| Neuropathology . | Categorization . | Hallmarks of microglial dysfunction . | Hallmarks of microbial dysbiosis . | References . |
|---|---|---|---|---|
| ASD | Neurodevelopmental | Elevated microglial activation and release of pro-inflammatory cytokines in several brain regions. | 23–70% of individuals with ASD report GI symptoms (e.g., constipation and abdominal bloating). | De Angelis et al., 2013; Hsiao et al., 2013; Kang et al., 2013; Wang et al., 2013; De Rubeis et al., 2014; Gupta et al., 2014; Hsiao, 2014; Zhan et al., 2014; Koyama and Ikegaya, 2015; Martínez-Cerdeño, 2017 |
| Synaptic and neural circuitry dysfunction found in postmortem brain tissue from individuals with ASD. | Increased Clostridium and Lactobacillus and decreased Bacteroidetes and Bifidobacterium found in fecal samples collected from children with ASD. | |||
| Mice lacking microglia during early stages of postnatal development demonstrate cognitive and behavioral hallmarks reminiscent of ASD, in addition to abnormal neuronal signaling. | Decreased SCFA levels in ASD patients compared to healthy controls. | |||
| Monocolonization of GF mice with Bacteroides fragilis attenuates cognitive and GI defects in mice. | ||||
| Schizophrenia | Neuropsychiatric | Increased microglial activity observed in PET scan of schizophrenic patients. | Risk factors for schizophrenia involve disruptions to gut microbial community, including maternal infection, premature delivery, cesarean section delivery, and young-age viral infection. | West et al., 2006; Severance et al., 2010, 2015; Shaw, 2010; Diaz Heijtz et al., 2011; Miller et al., 2011; Monji et al., 2013; Hercher et al., 2014; Na et al., 2014; Yolken and Dickerson, 2014; Castro-Nallar et al., 2015; Reisinger et al., 2015; Bloomfield et al., 2016; Sekar et al., 2016; van Kesteren et al., 2017 |
| Elevated pro-inflammatory cytokine release (IL-2, IL-6, IL-8, and TNF-α) and neuroinflammation in the CNS. | High levels of colitis and GI dysfunction in schizophrenic patients. | |||
| Elevated microglial density in temporal cortex of schizophrenic patients. | GF and MIA mice display schizophrenic-like behaviors (e.g., decreased sociability and anhedonia). | |||
| Microglia-mediated disruptions in white matter structure and volume in the prefrontal cortex. | Oropharyngeal microbiota of schizophrenic patients is less diverse than controls and enriched in Lactobacilli, Bifidobacterium, and Eubacterium and depleted in Neisseria and Haemophilus. | |||
| Abnormal synaptic remodeling by microglia disrupts neural circuitry in schizophrenic patients due to increased expression of complement proteins C3 and C4. | Schizophrenic patients demonstrate dysregulation of several metabolic pathways regulated by the gut microbiota. | |||
| MDD | Neuropsychiatric | Postmortem analysis of human brain tissue reveals elevated microglial activation and density in MDD patients. | High concurrence between GI disorders, such as IBS and MDD. | Benton et al., 2007; Bailey et al., 2011; Dinan and Cryan, 2013; Brites and Fernandes, 2015; Yirmiya et al., 2015; Marin et al., 2017 |
| Increased microglial secretion of exosomes carrying pro-inflammatory cytokines in individuals with MDD. | Probiotic supplementation of Lactobacillus casei improved mood in patients with depression. | |||
| Chronic stress, a partial contributor to/risk factor for depression, is attributed to increased microglia-driven neuroinflammation. | Mouse model of MDD exhibiting high levels of stress has increased levels of Clostridium and reduced levels of Lactobacillus and Bacteroides. | |||
| Precise role of heightened neuroinflammation in the brain in MDD remains poorly understood. | ||||
| PD | Neurodegenerative | High levels of microglial activation found in the substantia nigra in brain tissue from PD patients. | >80% of PD patients report GI dysfunction (e.g., increased intestinal permeability, constipation, and nausea) 10–20 yr prior to onset of motor symptoms. | McGeer et al., 1988; Akiyama and McGeer, 1989; Gerhard et al., 2006; Kim and Joh, 2006; Watson et al., 2012; Fasano et al., 2013; Tan et al., 2014a; Keshavarzian et al., 2015; Scheperjans et al., 2015; Machado et al., 2016; Poirier et al., 2016; Sampson et al., 2016; Unger et al., 2016; Zhang et al., 2017 |
