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The Gut Microbiome

MICROBIAL VOLUME AND DIVERSITY

THE GUT MICROBIOME IS COMPOSED OF HIGHLY DIVERSE MICROORGANISMS LIVING IN THE HUMAN INTESTINAL TRACT

Considered a distinct and essential organ within the human body, the gut microbiome contains 100 trillion microorganisms and consists of an estimated 500-1000 different species.1-4

Microbiome composition

Common bacterial phyla in the gut1,5:

  • Bacteroidetes
  • Firmicutes
  • Proteobacteria
  • Actinobacteria
  • Fusobacteria
  • Verrucomicrobia

Comprise ~90% of microbiota

References: 1. Thursby E, Juge N. Biochem J. 2017;474(11):1823-1836. 2. Gilbert JA, et al. Nat Med. 2018;24(4):392-400. 3. Antharam VC, et al. J Clin Microbiol. 2013;51(9):2884-2892. 4. Marchesi JR, et al. Gut. 2016;65(2):330-339. 5. Jandhyala SM, et al. World J Gastroenterol. 2015;21(29):8787-8803. 6. Wexler AG, Goodman AL. Nat Microbiol. 2017;2(1):17115. 7. Rinninella E, et al. Microorganisms. 2019;7(1):14. 8. Gill SR, et al. Science. 2006;312(5778):1355-1359. 9. Kurokawa K, et al. DNA Res. 2007;14(4):169-181. 10. Li X, et al. Biomed Pharmacother. 2021;137:111290. 11. Kho ZY, Lal SK. Front Microbiol. 2018;9(1835):1-23. 12. Sokol H, et al. Proc Natl Acad Sci USA. 2008;105(43):16731-16736. 13. Willing BP, et al. Gastroenterology. 2010;139(6):1844-1854.e1. 14. Machiels K, et al. Gut. 2014;63(8):1275-1283. 15. Paust S, et al. Proc Natl Acad Sci USA. 2004;101(28):10398-10403. 16. El Aidy S, et al. Mucosal Immunol. 2012;5(5):567-579. 17. Lawley TD, Walker AW. Immunology. 2013;138(1):1-11. 18. Herrera G, et al. Sci Rep. 2021;11(1):10849. 19. Theriot CM, Young VB. Annu Rev Microbiol. 2015;69:445-461.

BACTEROIDETES and FIRMICUTES

MICROBIAL VOLUME AND DIVERSITY

BACTEROIDETES AND FIRMICUTES ARE MOST PREVALENT IN THE GUT MICROBIOME AND WORK SYMBIOTICALLY6-8

Bacteroides

Gram-negative Bacteroidetes
Their ability to adapt and persist in changing gut environments allows abundance and stability,6,9-11 providing long-term associations with human hosts and enabling functions that include6..

  • Immunomodulatory effects6,a
  • Inhibitory activities against C. diff and reduction of colonization12,a,b
Firmicutes

Gram-positive Firmicutes
Composed of helpful and harmful bacteria,3,13 Firmicutes are the most abundant and diverse bacterial gut species,3 with functions that include:

  • Anti-inflammatory effects14-16,c
  • Fortification of gut barrier (along with other bacteria)17-19,b

aSome Bacteroidetes. bIn preclinical studies. cDemonstrated in Crohn's disease, inflammatory bowel disease, and ulcerative colitis studies.

Deficiencies in
Bacteroidetes and
Firmicutes are
particularly
associated with
C. diff infection.3,8,20

