Human Gut Microbiota from Autism Spectrum Disorder Promote Behavioral Symptoms in Mice

Sharon, Gil; Cruz, Nikki Jamie; Kang, Dae Wook; Gandal, Michael J.; Wang, Bo; Kim, Young Mo; Zink, Erika; Casey, Cameron; Taylor, Bryn C.; Lane, Christianne J.; Bramer, Lisa; Isern, Nancy G.; Hoyt, David; Noecker, Cecilia; Sweredoski, Michael J.; Moradian, Annie; Borenstein, Elhanan; Jansson, Janet K.; Knight, Rob; Metz, Thomas O.; Lois, Carlos; Geschwind, Daniel H.; Krajmalnik‐Brown, Rosa; Mazmanian, Sarkis K.

doi:10.1016/j.cell.2019.05.004

Cited by 745 publications

(556 citation statements)

References 188 publications

(234 reference statements)

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“…Therefore, most of such conditions represent the consequence of interaction between individual's genetic profile and the environment that he/she is exposed to (Blatt, ). Emerging research has shown microbiota and their metabolites dynamically affect host metabolic, immune, behavioural processes and gut‐brain communications throughout the lifecycle (Bilbo, Block, Bolton, Hanamsagar, & Tran, ; Kim, Yun, Oh, & Choi, ; MacFabe, ; Sharon et al, ; Shenderov & Midtvedt, ; Slattery, MacFabe, Kahler, & Frye, ;). The relationship between gastrointestinal symptoms and many neurological states, such as anxiety, depression, stress and ASD is shown in numerous studies (Foster, Rinaman, & Cryan, ; Fung, Olson, & Hsiao, ; Ishii et al, ).…”

Section: Introductionmentioning

confidence: 99%

Behavioural and brain ultrastructural changes following the systemic administration of propionic acid in adolescent male rats. Further development of a rodent model of autism

Lobzhanidze

Japaridze²,

Lordkipanidze

et al. 2020

Intl J of Devlp Neuroscience

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Short chain fatty acids, produced as gut microbiome metabolites but also present in the diet, exert broad effects in host physiology. Propionic acid (PPA), along with butyrate and acetate, plays a growing role in health, but also in neurological conditions. Increased PPA exposure in humans, animal models and cell lines elicit diverse behavioural and biochemical changes consistent with organic acidurias, mitochondrial disorders and autism spectrum disorders (ASD). ASD is considered a disorder of synaptic dysfunction and cell signalling, but also neuroinflammatory and neurometabolic components. We examined behaviour (Morris water and radial arm mazes) and the ultrastructure of the hippocampus and medial prefrontal cortex (electron microscopy) following a single intraperitoneal (i.p.) injection of PPA (175 mg/kg) in male adolescent rats. PPA treatment showed altered social and locomotor behaviour without changes in learning and memory. Both transient and enduring ultrastructural alterations in synapses, astro‐ and microglia were detected in the CA1 hippocampal area. Electron microscopic analysis showed the PPA treatment significantly decreased the total number of synaptic vesicles, presynaptic mitochondria and synapses with a symmetric active zone. Thus, brief systemic administration of this dietary and enteric short chain fatty acid produced behavioural and dynamic brain ultrastructural changes, providing further validation of the PPA model of ASD.

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Section: Introductionmentioning

confidence: 99%

Behavioural and brain ultrastructural changes following the systemic administration of propionic acid in adolescent male rats. Further development of a rodent model of autism

Lobzhanidze

Japaridze²,

Lordkipanidze

et al. 2020

Intl J of Devlp Neuroscience

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“…It is therefore interesting to note that the use of both IL-2 and IL-4 appears to be a characteristic of some beneficial microbiota antigen responses. For example, Bacteroides fragilis, which is native to a healthy human gut ( 48, 49 ), is known to regulate the peripheral immune system ( 37, 38, 50, 51 ) and even benefit the gut-brain axis ( 52, 53 ) through T cell recognition of its capsular polysaccharide PSA ( 54 ). It is now clear that PSA-specific effector T cells require communication with Tregs, and that immune suppression and inflammatory disease reversal depends upon both IL-4 ( 29, 39 ) and IL-2 ( 55 ), thereby providing a biological context in which the use of cytokines in combination has evolved to direct a healthy immune tone.…”

Section: Discussionmentioning

confidence: 99%

Integration of IL-2 and IL-4 Signals Coordinates Divergent Regulatory T cell Responses and Drives Therapeutic Efficacy

