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Maternal gut bacteria drive intestinal inflammation in offspring with neurodevelopmental disorders by altering the chromatin landscape of CD4⁺ T cells.

ABSTRACT: Children with autism spectrum disorders often display dysregulated immune responses and related gastrointestinal symptoms. However, the underlying mechanisms leading to the development of both phenotypes have not been elucidated. Here, we show that mouse offspring exhibiting autism-like phenotypes due to prenatal exposure to maternal inflammation were more susceptible to developing intestinal inflammation following challenges later in life. In contrast to its prenatal role in neurodevelopmental phenotypes, interleukin-17A (IL-17A) generated immune-primed phenotypes in offspring through changes in the maternal gut microbiota that led to postnatal alterations in the chromatin landscape of naive CD4⁺ T cells. The transfer of stool samples from pregnant mice with enhanced IL-17A responses into germ-free dams produced immune-primed phenotypes in offspring. Our study provides mechanistic insights into why children exposed to heightened inflammation in the womb might have an increased risk of developing inflammatory diseases in addition to neurodevelopmental disorders.

SUBMITTER: Kim E

PROVIDER: S-EPMC8755621 | biostudies-literature | 2022 Jan

REPOSITORIES: biostudies-literature

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Maternal gut bacteria drive intestinal inflammation in offspring with neurodevelopmental disorders by altering the chromatin landscape of CD4<sup>+</sup> T cells.

Kim Eunha E Paik Donggi D Ramirez Ricardo N RN Biggs Delaney G DG Park Youngjun Y Kwon Ho-Keun HK Choi Gloria B GB Huh Jun R JR

Immunity 20211207 1

Children with autism spectrum disorders often display dysregulated immune responses and related gastrointestinal symptoms. However, the underlying mechanisms leading to the development of both phenotypes have not been elucidated. Here, we show that mouse offspring exhibiting autism-like phenotypes due to prenatal exposure to maternal inflammation were more susceptible to developing intestinal inflammation following challenges later in life. In contrast to its prenatal role in neurodevelopmental ...[more]

PMID: 34879222

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Project description:IntroductionAsthma is the most common chronic disease during pregnancy. Maternal asthma has been associated with a multitude of unwanted pregnancy outcomes, in some studies also with neurodevelopmental disorders. Here we investigated associations between maternal asthma and neurodevelopmental disorders.Material and methodsWe studied a retrospective population-based cohort of 1 271 439 mother-child pairs from singleton live births in Finland between the years 1996-2018. We used multiple high-cover registers for data collection. Adjusted unconditional Cox regression models were used to investigate associations between maternal asthma, asthma medication used during pregnancy, and offspring's neurodevelopmental disorder diagnoses.ResultsWe identified 106 163 mother-child pairs affected by maternal asthma. We found that maternal asthma was associated with offspring neurodevelopmental disorders, but the differences in absolute prevalence between the control and exposure groups were small. Attention-deficit hyperactivity disorder (ADHD) was found in 4114 (3.9%) offspring with maternal asthma and in 32 122 (3.0%) controls (adjusted hazard ratio (HR): 1.49; 95% CI 1.44-1.54); autism in 1617 (1.5%) offspring vs 13 701 (1.3%) controls (HR: 1.33; 95% CI 1.26-1.40); motor-developmental disorder in 1569 (1.5%) offspring vs 12 147 (1.1%) controls (HR: 1.37; 95% CI 1.30-1.45); language disorder in 3057 (2.9%) offspring vs 28 421 (2.7%) controls (HR: 1.13; 95% CI 1.08-1.17), learning disabilities in 849 (0.8%) offspring vs 6534 (0.6%) controls (HR: 1.51; 95% CI 1.41-1.62); mixed developmental disorder in 1633 (1.5%) offspring vs 14 434 (1.3%) controls (HR 1.20; 95% CI, 1.14-1.26); and intellectual disability in 908 (0.9%) vs 9155 (0.9%) controls (HR: 1.12; 95% CI 1.04-1.20). No substantial differences were found between allergic and non-allergic asthma phenotypes, and neither allergic tendency nor respiratory infection was associated with a similar likelihood of neurodevelopmental disorders.ConclusionsMaternal asthma and allergic and non-allergic phenotypes showed weak associations with the offspring's neurodevelopmental disorders. The association is concerned especially with learning disabilities, ADHD, motor development, and autism.

