Gut microbiota drives age-related oxidative stress and mitochondrial damage in microglia via the metabolite N6-carboxymethyllysine

Mossad, Omar; Batut, Bérénice; Yılmaz, Bahtiyar; Dokalis, Nikolaos; Mezö, Charlotte; Nent, Elisa; Nabavi, Lara Susann; Mayer, Melanie; Marón, Feres José Mocayar; Buescher, Joerg M.; Agüero, Mercedes Gomez de; Szalay, Antal; Lämmermann, Tim; Macpherson, Andrew J.; Ganal‐Vonarburg, Stephanie C.; Backofen, Rolf; Erny, Daniel; Prinz, Marco; Blank, Thomas

doi:10.1038/s41593-022-01027-3

Cited by 99 publications

(49 citation statements)

References 62 publications

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“…Combined with the change in Crystallin gene expression and impaired mitochondrial function that we and others describe [60,84], this supports the idea that the microbiota is critical for normal metabolic activity in amoeboid microglia. Our observation that the microbiota broadly promotes expression, in amoeboid microglia, of genes involved in mitochondrial oxidative phosphorylation is consistent with the idea that the microbiota supports microglial function in part by minimizing mitochondrial oxidative stress [48,60].…”

Section: Discussionsupporting

confidence: 89%

“…There is precedence for this idea in the literature; murine microbiota disruption impairs responses to social novelty and alters microglial morphology and reactivity in the hippocampus and cortex [72, 82]. Microglia in GF mice are also metabolically dysfunctional, larger, less mature, less responsive to LPS challenge, and more abundant in the cortex, corpus callosum, hippocampus, olfactory bulb, and cerebellum than in specific pathogen free (SPF) controls [48,83,84]. Contrary to these murine phenotypes, zebrafish forebrain microglia are reduced in GF larvae relative to CVZ controls and forebrain microglial morphology does not appear influenced by the microbiota.…”

Section: Discussionmentioning

confidence: 99%

“…However, these probiotic Lactobacillus strains were applied to adult zebrafish and do not normally populate the zebrafish intestine, so it is unclear whether microbial modulation occurs through a similar mechanism during normal neurodevelopment of circuits that regulate social behavior [45, 46]. Like many circulating immune cells, microglia are responsive to microbial signals, and the microbiota appears to influence normal microglial colonization, maturation, morphology, activation, and homeostasis [21,47,48]. However, how microbial modulation of microglial function feeds forward to influence neural circuit architecture, especially in brain regions that regulate social behavior, has not been studied.…”

Section: Introductionmentioning

confidence: 99%

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The microbiota promotes social behavior by modulating microglial remodeling of forebrain neurons

Bruckner

Stednitz

Grice

et al. 2020

Preprint

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Host-associated microbiotas normally guide the trajectory of intrinsically encoded developmental programs, and dysbiosis is linked to neurodevelopmental disorders such as autism spectrum disorder.Recent work suggests that microbiotas modulate social phenotypes associated with these disorders, though developmental mechanisms linking microbiotas to social behavior are not well understood. We discovered that the zebrafish microbiota is required for normal social behavior. Using this model to examine neuronal features modulated by the microbiota during early development, we found that the microbiota restrains neurite complexity and targeting of specific forebrain neurons required for normal social behavior. The microbiota is also required for normal forebrain infiltration of microglia, the brain's resident phagocytes that remodel neuronal arbors, suggesting the microbiota modulates arborization via a neuro-immune route. Our work establishes a foundation for study of microbial and host mechanisms that link the microbiota and social behavior in an experimentally tractable model vertebrate.

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Section: Discussionsupporting

confidence: 89%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The microbiota promotes social behavior by modulating microglial remodeling of forebrain neurons

Bruckner

Stednitz

Grice

et al. 2020

Preprint

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“…ROS generated by NADPH oxidase (NOX2) in immune cells can be released in the brain by microglia, PVMs or infiltrating leukocytes, 165 , 207 , 208 in the blood by circulating leukocytes such as neutrophils (e.g., after stroke in humans 241 ) or from the meninges into the brain (e.g., after traumatic brain injury 170 ). ROS directly modulate the contractile tone of pericytes and SMCs; in pericytes by stimulating

release from stores (possibly via endothelin-1 release 5 ), which raises

and enhances vasoconstriction 206 , 212 and in SMCs by activating ATP-gated and

-activated

channels, which hyperpolarize

and evoke vasodilation.…”

