advances in fecal microbiota transformation · smits lp, et al. gastroenterology 2013 fmt process...

American Pediatric Surgical Nurses Association

One Parkview Plaza, Suite 800 | Oakbrook Terrace, IL 60181 | www.apsna.org

25th Annual Scientific Conference | May 12-15, 2016 | San Diego, CA

1

ADVANCES IN FECAL MICROBIOTA TRANSFORMATION

Amanda Bradshaw, MPAS, PA-C Seattle Children’s Hospital

Seattle, WA

DISCLOSURE STATEMENT

• Neither I nor any member of my immediate family has a financial relationship or interest with any proprietary entity producing heath care goods or services related to the content of this CME activity.

• My content will not include discussion/reference of any commercial products or services.

• I do not intend to discuss an unapproved/investigative use of commercial products/devices

OBJECTIVES

• Applications for Fecal Microbial Transplant

• Methods involved in Fecal Microbial Transplant

• Outcomes of Fecal Microbial Transplantation




2

HUMAN MICROBIOME

Microbiome – Referring to the distinctive populations of microrganisms inhabiting a location

Wu and Lewis. CGH 2013

HUMAN MICROBIOME

Weight Cells Genes Microbiome Human

99% 10% 1%

• 100 trillion microorganisms

• Human gut - 2lbs of bacteria

• Outnumber human cells by a factor of ten • Genomes encode around 3 million different genes

FECAL MICROBIOME

6

Who’s there?

What are they doing?

Who’s they are varies: your microbiota is plastic and

personalized.

What they’re doing is adapting to

their environment:

you, your body, and your environment.

Savage, DC. Annu Rev Microbiol 1977; 31:107-133

Backhed, F ,et al Science. 2005; 307: 1915-1920.




3

FECAL MICROBIOME

Diversity within the human fecal microbiome may supply broader insight into the overall health of the individual.

Hollister, et al Gastroenterology 2014

MICROBIOME AND HUMAN DISEASE

Dysbiosis – Alterations in the microbiota composition associated with disease

Impacted by:

Diet

Antibiotics

Other


EFFECTS OF MODIFYING THE DIET ON MICROBIOME

Wu, G, Science 334, 105 (2011); 105-108




4

MICROBIOME AND HUMAN DISEASE

Described possible associations in the gut for numerous disease processes:

Infection (Clostridium Difficile)

Inflammatory Bowel Disease (IBD)

Cancer

Metabolic Disorders

C. DIFFICILE PARADIGM

C. difficile Dysbiotic Microbiome

Environment

Antibiotics

Diet

CDI: PATHOGENESIS Step 1- Ingestion

of spores

transmitted

from other

patients Step 2- Germination into

growing (vegetative) form

Step 3 - Altered lower intestine

flora (due to antimicrobial use)

allows proliferation of C. difficile

in colon

Step 4 . Toxin B & A production leads to

colon damage +/- pseudomembrane




5

CLOSTRIDIUM DIFFICILE

Increasing rates of relapsing C. dificile

Cure is common; resurgence is common too!

Nosocomial infection resistance to metronidazole

Flagyl, vancomycin, rifixamin, nitazoxanide, and probiotics

INCIDENCE RATE OF CDI

Pepin et al. CMAJ. 2004;171:466-472.

CURRENT APPROVED FMT APPLICATIONS

Recurrent C. Difficile Infections

Research Applications:

IBD

Obesity

Antibiotic resistant bacterias

Graft versus host




6

FECAL BACTERIOTHERAPY FOR RELAPSING C. DIFFICILE IN A CHILD

2 year old girl – 8 months ordeal

Watery diarrhea 1

Treatment

10 days of metronidozole

30 day of vancomycin and lactobacillus gg

Vanco plus rifixamin plus Saccharomyces boulardii plus lactobaccillus gg

Re-occurred after 14 days

George Russell, et al Pediatrics 126, number 1, July 2010

FECAL BACTERIOTHERAPY FOR RELAPSING C. DIFFICILE IN A CHILD

Vanco another 2 weeks

Then

Vanco – 2 weeks

Nitazoxanide 3 days then

Vanco 2 weeks then

Rifixamin 7 days then

Pulsed dose of vanco over 6 weeks

DID NOT WORK! What next! George Russell, et al Pediatrics 126, number 1, July 2010

FMT AND… IT WORKED!