| PET scans from 11 PD patients reveal widespread microglial activation in the basal ganglia and the temporal and frontal cortex that exceeds the level of activation found in healthy controls. | Microbiota of PD patients demonstrate increased levels of Enterobacteriaceae and decreased levels of Bacteroidetes and Prevotellaceae. | |||
| α-Synuclein aggregates trigger microglial activation in the substantia nigra. | Concentrations of SCFAs (acetate, propionate, and butyrate) were lower in fecal samples collected from PD patients. | |||
| Microglial release of pro-inflammatory cytokines and neurotoxic factors is a contributing factor to dopaminergic cell death. | SIBO was observed in 25–54.5% of patients. | |||
| Heightened microglial activation observed in several Parkinsonian-like transgenic mice (α-synuclein overexpression) and toxin-induced mouse models (MPTP, 6-OHDA, and rotenone). | Misfolding and aggregation of α-synuclein may begin in enteric neurons that innervate the gut. | |||
| GF mice overexpressing α-synuclein demonstrate attenuated motor and GI symptoms compared to their SPF counterparts. | ||||
| AD | Neurodegenerative | PET scans and postmortem analysis of brain tissue from AD patients reveal elevated microglial activation correlating with severity of disease in several brain regions (hippocampus, entorhinal cortex, and parietal cortex). | The absence of a microbiota in a GF mouse model of AD reduces aggregation of amyloid beta, microglial activation, and neuroinflammation. | Xiang et al., 2006; Koenigsknecht-Talboo et al., 2008; Shie et al., 2009; Ferrarelli, 2015; Hamelin et al., 2016; Hong et al., 2016; Minter et al., 2016; Harach et al., 2017; Keren-Shaul et al., 2017; Ho et al., 2018 |
| Microglia were found to drive propagation of tau protein. | Reduction of microbial diversity following antibiotic administration reduced amyloid beta pathology and microglial activation in AD mice. | |||
| Microglia aggregation surrounds amyloid beta plaques. | Microbiota of APPPS1 transgenic mice have a higher Bacteroidetes/Firmicutes ratio compared to WT mice along with reduced levels of Verrucomicrobia. | |||
| Neurodegeneration occurs partially in response to microglia-driven chronic inflammation. | In vitro administration of several SCFAs (valeric acid, propionic acid, and butyric acid) obstructs aggregation of amyloid beta protein. | |||
| Neuroprotective microglia subtype recently identified operating through a TREM2-mediated signaling pathway. | ||||
| Complement protein (C1q), involved in mediating microglial synaptic remodeling, is upregulated in AD mouse models. | ||||
| ALS | Neurodegenerative | PET scans from ALS patients demonstrate high levels of microglial activation in the motor cortex and prefrontal cortex. | Small pilot study finds decreased microbial diversity in five ALS patients characterized by intestinal inflammation, low Firmicutes/Bacteroidetes ratio, and low SCFA levels. | Turner et al., 2004; Beers et al., 2006; Zhao et al., 2010, 2013; Gerber et al., 2012; Wu et al., 2015; Geloso et al., 2017; Rowin et al., 2017; Zhang et al., 2017 |
| Microglial release of pro-inflammatory cytokines and neurotoxic factors (TNF-α and IL-1β) increases as disease progresses. | G93 ALS mice expressing mutant SOD1 protein have lower expression of intestinal epithelial tight junction proteins and subsequent disruption to the intestinal barrier. | |||
| Microglia expressing mutated Cu,Zn superoxide dismutase (SOD1), a familial ALS gene, accelerates loss of motor neurons and disease progression, while WT microglia conferred neuroprotective effects. | G93 mice have a varying gut microbiota composition compared to healthy control mice with reduced levels of Escherichia coli, Fermicus, and butyrate-producing bacteria. | |||
| The neuroprotective role of anti-inflammatory microglia found in early stages of ALS is lost as increased levels of pro-inflammatory microglial activity drive neurodegeneration. | Drinking water supplemented with the SCFA butyrate improved intestinal barrier function and life expectancy in a G93 ALS mouse model. | |||
| Secretion of mutated SOD1 protein into extracellular space triggers microglial dysfunction and activation. | ||||
