Malnutrition & the Microbiome Prof James A Berkley

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

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

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

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

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

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

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

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

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

Malawi

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

HIV trial HR 0.57

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

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

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

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

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

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

Phase 1 (2016-2017) Phase 2 (2017-2020) 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)

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

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

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

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

SAM MAM Well-nourished

Thank you