The Genetic Background Is Shaping Cecal Enlargement in the Absence of Intestinal Microbiota

Bolsega, Silvia; Smoczek, Anna; Meng, Chen; Kleigrewe, Karin; Scheele, Tim; Meller, Sebastian; Glage, Silke; Volk, Holger A.; Bleich, André; Basic, Marijana

doi:10.3390/nu15030636

“…Such phenotypic features are recapitulated in preclinical models, notably in mice models of disorders such as autism 34 , 45 . Abnormalities in cecal weight and microbial populations are typically reported in a myriad of animal models including germ-free 46 , 47 , antibiotic-treated 48 and models of inflammation and neurological diseases 38 , 49 , yet in the Nlgn3 R451C mouse cecum, a detailed characterisation of cecal motility in combination with GALT structural analysis has not been reported.…”

Section: Discussionmentioning

confidence: 99%

Impaired cecal motility and secretion alongside expansion of gut-associated lymphoid tissue in the Nlgn3R451C mouse model of autism

Lee

¹

,

Balasuriya

²

,

Herath

³

et al. 2023

Sci Rep

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0

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Individuals with Autism Spectrum Disorder (ASD; autism) commonly present with gastrointestinal (GI) illness in addition to core diagnostic behavioural traits. The appendix, or cecum in mice, is important for GI homeostasis via its function as a key site for fermentation and a microbial reservoir. Even so, the role of the appendix and cecum in autism-associated GI symptoms remains uninvestigated. Here, we studied mice with an autism-associated missense mutation in the post-synaptic protein neuroligin-3 (Nlgn3R451C), which impacts brain and enteric neuronal activity. We assessed for changes in cecal motility using a tri-cannulation video-imaging approach in ex vivo preparations from wild-type and Nlgn3R451C mice. We investigated cecal permeability and neurally-evoked secretion in wild-type and Nlgn3R451C tissues using an Ussing chamber set-up. The number of cecal patches in fresh tissue samples were assessed and key immune populations including gut macrophages and dendritic cells were visualised using immunofluorescence. Nlgn3R451C mice displayed accelerated cecal motor complexes and reduced cecal weight in comparison to wildtype littermates. Nlgn3R451C mice also demonstrated reduced neurally-evoked cecal secretion in response to the nicotinic acetylcholine receptor agonist 1,1-dimethyl-4-phenylpiperazinium (DMPP), but permeability was unchanged. We observed an increase in the number of cecal patches in Nlgn3R451C mice, however the cellular morphologies of key immune populations studied were not significantly altered. We show that the R451C nervous system mutation leads to cecal dysmotility, impaired secretion, and neuro-immune alterations. Together, these results suggest that the R451C mutation disrupts the gut-brain axis with GI dysfunction in autism.

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A systematic framework for understanding the microbiome in human health and disease: from basic principles to clinical translation

Ma,

Zuo,

Frey

et al. 2024

Sig Transduct Target Ther

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The human microbiome is a complex and dynamic system that plays important roles in human health and disease. However, there remain limitations and theoretical gaps in our current understanding of the intricate relationship between microbes and humans. In this narrative review, we integrate the knowledge and insights from various fields, including anatomy, physiology, immunology, histology, genetics, and evolution, to propose a systematic framework. It introduces key concepts such as the ‘innate and adaptive genomes’, which enhance genetic and evolutionary comprehension of the human genome. The ‘germ-free syndrome’ challenges the traditional ‘microbes as pathogens’ view, advocating for the necessity of microbes for health. The ‘slave tissue’ concept underscores the symbiotic intricacies between human tissues and their microbial counterparts, highlighting the dynamic health implications of microbial interactions. ‘Acquired microbial immunity’ positions the microbiome as an adjunct to human immune systems, providing a rationale for probiotic therapies and prudent antibiotic use. The ‘homeostatic reprogramming hypothesis’ integrates the microbiome into the internal environment theory, potentially explaining the change in homeostatic indicators post-industrialization. The ‘cell-microbe co-ecology model’ elucidates the symbiotic regulation affecting cellular balance, while the ‘meta-host model’ broadens the host definition to include symbiotic microbes. The ‘health-illness conversion model’ encapsulates the innate and adaptive genomes’ interplay and dysbiosis patterns. The aim here is to provide a more focused and coherent understanding of microbiome and highlight future research avenues that could lead to a more effective and efficient healthcare system.

show abstract

Impaired cecal motility and secretion alongside expansion of gut-associated lymphoid tissue in the Nlgn3R451C mouse model of autism

Lee

¹

,

Balasuriya

²

,

Herath

³

et al. 2023

Preprint

1

0

View full text Add to dashboard Cite

Individuals with Autism Spectrum Disorder (ASD; autism) commonly present with gastrointestinal (GI) illness in addition to core diagnostic behavioural traits. The appendix, or cecum in mice, is important for GI homeostasis via its function as a key site for fermentation and a microbial reservoir. Even so, the role of the appendix and cecum in autism-associated GI symptoms remains uninvestigated. Here, we studied mice with an autism-associated missense mutation in the post-synaptic protein neuroligin-3 (Nlgn3R451C), which impacts brain and enteric neuronal activity. We assessed for changes in cecal motility using a tri-cannulation video-imaging approach in ex vivo preparations from wild-type and Nlgn3R451C mice. We investigated cecal permeability and neurally-evoked secretion in wild-type and Nlgn3R451C tissues using an Ussing chamber set-up. The number of cecal patches in fresh tissue samples were assessed and key immune populations including gut macrophages and dendritic cells were visualised using immunofluorescence. Nlgn3R451C mice displayed accelerated cecal motor complexes and reduced cecal weight in comparison to wildtype littermates. Nlgn3R451C mice also demonstrated reduced neurally-evoked cecal secretion in response to the nicotinic acetylcholine receptor agonist 1,1-dimethyl-4-phenylpiperazinium (DMPP), but permeability was unchanged. We observed an increase in the number of cecal patches in Nlgn3R451C mice, however the cellular morphologies of key immune populations studied were not significantly altered. We show that the R451C nervous system mutation leads to cecal dysmotility, impaired secretion, and neuro-immune alterations. Together, these results suggest that the R451C mutation disrupts the gut-brain axis with GI dysfunction in autism.

show abstract

The Genetic Background Is Shaping Cecal Enlargement in the Absence of Intestinal Microbiota

Cited by 3 publications

References 65 publications

Impaired cecal motility and secretion alongside expansion of gut-associated lymphoid tissue in the Nlgn3R451C mouse model of autism

Impaired cecal motility and secretion alongside expansion of gut-associated lymphoid tissue in the Nlgn3R451C mouse model of autism

A systematic framework for understanding the microbiome in human health and disease: from basic principles to clinical translation

Impaired cecal motility and secretion alongside expansion of gut-associated lymphoid tissue in the Nlgn3R451C mouse model of autism

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