Prenatal exposure to environmental stressors alters gut macrophage development and gastrointestinal function of male offspring

Introduction

More and more studies point at the critical role of environmental factors in shaping developmental outcomes. To give but one example, exposure to immune challenges during pregnancy, whether through infections, toxicants, or maternal health issues, can significantly increase the risk of neurodevelopmental disorders (NDDs) like autism. What’s particularly intriguing is that recent findings point to the gut-brain axis as a central player in this process.

Many individuals diagnosed with NDDs also experience common gastrointestinal problems, such as gastritis, diarrhea, or acid reflux. Interestingly, these symptoms often appear around the same time as behavioural changes associated with NDDs. This suggests that there may be a link between brain development and GI health, with potential implications for understanding how environmental factors impact both.

Despite a growing body of evidence, the biological mechanisms behind this gut-brain connection remain unclear, especially in relation to how environmental exposures might contribute to these disruptions. Understanding these connections could be key to unlocking better prevention and treatment strategies for NDDs.

Former research shows a fascinating difference between the two genders. Prenatal exposure to air pollution and maternal stress, which are two major risk factors for NDDs, affects male and female mice differently. While male mice exhibit significant social deficits, females appear to be resilient. Moreover, changes in the gut microbiome and gut architecture were observed in the males, and remarkably, normalizing the gut microbiome at birth prevented the emergence of these social deficits later in life. This suggests that the gut plays a key role in the development of behaviour through its influence on brain function and the gut-brain connection as a potential therapeutic target for NDDs

In this preprint, Nguyen and colleagues explored the effects of combined prenatal stressors on intestinal macrophages and gastrointestinal function in mice during the early postnatal period, specifically at postnatal day 4 (P4) and P14. Their findings highlight how prenatal environmental stressors can induce gastrointestinal dysfunction and offer potential insights into the mechanisms behind this dysmotility, particularly in males.

Key Results

Gastrointestinal Architecture:

Pregnant mice were exposed to chronic air pollution and maternal stress. Their male offspring showed significant changes in small intestine architecture including shorter villi and a thinner muscularis layer with no similar changes in female offspring.

Macrophage Activity:

The male offspring had reduced F4/80 expression, a macrophage surface receptor, in intestinal macrophages, with no significant changes in macrophage density. This suggests altered macrophage function rather than population size in response to exposure to chronic air pollution and maternal stress.

Impaired Synaptic Pruning and Disrupted Enteric Nervous System Development:

Gene expression studies revealed an upregulation of motor neuron markers (SNAP25, ChAT, nNOS, DBH) in the small intestine of male offspring at P14, suggesting disrupted enteric motor neuron development. These changes were not seen in sensory neurons or other neuron subtypes. Besides this, the preprint authors also noticed an impairment of macrophages’ synaptic pruning function, where macrophages engulf and clear synaptic material, in the muscularis layer of the small intestine. This impairment in synaptic engulfment, particularly in the muscularis layer of males, may directly affect the development and function of the enteric nervous system. Notably, the synaptic pruning function of these macrophages may be compromised due to their origin from the yolk sac, a precursor to immune cells, which could further contribute to the developmental abnormalities observed in the enteric nervous system.

They found that male mice exhibited unique responses to these stressors, with notable transcriptional changes linked to gut motor function starting in the second postnatal week. A striking male-specific deficit was identified in the ability of intestinal macrophages to refine synapses within the muscularis externa, the part of the gut responsible for smooth muscle contractions. Furthermore, accelerated GI transit was observed in prenatally stressed males at P14, indicating enteric neuron hyperactivity, a symptom of GI dysmotility.

Gastrointestinal Motility:

The GI transit rate in male offspring was accelerated at P14, indicating potential gastrointestinal dysmotility linked to disrupted enteric nervous system function. This observation was again specific for male offspring of mothers exposed to chronic air pollution and maternal stress.

Why This Research is Important

Children with neurodevelopmental disorders often experience various GI problems, such as gastritis, bloating, and motility disorders. While the immune system is thought to play a role in these issues, most research has focused on inflammatory pathways in later life, neglecting the developmental functions of immune cells in the gut. This study found that intestine-resident macrophages, which typically help maintain homeostasis by engulfing synaptic material, were impaired by prenatal exposure to air pollution and maternal stress, a model for environmental factors linked to neurodevelopmental disorders. This impairment disrupted the normal development of the enteric nervous system, particularly affecting synaptic pruning in the muscularis layer of the small intestine. The impaired macrophage function, specifically in synaptic engulfment, could be responsible for dysmotility in the gut, contributing to GI disorders observed in NDDs.

These findings suggest that environmental exposures during gestation can affect the development of both the central nervous system and the gut-brain axis, potentially leading to long-term GI and behavioural issues.

The study showed that males were particularly affected, with disruptions in macrophage function leading to changes in motor neuron activity in the small intestine, and females, when affected, were affected to a lesser degree.

While not a complete 100%, mice share around 85-90% of their genes with humans. This makes them valuable for studying human biology, genetics, and diseases. Many biological processes, such as immune function, metabolism, and neurodevelopment, are conserved between humans and mice.

Glossary

Enteric nervous system = a complex network of neurons that governs the function of the gastrointestinal tract.

Enteric neuron synapses = synaptic connections between neurons in the enteric nervous system, often called the “second brain,” and other neurons or target cells within the digestive system.

Macrophage = a type of white blood cell that plays a crucial role in the immune system. It is part of the body’s defense mechanism and is involved in several important functions such as phagocytosis, tissue repair, and regulating other immune signals.

Microglial pruning = the process by which microglia, a type of immune cell in the brain, remove or “prune” unnecessary or excess synapses during brain development.

Muscularis layer = a layer of smooth muscle found in the walls of most parts of the digestive tract. It plays a crucial role in the movement of food through the gastrointestinal system.

Synapse = the junction or connection between two neurons (or between a neuron and another type of cell, such as a muscle or gland cell) where communication occurs.

Synaptic engulfment = the process in which one cell, typically a glial cell, surrounds and engulfs synaptic components, such as parts of a synapse or the whole synapse. This process is important for the maintenance and proper functioning of synapses in the brain. The cells that perform synaptic engulfment are usually microglia or astrocytes, which are types of glial cells in the brain.

Tags: environment, gender differences, gestation, neurodevelopmental disorder

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