“It’s Not Just For C. difficile Anymore”

Prof Thomas J. BorodyMD, PhD, FRACP, FACP, FACG, AGAF

Centre for Digestive DiseasesSydney, Australia

August , 2014

Disclosure statement TJ Borody makes the following disclosures: RedHill Biopharma: scientific advisory board

(honorary) Salix Pharmaceuticals: research grant CIPAC Consultant (honorary) GSK, Salix Pharmaceuticals, Giaconda Pty Ltd:

stock Patents: in various fields, including FMT Pecuniary interest in Centre for Digestive Diseases,

where FMT is a treatment option

Centre for Digestive Diseases

Established October 1984Free standing GI endoscopic Clinic6 Gastroenterologists and a staff of 47FMT since 1998; > 4500 proceduresNo restrictions on use in CDI nor non – CDI

indicationsRestriction on “supply”

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FMT Outside Relapsing CDI-1FDA Guidance : FMT to treat C. difficile not

responding to standard therapies • CEBER July 2013

A. FMT in CDI and IBD- Common (Issa et al I B Dis 2008)- Eradicates 90% (Borody UEGJ 2013)- Prolongs remission in minority- Rarely dramatic reversal of IBD

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CASE 247 y male, 1 yr Hx severe CD (previous 3 yr Hx UC)Diarrhea 20-25/day, bleeding, cramping, fatigue – possible

surgery candidate, toxin-positive CDICRP=68.5*, Hb=114*35mg prednisone, 20mg/wk MTXSymptoms improved somewhat

on pre-FMT vancomycin regimePosterior fissures, very severe

distal inflammation with pseudopolyps, ulcers and scarring throughout bowel Sigmoid colon, fully-prepped bowel

FMT IBD :CD

Two-day infusion: transcolonoscopic + next day enemaCDI eradicated. At 13 mo F/U:1-2 formed stools/day. No bleeding, no mucus, no

urgencyCRP=6, Hb=160Able to return to work, 20kg

weight gainNo medication 1 yearBest result

Sigmoid colon, unprepped bowel

FMT IBD :CD

FMT Outside Relapsing CDI-2B. FMT in Non R-CDI

- With significant co-morbidities- Immunosuppressed / transplants (Kelly et al

2014 AmJG)

- Pregnancy - ?- With non-significant co-morbidities

- First time CDI – 2 infusions ~ 100%- D-IBS + CDI – Diarrhoea – occasional

cure- C-IBS + CDI – Rare cure with 1-2 FMT

Eradication still >90%

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Disorders associated with altered intestinal microbiome and/or

responded to FMT-1 GI

• Clostridium difficile infection (CDI)• IBD – UC and Crohn’s*• Sclerosing cholangitis*• IBS• Recurrent diverticulitis*• Halitosis

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Disorders associated with altered intestinal microbiome and/or

responded to FMT-2 Non GI

• Arthritis• Autoimmune – ITP*• Autism• Chronic Fatigue Syndrome• Diabetes mellitus and

insulin resistance

• Acne vulgaris• Mood disorders• Metabolic syndrome• Multiple sclerosis*• Parkinson’s disease

Modified : Brandt et al 2013 Am J Gastro

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FMT: Inflammatory Bowel Disease1988: Our first case (indeterminate colitis): 2 infusions. Remains cured >

25 years (Borody et al 1989)1989, Bennet et al: self-treated with FMT, clinical and histological

normality. (Bennet et al Lancet 1989)2003: 6 cases, remain ‘cured’ 1-15 years (Borody et al 2003)2011: repeated enema infusions – key to IBD2012: Systematic review. Majority of patients experience symptom

improvement (19/25), disease remission (15/24) and cessation of medication (13/17) (Anderson et al, 2012)

2012: 62 cases UC – Prolonged histological ‘remission’ (Borody et al 2012)Reports of isolated cases of dramatic clinical and histological

improvement: - Kao et al, 2014 ; Gordon et al, 2014 ; Zhang et al, 2013

Retrospective Review – FMT in UC62 UC patients – No CDISimple Clinical Colitis Activity Index (Walmsley)

Reduction >4 points – Marked improvement 2-4 points – moderate0 points – no improvement

• 17/62 (27%) – Marked improvement• 26/62 (42%) – Moderate• 16/62 (26%) – No improvement • 3/62 (5%) – Worsened

• 17 with marked improvement • Clinically well, formed stool• Endoscopically normal• Histologically normal• “Remission” = 1-24 years

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Changes by Age Group

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Group A (18 - 35 years)

Group B (36 - 80 years)

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Worsening of SymptomsNo ImprovementModerate Im-provementSignificant Improvement

Retrospective Review – FMT in UC62 UC patients – No CDISimple Clinical Colitis Activity Index (Walmsley)

Reduction >4 points – Marked improvement 2-4 points – moderate0 points – no improvement

• 17/62 (27%) – Marked improvement• 26/62 (42%) – Moderate• 16/62 (26%) – No improvement • 3/62 (5%) – Worsened

• 17 with marked improvement • Clinically well formed stool• Endoscopically normal• Histologically normal• “Remission” = 1-24 years

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FMT for IBD: UC

Pre-FMT Post-FMT 15

Case 1: 21 y; 10 yr Hx of severe UC failing Rx (steroids, anti-TNFs)Commenced FMT April 2010: immediate symptom

improvement, lowered CRP approx 1 month after starting enemas

Completed 26 FMT enemas

FMT for IBD: UCCase 233 y M. 8 wk abdominal pain, diarrhoea, mucus + blood.

First diagnosis of UC Rx: Standard anti-inflammatory : frequent relapses.

Before FMT pre-treated with ciprofloxacin, metronidazole, mesalazine and prednisone.