| MS | Autoimmune/ neurodegenerative | Colocalization of activated microglia and areas of demyelination and inflammatory lesion in MS patients and EAE mice. | Patients with MS have high levels of intestinal permeability. | Yacyshyn et al., 1996; Benveniste, 1997; Heppner et al., 2005; Sun et al., 2006; Piccio et al., 2007; Yokote et al., 2008; Frischer et al., 2009; Napoli and Neumann, 2010; Lee et al., 2011; Vogel et al., 2013; Miyake et al., 2015; Cekanaviciute et al., 2017; Gao et al., 2017; Kosmidou et al., 2017; Luo et al., 2017 |
| Activated microglia produce reactive oxygen species that contribute to oxidative stress and heightened neuronal injury, neurodegeneration, and demyelination. | High concurrence of inflammatory bowel disease and MS. | |||
| Inhibiting microglial activation prevented the onset of EAE in mice and decreased the presence of CNS lesions. | Dysbiosis found in MS patients (n = 20) characterized by depleted levels of Bacteroides and Prevotella and enriched levels of Bifidobacterium and Streptococcus compared to healthy controls. | |||
| Microglia-mediated remyelination is impaired in MS patients. | Patients (n = 31) with MS have an altered microbiota composition compared to age- and gender-matched controls, with increased levels of Pseudomonas and Mycoplana. | |||
| Activation of microglia during the early stage of disease facilitates recruitment of T cells from the periphery. | Monocolonization of GF mice with different species enriched in MS patients (Akkermansia muciniphila and Parabacteroides distasonis) influenced differentiation of regulatory T cells and lymphocytes. | |||
| Subsets of microglia with activated TNFR2 and TREM2 signaling demonstrate a neuroprotective role in EAE mice. | Development and severity of EAE is lower in GF mice and antibiotic-treated mice compared to SPF mice, as shown by an attenuated release of pro-inflammatory cytokines. | |||
| Whether microglial-driven neuroinflammation is a cause or consequence of neurodegeneration in MS remains unclear. |
| Neuropathology . | Categorization . | Hallmarks of microglial dysfunction . | Hallmarks of microbial dysbiosis . | References . |
|---|---|---|---|---|
| ASD | Neurodevelopmental | Elevated microglial activation and release of pro-inflammatory cytokines in several brain regions. | 23–70% of individuals with ASD report GI symptoms (e.g., constipation and abdominal bloating). | De Angelis et al., 2013; Hsiao et al., 2013; Kang et al., 2013; Wang et al., 2013; De Rubeis et al., 2014; Gupta et al., 2014; Hsiao, 2014; Zhan et al., 2014; Koyama and Ikegaya, 2015; Martínez-Cerdeño, 2017 |
| Synaptic and neural circuitry dysfunction found in postmortem brain tissue from individuals with ASD. | Increased Clostridium and Lactobacillus and decreased Bacteroidetes and Bifidobacterium found in fecal samples collected from children with ASD. | |||
| Mice lacking microglia during early stages of postnatal development demonstrate cognitive and behavioral hallmarks reminiscent of ASD, in addition to abnormal neuronal signaling. | Decreased SCFA levels in ASD patients compared to healthy controls. | |||
| Monocolonization of GF mice with Bacteroides fragilis attenuates cognitive and GI defects in mice. | ||||
| Schizophrenia | Neuropsychiatric | Increased microglial activity observed in PET scan of schizophrenic patients. | Risk factors for schizophrenia involve disruptions to gut microbial community, including maternal infection, premature delivery, cesarean section delivery, and young-age viral infection. | West et al., 2006; Severance et al., 2010, 2015; Shaw, 2010; Diaz Heijtz et al., 2011; Miller et al., 2011; Monji et al., 2013; Hercher et al., 2014; Na et al., 2014; Yolken and Dickerson, 2014; Castro-Nallar et al., 2015; Reisinger et al., 2015; Bloomfield et al., 2016; Sekar et al., 2016; van Kesteren et al., 2017 |
| Elevated pro-inflammatory cytokine release (IL-2, IL-6, IL-8, and TNF-α) and neuroinflammation in the CNS. | High levels of colitis and GI dysfunction in schizophrenic patients. | |||
| Elevated microglial density in temporal cortex of schizophrenic patients. | GF and MIA mice display schizophrenic-like behaviors (e.g., decreased sociability and anhedonia). | |||
