Sex-specific effects of microbiome perturbations on cerebral Aβ amyloidosis and microglia phenotypes

Dodiya, Hemraj B.; Kuntz, Thomas; Shaik, Shabana; Baufeld, Caroline; Leibowitz, Jeffrey; Zhang, Xulun; Gottel, Neil; Zhang, Xiaoqiong; Butovsky, Oleg; Gilbert, Jack A.; Sisodia, Sangram S.

doi:10.1084/jem.20182386

Cited by 203 publications

(260 citation statements)

References 71 publications

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“…Similar findings were obtained in 5xFAD and APPPS1 amyloidosis mouse models (Brandscheid et al, 2017;Harach et al, 2017). Other studies have identified that antibiotic treatment-induced changes in microbiota composition as well as microbial deficiency in GF animals was associated with reduced Ab pathology (Dodiya et al, 2019;Harach et al, 2017;Minter et al, 2017;Minter et al, 2016). This effect could result from reduced Ab production or increased clearance.…”

Section: Introductionsupporting

confidence: 74%

“…Given the critical role of microglia in AD and a demonstrated link between microglial function and Ab pathology, we next focused on microglia as the potential cellular mediators of the SCFA effect on Ab pathology (Dodiya et al, 2019). First, we observed that microglia in SCFAsupplemented GF APPPS1 mice had a significantly increased circularity index (i.e.…”

Section: Scfa Supplementation Results In Increased Microglial Activationmentioning

confidence: 99%

“…Moreover, microglia have been demonstrated in murine AD models to actively contribute to various pathophysiological process in AD such as plaque seeding, plaque phagocytosis and neuronal dysfunction by synaptic pruning (Heneka et al, 2014;Heneka et al, 2013;Hong et al, 2016;Sarlus and Heneka, 2017). Previous proof-of-concept studies investigating a potential role of the microbiome in AD have already indicated an effect of microbial colonization or antibiotic treatment on microglial activation (Dodiya et al, 2019;Harach et al, 2017;Minter et al, 2017). Although previous studies did not reveal a mechanistic link between microbiome function to Ab plaque pathology, they have reproducibly shown that microbiota eradication (GF mice) or impairing the microbiome's metabolic function (antibiotic treatment) reduced microglial activation and Ab plaque load, which is in accordance with our study.…”

Section: Discussionmentioning

confidence: 99%

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Microbiota-derived short chain fatty acids promote Aβ plaque deposition

Colombo

Sadler

Llovera

et al. 2020

Preprint

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One Sentence Summary:We identify short chain fatty acids as key microbial metabolites contributing to AD disease progression via activation of microglial cells and upregulation of ApoE. AbstractPrevious studies have identified a crucial role of the gut microbiome in modifying Alzheimer's disease (AD) progression. However, the mechanisms of microbiome-brain interaction in AD, including the microbial mediators and their cellular targets in the brain, were so far unknown. Here, we identify microbiota-derived short chain fatty acids (SCFA) as key metabolites along the gut-brain axis in AD. Germ-free (GF) AD mice exhibit a substantially reduced Ab plaque load and markedly reduced SCFA plasma concentrations; conversely, SCFA supplementation to GF AD mice was sufficient to increase the Ab plaque load to levels of conventionally colonized animals. While Ab generation was only mildly affected, we observed strong microglial activation and upregulation of ApoE upon the SCFA supplementation. Taken together, our results demonstrate that microbiota-derived SCFA are the key mediators along the gut-brain axis resulting in increased microglial activation, ApoE upregulation and Ab deposition.