FMT via trans-colonoscopic infusion then daily, twice-weekly, weekly, FMT infusions. After 80 FMT he was re-colonoscoped on 14/9/12.

He was passing normal stool once per day and was off all drugs then for 7 months and has continued well

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Before After

Above: Rectum (L), Rectum (R)

Above: Sigmoid colon (L), Terminal ileum (R)

Rectum

Sigmoid colon

Sigmoid colon

FMT for IBD: UCCase 338y M. Distal colitis proximal pseudopolyps - sclerosing

cholangitis with elevated LFT’s. C. difficile negative1st infusion transcolonoscopic, followed by daily infusions, then

three per week and reducing. 2nd colonoscopy 3/10/2012 after ~ 100 FMT infusions. Once per week for now. Stools formed for a couple of days after infusion and then they became unformed.

Next colonoscopy 6/2/2013. FMT now weekly or second weekly. Regained weight. No blood, no mucus and formed stools. Note: Serum ALP fell from 338 to 94 - other liver functions normal.

Unprepared colonoscopy showed no inflammation.

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Before After

Sigmoid colon

Hepatic flexure

Sigmoid colon, showing mucus, blood

Sigmoid colon, showing pseudopolyps

Transverse colon Hepatic flexure

Ascending colon Caecum, infusing FMT

Transverse colon

FMT for IBD: UCCase 453y M, severe distal colitis on immune-suppressants, 5ASA

antibiotics facing surgery. Chose recurrent FMT, C. difficile toxin positive found

9/12/2011 - first FMT. Severe distal inflammation. For CDI - had single trans-colonoscopic FMT followed by enema. 7 weeks later he felt “fantastic”. No urgency, no blood, one motion per day.

10/1/2013 – colonoscopy; tubular adenoma removed but mucosa normal. Histology - small numbers of neutrophils within laminar propria - focal mild cryptitis The patient was passing normal formed stools daily. Remains clinically well currently

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FMT for PROCTITIS: UC

Rectum - Prior FMT Rectum - Post FMT

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Case 557y F. Nine y history of refractory proctitis (failed 5-ASA , steroids,

antibiotics, probiotics, immunosuppressants and acetarsol). FMT commenced Dec 2007 (69 sessions of infusions) 10 days into FMT immediate clinical response diarrhoea ceased

Colonoscopy at 3y and 5y showed no visible or histological inflammation. Now asymptomatic >5y years + off all meds without relapse

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Before After

Top: Rectum. Below: sigmoid colon Top: Rectum showing adenomatous polyp. Below: sigmoid colon

Case 1:14 y M: Severe Crohn’s ileitis, C. difficile positivity on Prednisone

and Imuran. Marked symptoms – poorly controlled. Terminal ileitis - 17/1/2012, FMT 17/4/2012. Instead of doing 2

infusions mother continued home infusions with marked improvement. Total of 60 infusions. No antibiotics. Able to stop Imuran. Acne healed by 7 days. Stools: 1-2 formed per day with all inflammatory parameters normal.

15/11/2012 – Colonoscopy; terminal ileum was totally normal ,no aphthoid erosions, no cobblestoning, no inflammation. Donor was 15 year old cousin. Normal colonocopy March 2014

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FMT for IBD: CD

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Before After

Terminal ileum

Terminal ileum: erosions

Terminal ileum

Terminal ileum

Terminal ileum

Terminal ileum: no visible inflammation at all

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CDI

• No. of infusions:• SINGLE+

• Symptom Reversal• Rapid Cure

• Remission• >90%

• Possibility of Cure:

• CURE > 95%

• Measure of Success :• Negative Stool for CDI• No symptoms

• Published Evidence• Large volume of small case

reports > 1000 patients

IBD

• No. of infusions:• MULTIPLE INFUSIONS

• Symptom Reversal• Slow then rapid REVERSAL

• Remission• > 80%

• Possibility of Cure: • Real Possibility: 10-15%

• Measure of Success :• Normal histology• No Symptoms

• Published Evidence• Case reports [n=?12]

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Experience in IBS

First reported by us in 1989 in 55 patients – most IBS@ CDD - most common indication is D-IBSConstipation-IBS more difficult to reverse – requires

repeated bowel cleaning and enema infusionsSeveral ‘chronic nausea’ patients treatedSeveral ‘abdominal pain’ only also treated

Borody et al 1989; MJA 150: 604

Refractory D-IBS in 13 patients – 70% Improved Pinn et al 2013; Am J Gast 108:S563

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Use of FMT in Neurological conditionsFMT in three atypical MS patients at CDD. FMT found to reverse MS symptoms in 3/6

cases resulting in regaining lower motor skills and urinary function and these patients remained asymptomatic after receiving FMT – F/U up to 17 y

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Future of FMTInitial use of ‘frozen’ microbiota preparationDevelopment and use of freeze-dried ‘enteric-coated’

microbiota capsulesExpansion of use to growing number of applications

including – IBD, IBS, Diverticulitis; Acne; Halitosis; Anorexia Nervosa; Metabolic Syndrome; Autism; Other Neurologic indications; Autoimmune diseases; ?Prevention of Ca colon; Others

Post-Antibiotic microbiota restoration

CONCLUSIONSFMT in Relapsing CDI is becoming mainstreamIn IBD FMT shows promise but need for repeated infusions is

a barrierMany unanswered questions in IBD – e.g. treat actively using

FMT inflamed mucosa or heal first with conventional therapiesFuture oral enteric coated FMT may be the ultimate therapy –

to maintain remissionGiven the unprecedented sporadic IBD resolution with FMT

the mechanisms underlying IBD may need re-examinationOther areas are of interest and expose new mechanisms

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