References: 1. Thursby E, Juge N. Biochem J. 2017;474(11):1823-1836. 2. Gilbert JA, et al. Nat Med. 2018;24(4):392-400. 3. Antharam VC, et al. J Clin Microbiol. 2013;51(9):2884-2892. 4. Marchesi JR, et al. Gut. 2016;65(2):330-339. 5. Jandhyala SM, et al. World J Gastroenterol. 2015;21(29):8787-8803. 6. Wexler AG, Goodman AL. Nat Microbiol. 2017;2(1):17115. 7. Rinninella E, et al. Microorganisms. 2019;7(1):14. 8. Gill SR, et al. Science. 2006;312(5778):1355-1359. 9. Kurokawa K, et al. DNA Res. 2007;14(4):169-181. 10. Li X, et al. Biomed Pharmacother. 2021;137:111290. 11. Kho ZY, Lal SK. Front Microbiol. 2018;9(1835):1-23. 12. Sokol H, et al. Proc Natl Acad Sci USA. 2008;105(43):16731-16736. 13. Willing BP, et al. Gastroenterology. 2010;139(6):1844-1854.e1. 14. Machiels K, et al. Gut. 2014;63(8):1275-1283. 15. Paust S, et al. Proc Natl Acad Sci USA. 2004;101(28):10398-10403. 16. El Aidy S, et al. Mucosal Immunol. 2012;5(5):567-579. 17. Lawley TD, Walker AW. Immunology. 2013;138(1):1-11. 18. Herrera G, et al. Sci Rep. 2021;11(1):10849. 19. Theriot CM, Young VB. Annu Rev Microbiol. 2015;69:445-461.

Role in overall Health

MICROBIAL VOLUME AND DIVERSITY

THE BROAD CONSORTIUM OF BACTERIA WITHIN THE GUT MICROBIOME FUNCTIONS TO PROMOTE OVERALL HEALTH

Intestine

Aids in health digestive function19

Check mark

Protects from harmful  microorganisms and plays a role in immunity19

Barrier

Acts as a barrier and achieves colonization resistance1,19

References: 1. Thursby E, Juge N. Biochem J. 2017;474(11):1823-1836. 2. Gilbert JA, et al. Nat Med. 2018;24(4):392-400. 3. Antharam VC, et al. J Clin Microbiol. 2013;51(9):2884-2892. 4. Marchesi JR, et al. Gut. 2016;65(2):330-339. 5. Jandhyala SM, et al. World J Gastroenterol. 2015;21(29):8787-8803. 6. Wexler AG, Goodman AL. Nat Microbiol. 2017;2(1):17115. 7. Rinninella E, et al. Microorganisms. 2019;7(1):14. 8. Gill SR, et al. Science. 2006;312(5778):1355-1359. 9. Kurokawa K, et al. DNA Res. 2007;14(4):169-181. 10. Li X, et al. Biomed Pharmacother. 2021;137:111290. 11. Kho ZY, Lal SK. Front Microbiol. 2018;9(1835):1-23. 12. Sokol H, et al. Proc Natl Acad Sci USA. 2008;105(43):16731-16736. 13. Willing BP, et al. Gastroenterology. 2010;139(6):1844-1854.e1. 14. Machiels K, et al. Gut. 2014;63(8):1275-1283. 15. Paust S, et al. Proc Natl Acad Sci USA. 2004;101(28):10398-10403. 16. El Aidy S, et al. Mucosal Immunol. 2012;5(5):567-579. 17. Lawley TD, Walker AW. Immunology. 2013;138(1):1-11. 18. Herrera G, et al. Sci Rep. 2021;11(1):10849. 19. Theriot CM, Young VB. Annu Rev Microbiol. 2015;69:445-461.

Dysbiosis Factors

DYSBIOSIS AND C. diff Infection

DYSBIOSIS IS MOST OFTEN CAUSED BY ENVIRONMENTAL FACTORS, INCLUDING ANTIBIOTICS1

HOMEOSTASIS

Normal microbiome

During homeostasis, the microbiota is composed of diverse organisms known to benefit host health

STRESS DIET HYGIENE USE OF ANTIMICROBIALS
Arrow

DYSBIOSIS

Less healthy microbiomePathobiont
expansion
Microbiome with less diversityReduced
diversity
Unhealthy microbiomeLoss of beneficial microbes

Dysbiosis is the disruption of the
composition and/or diversity of the
gut microbiome

References: 1. Petersen C, Round JL. Cellular Microbial. 2014;16(7):1024-1033. 2. Bien J, et al. Ther Adv Gastroenterol. 2013;6(1):53-68. 3. Staley C, et al. Arch Med Res. 2017;48(8):766-773.