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Section: Introductionsupporting

confidence: 74%

Section: Scfa Supplementation Results In Increased Microglial Activationmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Microbiota-derived short chain fatty acids promote Aβ plaque deposition

Colombo

Sadler

Llovera

et al. 2020

Preprint

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“…These two studies suggest that antibiotics decrease cognitive function in mice, which may be reversed by FMT. In contrast, two studies (Harach et al, 2017;Dodiya et al, 2019) observed reduced Aβ-pathology and neuroinflammation in male mice (not in female mice) when the gut microbiota was depleted. When an AB-treated AD mouse model received FMT with feces from age-and sex-matched AD mice without antibiotics, the positive effect of antibiotics was partially reversed (Dodiya et al, 2019).…”

Section: Role Of the Gut Microbiota In Disease Symptoms And Pathogenesismentioning

confidence: 90%

“…In contrast, two studies (Harach et al, 2017;Dodiya et al, 2019) observed reduced Aβ-pathology and neuroinflammation in male mice (not in female mice) when the gut microbiota was depleted. When an AB-treated AD mouse model received FMT with feces from age-and sex-matched AD mice without antibiotics, the positive effect of antibiotics was partially reversed (Dodiya et al, 2019). In a germ-free AD mouse model, FMT with conventional microbiota or conventional AD microbiota caused an increase of pathology, with the latter showing a stronger effect (Harach et al, 2017).…”

Section: Role Of the Gut Microbiota In Disease Symptoms And Pathogenesismentioning

confidence: 90%

Fecal Microbiota Transplantation in Neurological Disorders

Vendrik

Ooijevaar

Jong

et al. 2020

Front. Cell. Infect. Microbiol.

280

174

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Conclusions: Preliminary literature suggests that FMT may be a promising treatment option for several neurological disorders. However, available evidence is still scanty and some contrasting results were observed. A limited number of studies in humans have been performed or are ongoing, while for some disorders only animal experiments have been conducted. Large double-blinded randomized controlled trials are needed to further elucidate the effect of FMT in neurological disorders.

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The link between gut microbiome and Alzheimer's disease: From the perspective of new revised criteria for diagnosis and staging of Alzheimer's disease

Liang,

Liu,

Cheng

et al. 2024

Alzheimer's & Dementia

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Over the past decades, accumulating evidence suggests that the gut microbiome exerts a key role in Alzheimer's disease (AD). The Alzheimer's Association Workgroup is updating the diagnostic criteria for AD, which changed the profiles and categorization of biomarkers from “AT(N)” to “ATNIVS.” Previously, most of studies focus on the correlation between the gut microbiome and amyloid beta deposition (“A”), the initial AD pathological feature triggering the “downstream” tauopathy and neurodegeneration. However, limited research investigated the interactions between the gut microbiome and other AD pathogenesis (“TNIVS”). In this review, we summarize current findings of the gut microbial characteristics in the whole spectrum of AD. Then, we describe the association of the gut microbiome with updated biomarker categories of AD pathogenesis. In addition, we outline the gut microbiome‐related therapeutic strategies for AD. Finally, we discuss current key issues of the gut microbiome research in the AD field and future research directions.Highlights The new revised criteria for Alzheimer's disease (AD) proposed by the Alzheimer's Association Workgroup have updated the profiles and categorization of biomarkers from “AT(N)” to “ATNIVS.” The associations of the gut microbiome with updated biomarker categories of AD pathogenesis are described. Current findings of the gut microbial characteristics in the whole spectrum of AD are summarized. Therapeutic strategies for AD based on the gut microbiome are proposed.

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Sex-specific effects of microbiome perturbations on cerebral Aβ amyloidosis and microglia phenotypes

Abstract: An antibiotic cocktail leads to reductions in brain amyloidosis, altered morphology, and gene expression in microglia of male but not female transgenic mice that exhibit Aβ deposits. The microbiome plays a causal role in modulating Aβ burden and microglia phenotypes.

Cited by 203 publications

References 71 publications

Microbiota-derived short chain fatty acids promote Aβ plaque deposition

Microbiota-derived short chain fatty acids promote Aβ plaque deposition

Fecal Microbiota Transplantation in Neurological Disorders

The link between gut microbiome and Alzheimer's disease: From the perspective of new revised criteria for diagnosis and staging of Alzheimer's disease

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