On the horizon: Critical Care and the Microbiome - Hallie Prescott
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This is Hallie Prescott's presentation from the opening plenary session at the Intensive Care Society State of the Art Meeting 2018 Dr. Hallie Prescott is an Assistant Professor in Pulmonary & Critical Care Medicine at the University of Michigan and staff physician at the Ann Arbor Veterans Affairs Hospital. She leads grants on post sepsis morbidity and hospital performance measurement from the US National Institutes of Health and the US Department of Veteran’s Affairs. She is an expert in long-term outcomes and recovery after sepsis, with a focus on preventable hospital readmissions. She is co-chair of the Surviving Sepsis Campaign guidelines, inaugural Lowry-Fink fellow of the International Sepsis Forum (2017-2019), a former ANZICS Intensive Care Global Rising Star fellow (2015), and winner of the Early Career Achievement award from the American Thoracic Society’s Critical Care Assembly (2018).
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On the horizon: Critical Care and the Microbiome - Hallie Prescott
- 1. Hallie Prescott, MD, MSc ICS State of the Art LondonUK December10,2018 Critical Care and the Microbiome B17 - CRITICAL CARE: BURDEN OF SURVIVAL - OUTCOMES AFTER CRITICAL ILLNESS IN ADULTS AND CHILDREN @HalliePrescott
- 2. Disclosures • Funding: – NIH/NIGMS K08 GM115859 – US Department of Veterans Affairs IIR 17-219 • I am a VA employee. This talk does not represent views of US government or Department of Veterans Affairs
- 3. Human Microbiome: microorganisms that live within us
- 4. The forgotten organ of multi-organ failure “clinical guidelines on critical illness largely ignore the microbiome, neglecting what is, effectively, a 1.5 kg organ containing more DNA than every host organ combined.” Dickson, et al. Lancet Resp Med. 2016.
- 5. Overview Critical Illness/ Sepsis Microbiome Disruption • Critical illness (and it’s treatment) lead to microbiome disruption • Microbiome disruption increases risk for developing sepsis • Microbiome restoration may prevent/treat sepsis
- 6. Determinants of microbiome composition Dickson, et al. Lancet Resp Med. 2016. • Microbial immigration • Microbial emigration • Environmental Growth Conditions
- 7. Mechanisms of microbiome disruption in ICU Dickson, et al. Lancet Resp Med. 2016. Microbial immigration Microbial emigration Environmental Growth Conditions Pathophysiological Processes Clinical Interventions Poor PO Intake Supine Positioning Intestinal dysmotility Gastric-acid suppression Hyperglycemia Enteral feeding Electrolyte disturbance Parenteral feeding Gut hypoperfusion Sedatives Reperfusion injury Opiods Impaired mucosal integrity Neuromuscular blockage Endogenous opiod production Systemic catecholamines Endogenous catecholame production Oral decontamination Endogenous cytokine production Selective gut decontamination Disruption of intestinal mucus layer Systemic antibiotics Impaired mucosal immunity
- 8. With prolonged illness, there is near-complete depletion of the gut microbiome Zaborin, et al. MBio. 2014. McDonald, et al. mSphere. 2016.
- 9. With prolonged illness, there is near-complete depletion of the gut microbiome Zaborin, et al. MBio. 2014. “Extremely Low Microbiome Health” “Low Microbiome Health”
- 10. Overview Critical Illness/ Sepsis Microbiome Disruption • Critical illness (and it’s treatment) lead to microbiome disruption • Microbiome disruption increases risk for developing sepsis • Microbiome restoration may prevent/treat sepsis
- 11. Deshmukh, et al. Nature Medicine. 2014 Schuijt, et al. Gut. 2015. In experimental animal studies, microbiome disruption increases susceptibility to sepsis
- 12. Deshmukh, et al. Nature Medicine. 2014 Pregnant Mice Antibiotics No Antibiotics Offspring w/ normal gut microbiome Offspring w/ altered gut microbiome intraperitoneal E. coli instillation Immune Response? Survival? In experimental animal studies, microbiome disruption increases susceptibility to sepsis
- 13. Deshmukh, et al. Nature Medicine. 2014 In experimental animal studies, microbiome disruption increases susceptibility to sepsis Antibiotic pre-treatment: • Altered microbial composition • Impaired response to E.coli challenge (neutropenia, IL-17, GM-CSF) • Failure to survive E.coli inoculation Pregnant Mice Antibiotics No Antibiotics Offspring w/ normal gut microbiome Offspring w/ altered gut microbiome intraperitoneal E. coli instillation Immune Response? Survival?
- 14. In experimental animal studies, microbiome disruption increases susceptibility to sepsis Deshmukh, et al. Nature Medicine. 2014
- 15. In experimental animal studies, microbiome disruption increases susceptibility to sepsis Schuijt, et al. Gut. 2015.
- 16. In humans, antibiotic-associated gut microbiome disruption also alters some aspects of immune response Lankelma, et al. Clin Transl Gastroenterol. 2016. Day 8: less TNF-alpha production during ex vivo stimulation by LPS By 6 weeks: TNF-alpha response restored Broad spectrum antibiotics X 7 days No Antibiotics
- 17. In humans, antibiotic-associated gut microbiome disruption also alters some aspects of immune response Lankelma, et al. Gut. 2017. Day 9: Following IV infusion of LPS, immune response was not different Broad spectrum antibiotics X 7 days No Antibiotics
- 18. In humans, sepsis is increased transiently following microbiome perturbation Prescott, et al. AJRCCM. 2015
- 19. Prescott, et al. AJRCCM. 2015
- 20. Exposures: • Spectrum of antibiotics • Number of antibiotic classes • Duration of treatment Finding: Dose-response relationship More antibiotics increased risk of sepsis Baggs, et al. Clinical Infectious Diseases. 2017.
