García-Mauriño Alcázar, Cristina; (2023) The neonatal gut microbiota and its association with viral respiratory disease in the first two years of life. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

My thesis hypothesises that early life gut microbiota is associated with childhood viral lower respiratory tract infections (vLRTI). I used data from the Baby Biome Study (BBS), a UK birth cohort of mother-baby pairs enrolled between 2016-2017 at three UK hospitals. Baby stool samples were collected for shotgun-metagenomic sequencing in the first and third weeks of life. I examined first-week gut microbiota diversity, and cluster composition stratified by birth mode, and followed up babies through electronic data linkage to Hospital Episode Statistics (HES) and parental questionnaires to determine vLRTI hospital admissions. I conducted longitudinal and cross-sectional analyses, adjusting for confounders identified through direct acyclic graphs, to explore the association between early gut microbiota and vLRTI hospital admissions in the first two years of life. Among BBS babies (n=3,305), 48% were born by caesarean section, 92% were born at term (>=37w gestational age), and 1,082 had a sequenced first-week stool sample. HES data linkage was successful for 3,253 (98.4%), with a median follow-up of two years (IQR 1.5-2.9 years). Higher gut microbiota alpha diversity at one week was associated with reduced rates of vLRTI hospital admissions (Chao1 Index: Adjusted HR (AHR) 0.92 (95% CI 0.85-0.99); Shannon Index AHR 0.57 (0.33-0.98)). Two microbiota clusters were identified in vaginally born and c-section babies; Cluster 1 had a mixed bacterial composition, while Cluster 2 was dominated by Bifidobacterium breve. A third cluster, exclusive to babies born vaginally, was dominated by Bifidobacterium Longum. Being in Clusters 1 and 2 was associated with increased rates of vLRTI admissions compared to Cluster 3 (Cluster 1 vs 3 [AHR 2.79 (1.35-5.79)]; Cluster 2 vs 3 [AHR 2.30 (1.04-5.10)]). No associations between bacterial relative abundance and vLRTI admissions were observed. However, the presence of Bacteroides dorei (AHR 0.09 (0.01-0.70) and Rocia mucilaginosa (ARR 1.82 (1.10-3.04) was associated with vLRTI admissions in opposite directions. First week higher alpha diversity, Cluster 3 composition, and the presence of B. dorei were independently associated with lower rates of vLRTI hospital admission in early life. This might have important implications for future preventative biotherapies.

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