Malnutrition & the Microbiome

1. Malnutrition& the Microbiome Prof James A Berkley

2. Terminology • Malnutrition • “Insufficient nutrient intake to preserve normal growth and function” • In practice = low anthropometric status • micronutrients and metabolism ??? • Immunity • Dysbiosis • Etc…

3. Malnutrition Reduced nutrient intake Energy cost of illness Nutrient losses ↓ immunity Infection

4. Malnutrition ↓ Growth ↓ Repair Microbiome Reduced nutrient intake Energy cost of illness Nutrient loss Defective barriers:skin, gut, respiratory ↓ immunity Infection: ↑ Susceptibility ↑ Severity ↑ Duration

5. Micronutrients Energy metabolism Gut mucus layer Short chain fatty acids Nutrient processing Amino acids Entero-pathogens Malnutrition Neuro-transmitters Appetite Mood Gut immune responses Gut inflammation Systemic inflammation

6. Persistent Gut Microbiota Immaturity in Malnourished Bangladeshi Children Nature. 2014 June 19; 510(7505): 417–421.

7. Persistent Gut Microbiota Immaturity in Malnourished Bangladeshi Children Nature. 2014 June 19; 510(7505): 417–421.

8. Persistent Gut Microbiota Immaturity in Malnourished Bangladeshi Children Nature. 2014 June 19; 510(7505): 417–421.

9. Persistent Gut Microbiota Immaturity in Malnourished Bangladeshi Children (validation in Malawi) Nature. 2014 June 19; 510(7505): 417–421.

10. Persistent Gut Microbiota Immaturity in Malnourished Bangladeshi Children Nature. 2014 June 19; 510(7505): 417–421.

11. Malawi

13. Therapeutics? • Water, Sanitation & Hygiene? • Probiotics? • Diet and pre-biotic foods? • Antimicrobials

14. HIV trial HR 0.57

15. Growth: Antibiotics in Animal Husbandry Clean Quarters Contaminated Quarters Eyssen et al. J Exp Med. 1963 January 1; 117(1): 127–138.

16. Hypothesis: co-trimoxazole in SAM (HIV-negative) Antimicrobial Prophylaxis ↓ Immune activation Microbiome ↑ Growth & Repair ↓ Infection ↓ Mortality

17. Co-trimoxazole prophylaxis in complicated SAM(HIV-negative) Hazard Ratio 0.90 (0.71 to 1.16) P=0.429 Placebo Cotrimoxazole

18. Growth Weight for Length Z Score MUAC cm Length for Age Z score Head Circum. for Age Z Score

19. Cotrimoxazole reduces systemic inflammation in HIV infection by altering the gut microbiome and immune activation Bourke et. al. Science Translational Medicine  03 Apr 2019:Vol. 11, Issue 486, eaav0537

20. Cotrimoxazole reduces systemic inflammation in HIV infection by altering the gut microbiome and immune activation Bourke et. al. Science Translational Medicine  03 Apr 2019:Vol. 11, Issue 486, eaav0537

21. Phase 1 (2016-2017) • PK ceftriaxone & metronidazole • Faecal carriage of ESBL in SAM/non-SAM • Phase 2 (2017-2020) • 2x2 factorial trial  Mortality, toxicity, readmission, growth • Pen/Gent vs Ceftriaxone (Sepsis, AMR) • Metronidazole vs Placebo (SIBO, parasites)

22. FLACSAM Schedule Screening at admission to hospital, information & consent Study drugs Follow up Discharge d7 d14 d45 d90

23. ENDPOINTS • Mortality to 90d • By time: 48h, 7d, inpatient, post-discharge • By causes • Growth to 90d – absolute MUAC • Toxicity • Weight for height • Height for age • Microbiome • Antibiotic usage, days on 1st, 2nd & 3rd line antimicrobials • AMR carriage and disease

25. CHAIN Cohort Deaths, readmissions & final anthropometry Household Survey Follow up Admission Discharge Day 45 Day 90 Day 180

26. Pakistan 1 site Bangladesh 2 sites West Africa 1 site Uganda 1 site Kenya 3 sites Malawi 1 site

28. SAM MAM Well-nourished

29. Thank you