Gut Microbiota Disruption

DYSBIOSIS AND C. diff Infection

DISRUPTION OF THE GUT MICROBIOME LEADS TO AN ENVIRONMENT SUITED FOR THE PROLIFERATION OF CLOSTRIDIOIDES DIFFICILE 2,3

The gut microbiota generally play a role in colonization resistance by which the native organisms prevent pathogenic microbes from flourishing.2,3

When the relationship between the gut and its healthy flora becomes imbalanced, dysbiosis results...leading to an intestinal microenvironment susceptible to pathogenic insult from opportunistic bacteria, such as C. diff—capable of causing a wide spectrum of symptoms ranging from mild diarrhea to sepsis.2

References: 1. Petersen C, Round JL. Cellular Microbial. 2014;16(7):1024-1033. 2. Bien J, et al. Ther Adv Gastroenterol. 2013;6(1):53-68. 3. Staley C, et al. Arch Med Res. 2017;48(8):766-773.

C. diff Infection: An Urgent Threat

CLOSTRIDIOIDES DIFFICILE INFECTION DECLARED AN URGENT PUBLIC HEALTH THREAT1

C. diff bacteria

C. diff emerged as an important pathogen, following the introduction of broad-spectrum antibiotics2

US map

An increase in severe cases of CDI was noted in Canada, the United States, and Europe, which was attributed to the emergence of epidemic types of C. difficile3

Hypervirulent NAP1/B1/027 strain emerges in North America and Europe4

Hospital bed

Reported that CDI eclipsed methicillin-resistant Staphylococcus aureus (MRSA) as the leading hospital onset healthcare-facility-related infection5,6

Alert symbol

CDC identified CDI as an URGENT PUBLIC HEALTH THREAT1,a

CDC = US Centers for Disease Control and Prevention.

aCDC defines urgent threats as those that may not be currently widespread but have the potential to become so and require urgent public health attention to identify infections and to limit transmission.1

References: 1. Centers for Disease Control and Prevention. https://www.cdc.gov/drugresistance/pdf/ar-threats-2013-508.pdf. Accessed August 31, 2021. 2. Kelly CP. Clin Microbiol Infect. 2012;18(suppl 6):21-27. 3. Smits WK, et al. Nat Rev Dis Primers 2016;2:16020. 4. Fatima R, Aziz M. Cureus. 2019;11(1):e3977. 5. Lessa FC, et al. N Engl J Med. 2015;372(9):825-834. 6. Miller BA, et al. Infect Control Hosp Epidemiol. 2011;32(4):387-390.

Clinical Burden

CLINICAL BURDEN OF C. DIFF INFECTION

A VICIOUS CYCLE OF RECURRENCE WITH A SIGNIFICANT BURDEN1,2

Significant complications associated with CDI

Recurrence

Recurrence:

Up to 35%3,4,a
Subsequent recurrence

Subsequent Recurrence:

Up to 60%5-9
Sepsis

Sepsis:

27%6
Colectomy

Colectomy:

7%10,b
Heart Failure

Heart Failure:

43%9
Mortality

Mortality:

6%3
Virus

Mortality in patients with COVID-19 and CDI: 44%8

Virus

Financial Burden

RECURRENT C. DIFF INFECTION BURDEN

RECURRENT CDI (RCDI) AFFECTS PATIENT QUALITY OF LIFE, HOSPITAL QUALITY METRICS, AND REIMBURSEMENT

  • Patient in bed
    Up to 85% of all patients with rCDI were hospitalized in 12 months12
  • Patient
    57% of patients with at least one CDI recurrence experienced ≥2 admissions within 12 months9
  • Calendar
    Hospitalizations average 18 days for patients with rCDI9
  • Patient readmission
    84% of patients with rCDI are readmitted12
  • Dollar sign
    −$3K to −$29K gap exists in reimbursement per patient13
  • Hospital
    $131K to $207K comprised total cost of a patient with rCDI13

Physical/Psychological Burden

PHYSICAL/PSYCHOLOGICAL RECURRENT C. DIFF INFECTION BURDEN

THE PHYSICAL AND PSYCHOLOGICAL IMPACT OF RECURRENT CDI IS HIGH15

In an observational, cross-sectional study surveying 350 self-reported patients with CDI15

Person holding head

~41%

believed they would never get rid of post-CDI symptoms

Used with permission from Creative Commons. https://creativecommons.org/licenses/by/4.0/legalcode.15

aWithin 8 weeks after initial C. diff infection diagnosis.
bFirst recurrence.

