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The 16p11.2 microdeletion influences how early-life microbiota perturbations affect hippocampal development and
Courtney R McDermott1, Zhan Gao2, Anya S Mirmajlesi3
1Mortimer B. Zuckerman Mind Brain and Behavior Institute, Columbia University, NY.
Insights
Early antibiotic exposure alters the gut microbiome and behavior in mice. Genetic mutations like 16p11.2 microdeletion can worsen these neurodevelopmental effects, impacting brain development and raising concerns about infant antibiotic use.
Area of Science:
- Neuroscience
- Microbiology
- Genetics
Background:
- Neurodevelopmental disorders arise from genetic and environmental factors, with infancy being a critical developmental window.
- Early-life antibiotic exposure is a potential environmental risk factor impacting gut microbiome and neurodevelopment.
- The 16p11.2 microdeletion (16pDel) is associated with neurodevelopmental disorders and may influence responses to environmental insults.
Purpose of the Study:
- To investigate the impact of short-term antibiotic exposure (cefdinir) during early postnatal life on the gut microbiome, neurodevelopment, and behavior.
- To determine if the 16p11.2 microdeletion exacerbates antibiotic-induced alterations in neurodevelopment and behavior.
- To explore potential gastrointestinal and metabolic mechanisms underlying these effects.
Main Methods:
- Longitudinal study design in a mouse model.
- Administration of cefdinir during early postnatal life.
- Analysis of gut microbiome composition, behavioral assessments (sociability, risk assessment, learning), hippocampal stem cell proliferation, cell numbers, gene expression, intestinal permeability, and metabolite profiling.
Main Results:
- Cefdinir acutely altered the gut microbiome, causing persistent reductions in certain Lachnospiraceae genera.
- Antibiotic exposure led to long-term behavioral changes, including reduced sociability and learning deficits.
- Cefdinir-exposed 16pDel mice exhibited unique alterations in hippocampal stem cell proliferation, adolescent cell numbers, and gene expression compared to other groups.
- Gastrointestinal disturbances, including increased intestinal permeability and altered metabolite profiles (arginine biosynthesis, glycerophospholipid metabolism), were observed in cefdinir-exposed 16pDel males.
Conclusions:
- Early-life microbial alterations induced by antibiotics can affect behavior and neurodevelopment.
- Genetic predisposition (16p11.2 microdeletion) modulates the impact of early-life antibiotic exposure on hippocampal development.
- Metabolic pathways in the gut may mediate these effects, suggesting potential targets for intervention.
- Findings raise concerns regarding the use of antibiotics during infancy due to potential long-term neurodevelopmental consequences.
Abstract:
Neurodevelopmental disorders result from interactions between genetic predisposition and environmental risk factors, with infancy being the most vulnerable period. We designed a longitudinal study to determine how short-term antibiotic exposure during early postnatal life impacts the gut microbiome, neurodevelopment, and behavior, and whether these alterations were exacerbated by the neurodevelopmental disorder-associated 16p11.2 microdeletion (16pDel) mutation. The cephalosporin antibiotic, cefdinir, broadly altered the gut microbiome acutely, with persistent reductions in several Lachnospiraceae genera despite overall recovery. These alterations preceded long-term behavioral changes, including reduced juvenile sociability, compromised risk assessment, and deficits in associative learning. Remarkably, only cefdinir-exposed 16pDel mice had changes in hippocampal stem cell proliferation, subsequent adolescent cell numbers, and gene expression compared to other groups, demonstrating that genetic predisposition can modulate the effects of early-life antibiotic exposure on neurodevelopment. These alterations may be mediated by gastrointestinal disturbances, as cefdinir-exposed 16pDel males had increased intestinal permeability and shifted metabolite profiles including arginine biosynthesis and glycerophospholipid metabolism. Taken together, this study highlights how early-life microbial alterations affect behavior and reveals that genetic predisposition influences antibiotic-induced changes in hippocampal development. Further, these insights identify metabolic mechanisms as potential targets for intervention and may raise concerns regarding antibiotic use during infancy.
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