| Microglia-mediated disruptions in white matter structure and volume in the prefrontal cortex. | Oropharyngeal microbiota of schizophrenic patients is less diverse than controls and enriched in Lactobacilli, Bifidobacterium, and Eubacterium and depleted in Neisseria and Haemophilus. | |||
| Abnormal synaptic remodeling by microglia disrupts neural circuitry in schizophrenic patients due to increased expression of complement proteins C3 and C4. | Schizophrenic patients demonstrate dysregulation of several metabolic pathways regulated by the gut microbiota. | |||
| MDD | Neuropsychiatric | Postmortem analysis of human brain tissue reveals elevated microglial activation and density in MDD patients. | High concurrence between GI disorders, such as IBS and MDD. | Benton et al., 2007; Bailey et al., 2011; Dinan and Cryan, 2013; Brites and Fernandes, 2015; Yirmiya et al., 2015; Marin et al., 2017 |
| Increased microglial secretion of exosomes carrying pro-inflammatory cytokines in individuals with MDD. | Probiotic supplementation of Lactobacillus casei improved mood in patients with depression. | |||
| Chronic stress, a partial contributor to/risk factor for depression, is attributed to increased microglia-driven neuroinflammation. | Mouse model of MDD exhibiting high levels of stress has increased levels of Clostridium and reduced levels of Lactobacillus and Bacteroides. | |||
| Precise role of heightened neuroinflammation in the brain in MDD remains poorly understood. | ||||
| PD | Neurodegenerative | High levels of microglial activation found in the substantia nigra in brain tissue from PD patients. | >80% of PD patients report GI dysfunction (e.g., increased intestinal permeability, constipation, and nausea) 10–20 yr prior to onset of motor symptoms. | McGeer et al., 1988; Akiyama and McGeer, 1989; Gerhard et al., 2006; Kim and Joh, 2006; Watson et al., 2012; Fasano et al., 2013; Tan et al., 2014a; Keshavarzian et al., 2015; Scheperjans et al., 2015; Machado et al., 2016; Poirier et al., 2016; Sampson et al., 2016; Unger et al., 2016; Zhang et al., 2017 |
| PET scans from 11 PD patients reveal widespread microglial activation in the basal ganglia and the temporal and frontal cortex that exceeds the level of activation found in healthy controls. | Microbiota of PD patients demonstrate increased levels of Enterobacteriaceae and decreased levels of Bacteroidetes and Prevotellaceae. | |||
| α-Synuclein aggregates trigger microglial activation in the substantia nigra. | Concentrations of SCFAs (acetate, propionate, and butyrate) were lower in fecal samples collected from PD patients. | |||
| Microglial release of pro-inflammatory cytokines and neurotoxic factors is a contributing factor to dopaminergic cell death. | SIBO was observed in 25–54.5% of patients. | |||
| Heightened microglial activation observed in several Parkinsonian-like transgenic mice (α-synuclein overexpression) and toxin-induced mouse models (MPTP, 6-OHDA, and rotenone). | Misfolding and aggregation of α-synuclein may begin in enteric neurons that innervate the gut. | |||
| GF mice overexpressing α-synuclein demonstrate attenuated motor and GI symptoms compared to their SPF counterparts. | ||||
| AD | Neurodegenerative | PET scans and postmortem analysis of brain tissue from AD patients reveal elevated microglial activation correlating with severity of disease in several brain regions (hippocampus, entorhinal cortex, and parietal cortex). | The absence of a microbiota in a GF mouse model of AD reduces aggregation of amyloid beta, microglial activation, and neuroinflammation. | Xiang et al., 2006; Koenigsknecht-Talboo et al., 2008; Shie et al., 2009; Ferrarelli, 2015; Hamelin et al., 2016; Hong et al., 2016; Minter et al., 2016; Harach et al., 2017; Keren-Shaul et al., 2017; Ho et al., 2018 |
| Microglia were found to drive propagation of tau protein. | Reduction of microbial diversity following antibiotic administration reduced amyloid beta pathology and microglial activation in AD mice. | |||
| Microglia aggregation surrounds amyloid beta plaques. | Microbiota of APPPS1 transgenic mice have a higher Bacteroidetes/Firmicutes ratio compared to WT mice along with reduced levels of Verrucomicrobia. | |||