- 21. Lower Microbiome Health Greater Microbiome Health Montassier, et al. Genome Medicine. 2016.
- 22. Overview Critical Illness/ Sepsis Microbiome Disruption • Critical illness (and it’s treatment) lead to microbiome disruption • Microbiome disruption increases risk for developing sepsis • Microbiome restoration may prevent/treat sepsis
- 23. Restoring the microbiome improves survival Khailova, et al. Anesthesiology. 2013. Deshmukh, et al. Nature Medicine. 2014 Schuijt, et al. Gut. 2015. Wilmore, et al. Cell Host & Microbe. 2018
- 24. Deshmukh, et al. Nature Medicine. 2014 Restoring the microbiome improves survival
- 25. Schuijt, et al. Gut. 2015. Restoring the microbiome improves immune response Microbiota transplant at hour 6 lead to: • Normalization of bacterial counts in the lung • Normalization of TNF-alpha and IL-10
- 26. Interim summary • Microbiome disruption increases risk for sepsis in animals • Restoring microbiome improves outcome in animals • Microbiome disruption is common in critically ill patients • May impair immunity and increase risk for sepsis
- 27. Are we ready to test the microbiome as a therapeutic target? • To prevent sepsis in high-risk populations (ie. ICU patients, sepsis survivors) • As an adjunct treatment in refractory sepsis
- 28. 1. Probiotic therapy is effective at restoring the microbiome McFarland. BMJ Open. 2014. (A) Acute disruption (e.g. antibiotics, travelers diarrhea): 83% (B) Chronic disruption (e.g. inflammatory bowel disease): 56% (C) Healthy microbiome: 21%
- 29. Manzanares, et al. Crit Care. 2016. 2. Probiotics decrease all-cause infection in ICU patients
- 30. Cook, et al. Trials. 2016.
- 31. Panigrahi, et al. Nature. 2017. Relative risk = 0.60 NNT = 27 3. Probiotics reduce sepsis in term neonates
- 32. 4. Probiotic therapy is safe in most patients N=384 trials 72% reported harms, but description was often rated as inadequate. Basselink, et al. Lancet, 2008. Bafeta, et al. Annals Int Med. 2018. Cohen. JAMA Int Med. 2018. Use in healthy patients. Confer antibiotic resistance genes. Naso-jejunal tube administration along with high-fiber feeds Increased bowel ischemia, mortality
- 33. 5. Case reports suggest benefit in refractory sepsis Li, et al. Am J Gastro. 2014. Li, et al. Crit Care. 2015. Wei, et al. Crit Care. 2016.
- 34. Conclusions • Critical illness alters the microbiome • Microbiome disruption impairs our ability to fend off sepsis • Probiotics / fecal transplant may help prevent/cure sepsis • Sufficient mechanistic and safety data to justify larger trials • But… dosing, type, and the need to personalize?
- 35. Implications for Clinical Practice Today • Still give broad-spectrum antibiotics for sepsis • Stop antibiotics ASAP • When de-escalating, be wary of additional classes • Consider probiotic, esp if diarrhea, prolonged course
- 36. Questions @hallieprescott hprescot@med.umich.edu Please contact me for any slides or references from this talk.
Editor's Notes
- Increasingly recognized to be important for human health and disease
- However, the role of the microbiome in critical or acute illness has been somewhat under-appreciated. Despite a wealth of clinical and experimental evidence suggests that the microbiome is central to the pathogenesis of critical illness…
- However, the role of the microbiome in critical or acute illness has been somewhat under-appreciated. Despite a wealth of clinical and experimental evidence suggests that the microbiome is central to the pathogenesis of critical illness…
- However, the role of the microbiome in critical or acute illness has been somewhat under-appreciated. Despite a wealth of clinical and experimental evidence suggests that the microbiome is central to the pathogenesis of critical illness…
- In the review article that I mentioned at the beginning of the talk, there is a large table that lists a variety of pathophysiologic processes and clinical interventions common to critical illness. And, for each of these factors, the tables provides evidence on how the physiologic process or treatment leads to microbiome disruption through at least one of these 3 mechanisms. So, there is a lot of evidence the common physiological derangements and interventions of critical illness. But, maybe you are not convinced by this wealth of mechanistic evidence and want to see hard proof that human microbiome is deranged during critical illness.
- Next, I will show you evidence that microbiome disruption…
- Lastly, I will show you a study in humans that actually measured the microbiome. The investigators sequenced the stool of 28 patients undergoing BMT for NHL. They founf that pre-BMT fecal microbiome composition was strongly predictive of which patients went on to develop a BSI during the engraftment period. Here you can see that the diversity (or health) of the microbiome is lower in the patients who went on to develop BSI vs those who did not develop BSI. So, again, more data that the microbiome is important to resisting sepsis.
- Next, I will show you evidence that microbiome disruption…
- First, this is the same neonatal mouse study I showed previously. The mice who were exposed to antibiotics via their mother routinely died during subsequent bacterial challenge. However, mice given Abx and fecal microbiota transplant survived for longer. So, not curative, but there is an indication that probiotics are doing something.
- Lactobacillus planatarum