Within 36 hours, abdominal symptoms and diarrhea resolved and did not re-occur during 6 months of monitoring.




7

FMT FOR RECURRENT CLOSTRIDIUM DIFFICILE

0

10

20

30

40

50

60

70

80

90

100

First Infusion ofDonor Feces (n=16)

Infusion of DonorFeces

Overall(n=16)

Vancomycin (n=13) Vancomycin withbowel lavage

(n=13)

81.3

93.8

30.823.1

Percentage Cured without Relapse

FMT AND C. DIFFICILE

Fecal Microbial Tansplant (Transfer) - Alteration of the gut microbiota by direct transfer of entire communities in the same relative abundance as exists in the healthy donor

Approximately 90% success rate


Smits LP, et al. Gastroenterology 2013

FMT PROCESS

Typically administered:

• Enema

• Colonoscopy

• Nasogastric – Infused, then followed with a normal saline flush

• Nasoduodenal

• Nasojejunal

• Capsules

It appears as if all routes are equal





8

FMT PROCESS

Openbiome – Stool repository

Donor Screening:

HAV antibody (IgM and IgG)

HBV Antibody to hepatitis B surface antigen,

Antibody to hepatitis B core antigen

HCV HCV antibody (RIBA-II)

HIV-1 and HIV-2 EIA

Treponema pallidum Rapid plasma reagin test

Stool Clostridium difficile Toxin A or toxin B (cytotoxin)

Enteric bacterial pathogens

Selective stool culture

Ova and parasites Light microscopy 2013 Joint Societal Guidelines for C. Diff

IBD AND THE MICROBIOME

Intestinal microbiota of IBD patients appears to have reduced diversity compared to healthy subjects.

Unclear whether these differences are a cause or consequence of development of IBD.


FMT IN IBD

Will it work

Crohn’s disease

Ulcerative colitis

Route

Dose

Frequency

Who is the best donor




9

Study #IBD

pts

IBD

Type

IBD

Severity

FMT

Dosage

FMT

Delivery

Pre-Abs/

Lavage

Frequency Donor Follow-Up

Borody et al.

(1989). 2 UC, CD Active NR NR NR NR NR 1-12 months

Borody et al.

(2001). 3 UC Quiescent Suspended in

200ml saline

Enema NR Daily x 5 days Healthy Adults 8-28 months

Borody et al.

(2003). 6 UC Severe 200-300g

(diluted to 200-

300ml)

Enema Vancomycin,

Metronidazole, and

rifampicin

Daily x 5 days Family or Close

Relation

1-13 years

Borody et al.

(2011). 3 IBD Isevere NR Enema

(Self)

NR Daily/Weekly X34-

70

Clinic donor,

family, partner

1-4 years

Kellermayer et al.

(2013). 4(-1a) UC IM/anti-TMF

Dependent

NR Colonoscopy NR Serial ? >5 months

Suskind et al. (2014) 3 UC Mild-Moderate 60ml NG Rifaximin X 1 Parent 12 weeks

Vermeire et al.

(2012).2 4 CD Medically-

refractory

200g feces NJ infusion NR 3x in 36 hours Healthy Donor 2 months

Kunde et al.

(2013). 10(-1a) UC Mild-moderate 90-113g/250ml Enema up to

(4x60ml)/day

NR x5 days Parents 6 weeks

Kump et al. (2013). 6 UC Therapy-refractory 150g/

200 saline

Colonoscopy Lavage of donor x1 Nonrelatives, 1 year

Angelberger et al.

(2013). 5 UC Severe 6-22g/100ml NJ + Enema Metronidazole x3 days No Family/

Hospital Staff

>1 year

Suskind et al.

(2014). 9 CD Mild-moderate 60ml NG Rifaximin x1 Parents 12 weeks

Landy et al. (2013). 5 UC refractory pouchitis 30g/250ml Saline Nasogastric NR x1 Nominated by

participating pts

4 weeks

Zhang et al.

(2013). 16 CD Refractory (HBI>8) NR Gastroscopic NR x1 NR 1 month

Damman et al.

(2014). 8(-1a) UC Mild-moderate

(UCDAI 3-10)

NR Colonoscopic Standard colon

prep

x1 Chosen by

Recipient

12 weeks

Vaughn et al.