| Neurodegeneration occurs partially in response to microglia-driven chronic inflammation. | In vitro administration of several SCFAs (valeric acid, propionic acid, and butyric acid) obstructs aggregation of amyloid beta protein. | |||
| Neuroprotective microglia subtype recently identified operating through a TREM2-mediated signaling pathway. | ||||
| Complement protein (C1q), involved in mediating microglial synaptic remodeling, is upregulated in AD mouse models. | ||||
| ALS | Neurodegenerative | PET scans from ALS patients demonstrate high levels of microglial activation in the motor cortex and prefrontal cortex. | Small pilot study finds decreased microbial diversity in five ALS patients characterized by intestinal inflammation, low Firmicutes/Bacteroidetes ratio, and low SCFA levels. | Turner et al., 2004; Beers et al., 2006; Zhao et al., 2010, 2013; Gerber et al., 2012; Wu et al., 2015; Geloso et al., 2017; Rowin et al., 2017; Zhang et al., 2017 |
| Microglial release of pro-inflammatory cytokines and neurotoxic factors (TNF-α and IL-1β) increases as disease progresses. | G93 ALS mice expressing mutant SOD1 protein have lower expression of intestinal epithelial tight junction proteins and subsequent disruption to the intestinal barrier. | |||
| Microglia expressing mutated Cu,Zn superoxide dismutase (SOD1), a familial ALS gene, accelerates loss of motor neurons and disease progression, while WT microglia conferred neuroprotective effects. | G93 mice have a varying gut microbiota composition compared to healthy control mice with reduced levels of Escherichia coli, Fermicus, and butyrate-producing bacteria. | |||
| The neuroprotective role of anti-inflammatory microglia found in early stages of ALS is lost as increased levels of pro-inflammatory microglial activity drive neurodegeneration. | Drinking water supplemented with the SCFA butyrate improved intestinal barrier function and life expectancy in a G93 ALS mouse model. | |||
| Secretion of mutated SOD1 protein into extracellular space triggers microglial dysfunction and activation. | ||||
| MS | Autoimmune/ neurodegenerative | Colocalization of activated microglia and areas of demyelination and inflammatory lesion in MS patients and EAE mice. | Patients with MS have high levels of intestinal permeability. | Yacyshyn et al., 1996; Benveniste, 1997; Heppner et al., 2005; Sun et al., 2006; Piccio et al., 2007; Yokote et al., 2008; Frischer et al., 2009; Napoli and Neumann, 2010; Lee et al., 2011; Vogel et al., 2013; Miyake et al., 2015; Cekanaviciute et al., 2017; Gao et al., 2017; Kosmidou et al., 2017; Luo et al., 2017 |
| Activated microglia produce reactive oxygen species that contribute to oxidative stress and heightened neuronal injury, neurodegeneration, and demyelination. | High concurrence of inflammatory bowel disease and MS. | |||
| Inhibiting microglial activation prevented the onset of EAE in mice and decreased the presence of CNS lesions. | Dysbiosis found in MS patients (n = 20) characterized by depleted levels of Bacteroides and Prevotella and enriched levels of Bifidobacterium and Streptococcus compared to healthy controls. | |||
| Microglia-mediated remyelination is impaired in MS patients. | Patients (n = 31) with MS have an altered microbiota composition compared to age- and gender-matched controls, with increased levels of Pseudomonas and Mycoplana. | |||
| Activation of microglia during the early stage of disease facilitates recruitment of T cells from the periphery. | Monocolonization of GF mice with different species enriched in MS patients (Akkermansia muciniphila and Parabacteroides distasonis) influenced differentiation of regulatory T cells and lymphocytes. | |||
| Subsets of microglia with activated TNFR2 and TREM2 signaling demonstrate a neuroprotective role in EAE mice. | Development and severity of EAE is lower in GF mice and antibiotic-treated mice compared to SPF mice, as shown by an attenuated release of pro-inflammatory cytokines. | |||
| Whether microglial-driven neuroinflammation is a cause or consequence of neurodegeneration in MS remains unclear. |
IBS, irritable bowel syndrome; MDD, major depressive disorder; MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; PET, positron emission tomography; SIBO, small intestinal bacterial overgrowth.