

l. Helicobacter pylori, where the FMT product is delivered by upper gastrointestinal route

J. Listeria

Patients are able to have their own donors screened however it is recommended to use more than one donor during treatment. 

References

Kunde S, Pham A, Bonczyk S, Crumb T, Duba M, Conrad H Jr, Cloney D, Kugathasan S, Safety, Tolerability, and Clinical Response After Fecal Transplantation in Children and Young Adults With Ulcerative Colitis, J Pediatr Gastroenterol Nutr., 2013 Jun; 56(6):597-601

Borody T J. & Khoruts A, Fecal microbiota transplantation and emerging applications, Nature Reviews Gastroenterology and Hepatology 9, 88-96, 2012 February

Anderson JL, Edney RJ, & Whelan K, Systematic review: faecal microbiota transplantation in the management of inflammatory bowel disease, Aliment Pharmacol Ther, 36(6):503-16, 2012 September

Gough E1, Shaikh H, Manges AR., Systematic Review of Intestinal Microbiota Transplantation (Fecal Bacteriotherapy) for Recurrent Clostridium difficile Infection, Clin Infect Dis. 53(10):994-1002, 2011 November