Zhou

Álvarez

Cobb

2020

Preprint

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19Cells exist within complex milieus of communicating factors, such as cytokines, that combine to 20 generate context-specific responses, yet nearly all knowledge about the function of each cytokine and 21 the signaling propagated downstream of their recognition is based upon the response to individual 22cytokines. Here, we found that regulatory T cells (Tregs) integrate concurrent signaling initiated by IL-2 23and IL-4 to generate a response divergent from the sum of the two pathways in isolation. IL-4 24 stimulation of STAT6 phosphorylation was blocked by IL-2, while IL-2 and IL-4 synergized to enhance 25 STAT5 phosphorylation, IL-10 production, and the selective proliferation of IL-10-producing Tregs, 26leading to increased inhibition of conventional T cell activation and the reversal of asthma and multiple 27 sclerosis in mice. These data define a mechanism of combinatorial cytokine signaling and lay the 28 foundation upon which to better understand the origins of cytokine pleiotropy while informing 29improved the clinical use of cytokines. 30 picture of cytokine pleiotropy and potentially leading to enhancements to the use of cytokines in the 77 clinical setting. 78 79 Results 80 IL-2 and IL-4 synergistically promote IL-10 production by Tregs 81Our previous findings demonstrated that IL-4 impacts IL-10 production in FoxP3 + Tregs (29), but the 82 nature of the functional interaction between IL-4 and IL-2, a key survival factor for Tregs in vitro and in 83 vivo, remained obscure. Thus, we created a novel dual reporter mouse by crossing FoxP3 RFP (30) and IL-84 10 GFP (31) mice, thereby enabling live sorting of FoxP3 + cells and analysis of IL-10 production on a per-cell 85 basis. CD4 + FoxP3 + Tregs isolated from the spleens of naïve dual reporter mice (Figure 1 -figure 86 supplement 1A-B) by magnetic bead and sterile fluorescence-activated cell sorting (FACS) were cultured 87 with T cell receptor (TCR) activation using αCD3ε antibody and all combinations of IL-2 and IL-4 for 3 88 days. We found that Tregs cultured with combinatorial cytokine stimulation resulted in synergistically 89higher numbers of IL-10 expressing cells (Figures 1A-1C) and IL-10 secretion ( Figure 1D) compared to 90 single cytokine stimulation. However, analysis of IL-10 + cells revealed that IL-10 expression was no 91 different than IL-2-stimulation in isolation ( Figure 1E), suggesting that the cytokines in combination do 92 not elicit a synergistic increase in IL-10 production on a per-cell basis. The sex-independent ( Figure 1F) 93and TCR-stimulation dependent synergy ( Figures 1A-1D) was present in FoxP3 + Tregs but not FoxP3 -94Tconv ( Figure 1A), and no loss of FoxP3 expression was observed ( Figure 1G), suggesting that the 95 machinery required for this effect was unique to FoxP3 + Tregs. 96In order to determine whether the cytokines must be present at the same time, we isolated Tregs 97 and stimulated them with cytokines in series over a 3-day culture and compared the response to 98 simultaneous stimulation. We discovered that b...

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“…Emerging experimental studies corroborate a more causal link between ASD symptoms and the microbiota, although all have been small studies and caution must therefore be taken in their interpretation. Fecal microbiota transplant from a small number of autistic individuals into germ‐free mice led to an emulation of aspects of autism (social deficits and increased repetitive behavior; Sharon et al, ). Three open‐label pilot studies have demonstrated promising effects of antibiotics (Sandler et al, ), probiotics (Shaaban et al, ), or fecal microbiota transplants from healthy donors (Kang et al, , ) as strategies to reduce symptom severity in ASD.…”

Section: Clinical Significancementioning

confidence: 99%

Annual Research Review: Critical windows – the microbiota–gut–brain axis in neurocognitive development

Cowan

Dinan

Cryan

2019

Child Psychology Psychiatry

107

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The gut microbiota is a vast, complex, and fascinating ecosystem of microorganisms that resides in the human gastrointestinal tract. As an integral part of the microbiota–gut–brain axis, it is now being recognized that the microbiota is a modulator of brain and behavior, across species. Intriguingly, periods of change in the microbiota coincide with the development of other body systems and particularly the brain. We hypothesize that these times of parallel development are biologically relevant, corresponding to ‘sensitive periods’ or ‘critical windows’ in the development of the microbiota–gut–brain axis. Specifically, signals from the microbiota during these periods are hypothesized to be crucial for establishing appropriate communication along the axis throughout the life span. In other words, the microbiota is hypothesized to act like an expected input to calibrate the development of the microbiota–gut–brain axis. The absence or disruption of the microbiota during specific developmental windows would therefore be expected to have a disproportionate effect on specific functions or potentially for regulation of the system as a whole. Evidence for microbial modulation of neurocognitive development and neurodevelopmental risk is discussed in light of this hypothesis, finishing with a focus on the challenges that lay ahead for the future study of the microbiota–gut–brain axis during development.

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Human Gut Microbiota from Autism Spectrum Disorder Promote Behavioral Symptoms in Mice

Cited by 745 publications

References 188 publications

Behavioural and brain ultrastructural changes following the systemic administration of propionic acid in adolescent male rats. Further development of a rodent model of autism

Behavioural and brain ultrastructural changes following the systemic administration of propionic acid in adolescent male rats. Further development of a rodent model of autism

Integration of IL-2 and IL-4 Signals Coordinates Divergent Regulatory T cell Responses and Drives Therapeutic Efficacy

Annual Research Review: Critical windows – the microbiota–gut–brain axis in neurocognitive development

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