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

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

5. Systemic inflammation
Energy metabolism
Micronutrients
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 June 19; 510(7505): 417–421.

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

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

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

10. Persistent Gut Microbiota Immaturity in Malnourished Bangladeshi Children
Nature 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. Contaminated Quarters
Growth: Antibiotics in Animal Husbandry
Clean Quarters
Contaminated Quarters
Eyssen et al. J Exp Med January 1; 117(1): 127–138.

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

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) Phase 2 (2017-2020) PK ceftriaxone & metronidazole
Faecal carriage of ESBL in SAM/non-SAM
Phase 2 ( )
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
Follow up
Study drugs
Discharge
d d d d90

23. ENDPOINTS Mortality to 90d Growth to 90d – absolute MUAC
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 Follow up
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