Section: Immune Cell Control Of Blood Supply To the Cnsmentioning

confidence: 99%

Immune–vascular mural cell interactions: consequences for immune cell trafficking, cerebral blood flow, and the blood–brain barrier

2022

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. Brain barriers are crucial sites for cerebral energy supply, waste removal, immune cell migration, and solute exchange, all of which maintain an appropriate environment for neuronal activity. At the capillary level, where the largest area of brain–vascular interface occurs, pericytes adjust cerebral blood flow (CBF) by regulating capillary diameter and maintain the blood–brain barrier (BBB) by suppressing endothelial cell (EC) transcytosis and inducing tight junction expression between ECs. Pericytes also limit the infiltration of circulating leukocytes into the brain where resident microglia confine brain injury and provide the first line of defence against invading pathogens. Brain “waste” is cleared across the BBB into the blood, phagocytosed by microglia and astrocytes, or removed by the flow of cerebrospinal fluid (CSF) through perivascular routes—a process driven by respiratory motion and the pulsation of the heart, arteriolar smooth muscle, and possibly pericytes. “Dirty” CSF exits the brain and is probably drained around olfactory nerve rootlets and via the dural meningeal lymphatic vessels and possibly the skull bone marrow. The brain is widely regarded as an immune-privileged organ because it is accessible to few antigen-primed leukocytes. Leukocytes enter the brain via the meninges, the BBB, and the blood-CSF barrier. Advances in genetic and imaging tools have revealed that neurological diseases significantly alter immune–brain barrier interactions in at least three ways: (1) the brain’s immune-privileged status is compromised when pericytes are lost or lymphatic vessels are dysregulated; (2) immune cells release vasoactive molecules to regulate CBF, modulate arteriole stiffness, and can plug and eliminate capillaries which impairs CBF and possibly waste clearance; and (3) immune–vascular interactions can make the BBB leaky via multiple mechanisms, thus aggravating the influx of undesirable substances and cells. Here, we review developments in these three areas and briefly discuss potential therapeutic avenues for restoring brain barrier functions.

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“…However, it is also worth mentioning that the aging process might influence the (generally beneficial) role of microbiota in terms of oxidative stress. The study on young-adult and aged mice proved that those old mice which had been housed under germ-free conditions showed a diminished oxidative stress and ameliorated mitochondrial dysfunction in microglia in comparison to the mice with retained microbiota ( 87 ). The association was assumed to be explained by a toxic metabolite derived from gut microbiota - N6-carboxymethyl lysine, which were found in the microglia of aging mice, but not in young-adult mice ( 87 ).…”

Section: Probiotics As a Potential Therapy For Cognitive Impairment I...mentioning

confidence: 99%

Mechanisms of Cognitive Impairment in Depression. May Probiotics Help?

Dobielska

Bartosik²,

Zyzik³

et al. 2022

Front. Psychiatry

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Depression is the major cause of disability globally. Apart from lowered mood and accompanying symptoms, it leads to cognitive impairment that altogether predicts disadvantaged social functioning. Reduced cognitive function in depression appears a bit neglected in the field of clinical and molecular psychiatry, while it is estimated to occur in two-thirds of depressed patients and persist in at least one third of remitted patients. This problem, therefore, requires elucidation at the biomolecular and system levels and calls for improvement in therapeutic approach. In this review study, we address the above-mentioned issues by discussing putative mechanisms of cognitive decline in depression: (1) increased oxidative stress and (2) inflammation, (3) disturbed hypothalamus-pituitary-adrenals axis, and (4) reduced monoamines functionality. Moreover, we acknowledge additional underpinnings of cognitive impairment in depressed elderly: (5) vascular-originated brain ischemia and (6) amyloid-beta plaque accumulation. Additionally, by reviewing molecular, pre-clinical and clinical evidence, we propose gut microbiota-targeted strategies as potential adjuvant therapeutics. The study provides a consolidated source of knowledge regarding mechanisms of cognitive impairment in depression and may path the way toward improved treatment options.

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Gut microbiota drives age-related oxidative stress and mitochondrial damage in microglia via the metabolite N6-carboxymethyllysine

Cited by 99 publications

References 62 publications

The microbiota promotes social behavior by modulating microglial remodeling of forebrain neurons

The microbiota promotes social behavior by modulating microglial remodeling of forebrain neurons

Immune–vascular mural cell interactions: consequences for immune cell trafficking, cerebral blood flow, and the blood–brain barrier

Mechanisms of Cognitive Impairment in Depression. May Probiotics Help?

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