Adrenergic Signaling in Muscularis Macrophages Limits Infection-Induced Neuronal Loss

Matheis, Fanny; Müller, Paul; Graves, Christina; Gabanyi, Ilana; Kerner, Zachary; Costa-Borges, Diego; Ahrends, Tomasz; Rosenstiel, Philip; Mucida, Daniel

doi:10.1016/j.cell.2019.12.002

Cited by 193 publications

(209 citation statements)

References 69 publications

(93 reference statements)

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“…Additional CG-SMG targets such as the spleen, pancreas, and liver may also be regulated by the microbiota with conceivable impact on systemic immunity and metabolism. Furthermore, sympathetic signalling can impact gene transcription in a variety of cell targets found in the intestine and elsewhere, including gut–resident macrophages and innate lymphoid cells 10 , 29 , 30 . We identified multiple potential microbiota–derived signals that can modulate gut sympathetic activity and neuronal populations synaptically connected to the gut.…”

mentioning

confidence: 99%

Microbiota modulate sympathetic neurons via a gut–brain circuit

Müller

Schneeberger

Matheis

et al. 2020

Nature

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244

177

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confidence: 99%

Microbiota modulate sympathetic neurons via a gut–brain circuit

Müller

Schneeberger

Matheis

et al. 2020

Nature

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244

177

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“…135 Recent studies have demonstrated that intestinal infections can lead to a rapid loss of neurons and that macrophages can play a neuroprotective role in preventing neuronal cell death via β2-adrenergic receptor signaling. 136…”

Section: Macrophages and Developmentmentioning

confidence: 99%

Macrophages and the maintenance of homeostasis

2020

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There have been many chapters written about macrophage polarization. These chapters generally focus on the role of macrophages in orchestrating immune responses by highlighting the T-cell-derived cytokines that shape these polarizing responses. This bias toward immunity is understandable, given the importance of macrophages to host defense. However, macrophages are ubiquitous and are involved in many different cellular processes, and describing them as immune cells is undoubtedly an oversimplification. It disregards their important roles in development, tissue remodeling, wound healing, angiogenesis, and metabolism, to name just a few processes. In this chapter, we propose that macrophages function as transducers in the body. According to Wikipedia, “A transducer is a device that converts energy from one form to another.” The word transducer is a term used to describe both the “sensor,” which can interpret a wide range of energy forms, and the “actuator,” which can switch voltages or currents to affect the environment. Macrophages are able to sense a seemingly endless variety of inputs from their environment and transduce these inputs into a variety of different response outcomes. Thus, rather than functioning as immune cells, they should be considered more broadly as cellular transducers that interpret microenvironmental changes and actuate vital tissue responses. In this chapter, we will describe some of the sensory stimuli that macrophages perceive and the responses they make to these stimuli to achieve their prime directive, which is the maintenance of homeostasis.

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“…However, there are still many questions on how enteric neurogenesis is regulated and to what extent the microbiota contributes to it. Nevertheless, the importance of this mechanism is underscored by the recent work from Matheis and colleagues, in which the authors showed that infection-induced neuronal loss can be reversed following reconstitution of the normal gut microbiota after Abx treatment [66].…”

Section: Discussion 341mentioning

confidence: 99%

Intestinal Microbiota Shapes Gut Physiology and Regulates Enteric Neurons and Glia

Vicentini

Keenan

Wallace

et al. 2020

Preprint

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Background: The intestinal microbiota plays an important role in regulating gastrointestinal (GI) physiology in part through interactions with the enteric nervous system (ENS). Alterations in the gut microbiome frequently occur together with disturbances in enteric neural control in pathophysiological conditions. However, the mechanisms by which the microbiota regulates GI function and the structure of the ENS are incompletely understood. Using a mouse model of antibiotic (Abx)-induced bacterial depletion, we sought to determine the molecular mechanisms of microbial regulation of intestinal function and the integrity of the ENS. Spontaneous reconstitution of the Abx-depleted microbiota was used to assess the plasticity of structure and function of the GI tract and neuronal survival and neurogenesis in the ENS. Results: Adult male and female Abx-treated mice exhibited alterations in GI structure and function, including a longer small intestine, slower transit time, increased carbachol-stimulated ion transport and increased intestinal permeability. These alterations were accompanied by the loss of enteric neurons in the ileum and proximal colon in both submucosal and myenteric plexuses. A reduction in the number of enteric glia were only observed in the ileal myenteric plexus. Recovery of the microbiota restored intestinal function and stimulated enteric neurogenesis leading to increases in the number of enteric glia and neurons. Lipopolysaccharide (LPS) supplementation enhanced neuronal survival alongside bacterial depletion but had no effect on neuronal recovery once the Abx-induced neuronal loss was established. In contrast, SCFA were able to restore neuronal numbers after Abx-induced neuronal loss, demonstrating that SCFA stimulate enteric neurogenesis in vivo. Conclusions: Our results demonstrate a role for the gut microbiota in regulating the structure function of the GI tract in a sex-independent manner. Moreover, the microbiota is essential for the maintenance of ENS integrity, by regulating enteric neuronal survival and promoting neurogenesis. Molecular determinants of the microbiota, LPS and SCFA, regulate enteric neuronal survival, while SCFA also stimulates neurogenesis. Our data reveal new insights into the role of the gut microbiota that could lead to therapeutic developments for the treatment of enteric neuropathies.

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Adrenergic Signaling in Muscularis Macrophages Limits Infection-Induced Neuronal Loss

Cited by 193 publications

References 69 publications

Microbiota modulate sympathetic neurons via a gut–brain circuit

Microbiota modulate sympathetic neurons via a gut–brain circuit

Macrophages and the maintenance of homeostasis

Intestinal Microbiota Shapes Gut Physiology and Regulates Enteric Neurons and Glia

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