References: 1. Centers for Disease Control and Prevention. https://www.cdc.gov/drugresistance/pdf/threats-report/clostridioides-difficile-508.pdf. Accessed August 25, 2021. 2. Feuerstadt P, et al. J Med Econ. 2020;23(6):603-609. 3. Lessa FC, et al. N Engl J Med. 2015;372(9):825-834. 4. Cornely OA, et al. Clin Infect Dis. 2012;55(suppl 2):s154-s161. 5. Leong C, Zelenitsky S. Can J Hosp Pharm. 2013;66(6):361-368. 6. Kelly CP. Clin Microbiol Infect. 2012;18(suppl 6):21-27. 7. Riddle DJ, et al. Infect Dis Clin North Am. 2009;23(3):727-743. 8. Smits WK, et al. Nat Rev Dis Primers. 2016;2:16020. 9. Nelson WW, et al. J Manag Care Spec Pharm. 2021;27(7):828-838. 10. Feuerstadt P, et al. SAGE Open Med. 2021;9:2050312120986733. 11. Sandhu A, et al. Emerg Infect Dis. 2020;26(9):2272-2274. 12. Rodrigues R, et al. Infect Control Hosp Epidemiol. 2017;38(2):196-202. 13. McDonald LC, et al. Clin Infect Dis. 2018;66(7):e1-e48. 14. Zilberberg MD, et al. Medicine. 2018;97(36):e12212. doi:10.1097/MD.0000000000012212. 15. Lurienne L, et al. J Patient Rep Outcomes. 2020;4(1):14.

Current Standard of care

STANDARD OF CARE MAY BE INCOMPLETE

THE STANDARD OF CARE FOR CDI IS ALSO A PREDOMINANT RISK FACTOR FOR RECURRENCE1-3

Up to 35% of patients with CDI will experience recurrence within 8 weeks after initial CDI diagnosis.4,5

CDI recurrence

Antibiotic treatment is commonly associated with high rates of rCDI because it6

  • Does not address the
    underlying dysbiosis
  • Has a deleterious impact
    on the microbiota
  • Negatively impacts colonization resistance

References: 1. DePestel DD, et al. J Pharm Pract. 2013;26(5):464-475. 2. Knight CL, Surawicz CM. Med Clin North Am. 2013;97(4):523-536. 3. Aukes L, et al. Open Forum Infect Dis. 2021;8(3):ofab052. 4. Lessa FC, et al. N Engl J Med. 2015;372(9):825-834. 5. Cornely OA, et al. Clin Infect Dis. 2012;55(suppl 2):s154-s161. 6. Antharam VC, et al. J Clin Microbiol. 2013;51(9):2884-2892. 7. Fitzpatrick F, et al. Clin Microbiol Infect. 2012;18(suppl 6):2-4. 8. van Nood E, et al. N Engl J Med. 2013;368(5):407-415.

Gut Microbiome Restoration

STANDARD OF CARE MAY BE INCOMPLETE

RESTORING A HEALTHY GUT MICROBI0ME IS ESSENTIAL

Thus starts a cycle of C. diff infection and reinfection—impeding microbiome recovery, exacerbating morbidity, and creating a substantial economic burden.7

References: 1. DePestel DD, et al. J Pharm Pract. 2013;26(5):464-475. 2. Knight CL, Surawicz CM. Med Clin North Am. 2013;97(4):523-536. 3. Aukes L, et al. Open Forum Infect Dis. 2021;8(3):ofab052. 4. Lessa FC, et al. N Engl J Med. 2015;372(9):825-834. 5. Cornely OA, et al. Clin Infect Dis. 2012;55(suppl 2):s154-s161. 6. Antharam VC, et al. J Clin Microbiol. 2013;51(9):2884-2892. 7. Fitzpatrick F, et al. Clin Microbiol Infect. 2012;18(suppl 6):2-4. 8. van Nood E, et al. N Engl J Med. 2013;368(5):407-415.

