Causal association between gut microbiota and neonatal digestive system diseases: A Mendelian randomization study

To delve into the underlying causal connections that may exist between the intestinal flora and disorders of the neonatal digestive system (DSD), aiming to identify specific pathogenic bacteria associated with the development and progression of neonatal DSD. We collected summary statistics from genome-wide association studies on neonatal DSD and gut microbiome-related phenotypes from the Finngen and MiBioGen consortia. We conducted a bidirectional, two-sample Mendelian randomization (MR) analysis to detect causal relationships between the gut microbiome and neonatal DSD. Data on 211 gut microbiome species were obtained from samples of various ethnicities (16,380,466 samples). DSD data were sourced from 143 cases and 218,649 control samples of European ancestry. Single nucleotide polymorphisms were chosen as instrumental variables in accordance with precise selection criteria. We primarily employed inverse variance weighted meta-analysis, supplemented by weighted median, MR-Egger, weighted mode, and simple mode analyses. Results were assessed using odds ratios (OR) and 95% confidence intervals (CI). Sensitivity analyses, including heterogeneity tests, horizontal pleiotropy tests, and Steiger directionality tests, were performed to rigorously examine and validate the stability and reliability of our findings. The inverse variance weighted methodology yields strong indications of a direct causality between 6 identified microbial species and neonatal DSD. Genus Lachnospiraceae UCG010, genus Peptococcus, and genus Tyzzerella3 Correlated with a heightened likelihood of neonatal DSD, with genus Lachnospiraceae UCG010 showing the highest risk (OR = 4.49, P = .034, 95% CI [1.13-17.89]). Conversely, Bacilli, genus Allisonella, and phylum Proteobacteria were associated with a reduced risk of neonatal DSD, with phylum Proteobacteria showing the lowest risk (OR = 0.23, P = .03, 95% CI [0.06-0.88]). Q-tests indicated no heterogeneity in these results, and MR-Egger tests showed no significant horizontal pleiotropy. Leave-one-out sensitivity analyses did not identify any Single nucleotide polymorphisms with a substantial impact on the overall results. Our study elucidates a clear causal relationship between the gut microbiome and neonatal DSD, identifying 6 specific microbial taxa with potential pathogenic roles. These results offer novel perspectives on potential therapeutic interventions and the underlying processes of neonatal DSD.