Gut microbiome and plasma metabolic signatures of one-carbon metabolism differentiate oedematous and non-oedematous severe acute malnutrition

Childhood severe acute malnutrition (SAM) occurs as either classical wasting (non-oedematous-SAM; NO-SAM) or with the presence of oedema (oedematous SAM; O-SAM). Both forms of SAM have distinct mortality and nutritional recovery rates, however, the underlying pathophysiology is poorly understood. We collected stool for whole metagenome shotgun sequencing and plasma for metabolic phenotyping from 238 children (79 NO-SAM, 159 O-SAM) hospitalised with complicated SAM and 141 adequately-nourished controls (ANC) from an observational, prospective cohort in Zimbabwe and Zambia. Children with SAM were followed up at 12-, 24- and 48-weeks post-discharge. During hospitalisation, there were significant alterations in taxonomic and functional microbiome diversity between O-SAM and NO-SAM. Lancefieldella parvula , a potent producer of hydrogen-sulfide from cysteine, was one of three species significantly elevated in O-SAM versus NO-SAM. Metagenomic analysis showed an overabundance of pathways involved in sulfur amino-acid and one-carbon metabolism in O-SAM compared to NO-SAM. Consistently, the sulfur amino acids cysteine and homocysteine were significantly depleted in the plasma of O-SAM versus NO-SAM, while histidine and various phosphatidylcholines were more abundant. During follow-up, O-SAM and NO-SAM microbiomes remained divergent up to 24 weeks post-discharge whilst alpha diversity recovery was delayed in NO-SAM. Plasma metabolomes also remained significantly different between O-SAM, NO-SAM and ANC throughout 48 weeks of follow-up. These findings demonstrate that distinct microbiome profiles may drive disturbance of systemic one-carbon metabolism in O-SAM and highlight persistent microbiome and metabolic dysfunction during nutritional recovery. This work supports further studies targeting the gut microbiome to correct metabolic disturbances and improve long-term clinical outcomes in complicated SAM.