Project description:BackgroundEngineered nanoparticles are smaller than 100 nm and designed to improve or creating even new physico-chemical properties. Consequently, toxicological properties of materials may change as size reaches the nm size-range. We examined outcomes related to the central nervous system in the offspring following maternal inhalation exposure to nanosized carbon black particles (Printex 90).MethodsTime-mated mice (NMRI) were exposed by inhalation, for 45 min/day to 0, 4.6 or 37 mg/m3 aerosolized carbon black on gestation days 4-18, i.e. for a total of 15 days. Outcomes included maternal lung inflammation (differential cell count in bronchoalveolar lavage fluid and Saa3 mRNA expression in lung tissue), offspring neurohistopathology and behaviour in the open field test.ResultsCarbon black exposure did not cause lung inflammation in the exposed females, measured 11 or 28-29 days post-exposure. Glial fibrillary acidic protein (GFAP) expression levels were dose-dependently increased in astrocytes around blood vessels in the cerebral cortex and hippocampus in six weeks old offspring, indicative of reactive astrogliosis. Also enlarged lysosomal granules were observed in brain perivascular macrophages (PVMs) in the prenatally exposed offspring. The number of parvalbumin-positive interneurons and the expression levels of parvalbumin were decreased in the motor and prefrontal cortices at weaning and 120 days of age in the prenatally exposed offspring. In the open field test, behaviour was dose-dependently altered following maternal exposure to Printex 90, at 90 days of age. Prenatally exposed female offspring moved a longer total distance, and especially males spent significantly longer time in the central zone of the maze. In the offspring, the described effects were long-lasting as they were present at all time points investigated.ConclusionThe present study reports for the first time that maternal inhalation exposure to Printex 90 carbon black induced dose-dependent denaturation of PVM and reactive astrocytes, similarly to the findings observed following maternal exposure to Printex 90 by airway instillation. Of note, some of the observed effects have striking similarities with those observed in mouse models of neurodevelopmental disorders.

Project description:The developing immune system and central nervous system in the fetus and child are extremely sensitive to both exogenous and endogenous signals. Early immune system programming, leading to changes that can persist over the life course, has been suggested, and other evidence suggests that immune dysregulation in the early developing brain may play a role in neurodevelopmental disorders such as autism spectrum disorder and schizophrenia. The timing of immune dysregulation with respect to gestational age and neurologic development of the fetus may shape the elicited response. This creates a possible sensitive window of programming or vulnerability. This review will explore the effects of maternal prenatal and infant nutritional status (from conception until early childhood) as well as maternal prenatal stress and anxiety on early programming of immune function, and how this might influence neurodevelopment. We will describe fetal immune system development and maternal-fetal immune interactions to provide a better context for understanding the influence of nutrition and stress on the immune system. Finally, we will discuss the implications for prevention of neurodevelopmental disorders, with a focus on nutrition. Although certain micronutrient supplements have shown to both reduce the risk of neurodevelopmental disorders and enhance fetal immune development, we do not know whether their impact on immune development contributes to the preventive effect on neurodevelopmental disorders. Future studies are needed to elucidate this relationship, which may contribute to a better understanding of preventative mechanisms. Integrating studies of neurodevelopmental disorders and prenatal exposures with the simultaneous evaluation of neural and immune systems will shed light on mechanisms that underlie individual vulnerability or resilience to neurodevelopmental disorders and ultimately contribute to the development of primary preventions and early interventions.

Dataset Information

Maternal gut bacteria drive intestinal inflammation in offspring with neurodevelopmental disorders by altering the chromatin landscape of CD4⁺ T cells.

Publications

Maternal gut bacteria drive intestinal inflammation in offspring with neurodevelopmental disorders by altering the chromatin landscape of CD4<sup>+</sup> T cells.

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Maternal gut bacteria drive intestinal inflammation in offspring with neurodevelopmental disorders by altering the chromatin landscape of CD4+ T cells.

Publications

Maternal gut bacteria drive intestinal inflammation in offspring with neurodevelopmental disorders by altering the chromatin landscape of CD4&lt;sup&gt;+&lt;/sup&gt; T cells.

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OmicsDI is part of the ELIXIR infrastructure

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Maternal gut bacteria drive intestinal inflammation in offspring with neurodevelopmental disorders by altering the chromatin landscape of CD4⁺ T cells.

Maternal gut bacteria drive intestinal inflammation in offspring with neurodevelopmental disorders by altering the chromatin landscape of CD4<sup>+</sup> T cells.