(2014). 9 CD Active CD (HBI>6) 50g in 250ml Saline Colonoscopic Standard colon

prep

x1 Healthy Unrelated 12 weeks

FMT IN CROHN’S DISEASE

Mild to moderate active disease

9 Patients

12-19 years of age

Medication therapy continued

Pre-FMT antibiotics

Nasogastric tube

Disease activity and microbiome

Follow up 2, 6, and 12 weeks

Suskind, et al Inflamm Bowel Dis 2015;0:1-8.

* Initiated Standard medical treatment prior to clinic visit

** Initiated Standard medical treatment after 12 week clinic visit

PEDIATRIC CROHN’S DISEASE ACTIVITY INDEX

(PCDAI)





10

* Initiated Standard medical treatment prior to clinic visit

** Initiated Standard medical treatment after 12 week clinic visit

Normal <0.8 mg/dL

C-REACTIVE PROTEIN (MG/DL)


FMT IN CROHN’S DISEASE

7 of 9 patients were in remission at 2 weeks

5 of 9 patients who did not receive additional medical therapy were in remission at 6 and 12 weeks

No or modest improvement was seen in patients who did not engraft or whose microbiome was most similar to their donor.

Suskind, et al Inflamm Bowel Dis 2015;0:1-8

FMT IN ULCERATIVE COLITIS

Studies suggest remission of disease is possible with multiple FMT’s for a subgroup of patients.





11

POTENTIAL FUTURE APPLICATIONS

Metabolic Disorders

Neuropsychiatric Disorders

Autoimmune Diseases

Allergic Disorders

Tumors

Meng-Que Xu, et al. World J. Gastroentol. 21(1), January 2015

CONCLUSION

• Fecal Microbiome is complex and biologically important in Health and Disease

• Fecal Microbiome modulates us, and we modulate our Fecal Microbiome

• FMT has impressive treatment success in cases of recurrent C. Difficile

• Role of FMT in other disease processes remains to be seen

• Further research is needed to move this discussion forward

REFERENCES

Bäckhed F, Ley RE, Sonnenburg JL, Peterson DA, Gordon JI. Host-bacterial mutualism in the human intestine. Science. 2005 Mar 25;307(5717):1915-20.

Hollister E., Gao C., Versalovic J. Compositional and functional features of the gastrointestinal microbiome and their effects on human health. Gastroenterology. 2014(146): 1449–1458.

Meng-Que X, Hai-Long C, Wei-Qiang W, Shan W, et al. Fecal microbiota transplantation broadening its application beyond intestinal disorders. World J Gastroenterol. 2015 Jan 7; 21(1): 102–111.

Pepin J, Valiquette L, Alary ME, et al. Clostridium difficile-associated diarrhea in a region of Quebec from 1991 to 2003: a changing pattern of disease severity. CMAJ. 2004;171:466-472.

Russell G, Kaplan, J, Ferraro M, Michelow I. Fecal microbiotherapy for relapsing Clostridium Difficile infection in a child: A proposed treatement protocol. Pediatrics. 2010 July; 126 (1).

Savage DC. Microbial ecology of the gastrointestinal tract. Annu Rev Microbiol. 1977;31:107-33.




12

REFERENCES (CONTINUED)

Suskind, et al. Fecal microbial transplant effect on clinical outcomes and fecal microbiome in active Chron’s Disease. Inflamm Bowel Dis 2015;0:1-8.

Smits LP, Bouter KE, de Vos WM, Borody TJ, Nieuwdorp M.Therapeutic potential of fecal microbiota transplantation. Gastroenterology. 2013 Nov;145(5):946-53.

Van Nood E, Vrieze A, Nieuwdorp M, et al. Duodenal infusion of donor feces for recurrent Clostridium difficile. N. Engl J Med. 2013;368:407–415.

Wu GD, Lewis JD. Analysis of the human gut microbiome and association with disease. Clin Gastroenterol Hepatol. 2013 Jul;11(7):774-7.

Xu MQ, Cao HL, Wang WQ, Wang S, Cao XC, Yan F, Wang BM. Fecal microbiota transplantation broadening its application beyond intestinal disorders. World J Gastroenterol. 2015 Jan 7;21(1):102-11

QUESTIONS?

advances in fecal microbiota transformation · smits lp, et al. gastroenterology 2013 fmt process...

Documents