Historic approach to restoration

LIMITATIONS OF CURRENT THERAPEUTIC OPTIONS

ONE HISTORIC APPROACH TO MICROBIOME RESTORATION
IS FECAL MICROBIOTA TRANSPLANTATION (FMT)1

Healthy Donor

Stool is harvested from a healthy donor

PATIENT WITH rCDI

Fecal sample is transplanted into the patient with rCDI

After FMT

The organisms from the donor sample restore a healthy gut microbiome in the patient

transpantation

References: 1. American Gastroenterological Association. https//www.gastro.org/practice-guidance/gi-patient-center/topic/fecal-microbiota-transplantation-fmt. Accessed August 31, 2021. 2. Tariq R, et al. Clin Infect Dis. 2019;68(8):1351-1358. 3. Bafeta A, et al. Ann Intern Med. 2017;167(1)34-39. 4. Joseph J, et al. Clin Transi Sci. 2019;12(3)206-208. 5. Guh AY, et al. N Engl J Med. 2020;382(14):1320-1330. 6. McDonald LC, et al. Clin Infect Dis. 2018;66:el-e48.

Limitations of current options

Limitations of Current Therapeutic Options

SEVERAL LIMITATIONS ARE FOUND ACROSS CLINICAL STUDIES,
DIAGNOSIS, AND TREATMENT

THERE IS VARIABILITY ACROSS CLINICAL TRIALS

Cure rates were lower in randomized controlled trials than in open-label studies (67.7% vs 82.7%, respectively; P<.001).2

This inconsistency is due to considerable heterogeneity among randomized controlled trials, with marked differences in study structure, control groups, fecal transplant materials, and outcome assessments.2,3

LACK OF
STANDARDIZATION

Likewise, the lack of product standardization and administration methods has created a situation where a regulated, safe, and effective product is critically needed.4

PATIENTS ENROLLED IN CLINICAL TRIALS MAY NOT BE A TRUE REFLECTION OF PATIENTS SEEN IN THE REAL WORLD

Strict inclusion and exclusion criteria in randomized controlled trials lead to inclusion of a small portion of patients from daily clinical practice, limiting generalizability of results to patients seen in clinical practice.2

CDI TESTING IS INCONSISTENT IN CLINICAL PRACTICE

There is no gold standard: sensitivity and specificity of current toxin tests for CDI are highly variable. Moreover, in the US, there is no consensus on best diagnostic testing for CDI.5,6

OUR
COMMITMENT

Ferring is committed to exploring the potential of a microbiome-based therapeutic that is studied in a comprehensive population reflective of routine clinical practice for the treatment of recurrent C. difficile infection.

References: 1. American Gastroenterological Association. https//www.gastro.org/practice-guidance/gi-patient-center/topic/fecal-microbiota-transplantation-fmt. Accessed August 31, 2021. 2. Tariq R, et al. Clin Infect Dis. 2019;68(8):1351-1358. 3. Bafeta A, et al. Ann Intern Med. 2017;167(1)34-39. 4. Joseph J, et al. Clin Transi Sci. 2019;12(3)206-208. 5. Guh AY, et al. N Engl J Med. 2020;382(14):1320-1330. 6. McDonald LC, et al. Clin Infect Dis. 2018;66:el-e48.

The New Frontier

RESTORE THE GUT MICROBIOME

RESTORE HOPE IN PATIENTS WITH RECURRENT C. diff INFECTION

Further research is essential to ensure availability of a safe, effective, and standardized microbiota-based therapeutic that can help—along with antibiotic treatment—restore the microbiome and break the vicious cycle of recurrent C. diff infection.

References: 1. American Gastroenterological Association. https//www.gastro.org/practice-guidance/gi-patient-center/topic/fecal-microbiota-transplantation-fmt. Accessed August 31, 2021. 2. Tariq R, et al. Clin Infect Dis. 2019;68(8):1351-1358. 3. Bafeta A, et al. Ann Intern Med. 2017;167(1)34-39. 4. Joseph J, et al. Clin Transi Sci. 2019;12(3)206-208. 5. Guh AY, et al. N Engl J Med. 2020;382(14):1320-1330. 6. McDonald LC, et al. Clin Infect Dis. 2018;66:el-e48.