Effect of Probiotics on Gut Microbiota and Brain Interactions in the Context of Neurodegenerative and Neurodevelopmental Disorders

In this narrative review, we summarize recent pieces of evidence of the role of microbiota alterations in Rett syndrome (RTT). Neurological problems are prominent features of the syndrome, but the pathogenic mechanisms modulating its severity are still poorly understood. Gut microbiota was recently demonstrated to be altered both in animal models and humans with different neurodevelopmental disorders and/or epilepsy. By investigating gut microbiota in RTT cohorts, a less rich microbial community was identified which was associated with alterations of fecal microbial short-chain fatty acids. These changes were positively correlated with severe clinical outcomes. Indeed, microbial metabolites can play a crucial role both locally and systemically, having dynamic effects on host metabolism and gene expression in many organs. Similar alterations were found in patients with autism and down syndrome as well, suggesting a potential common pathway of gut microbiota involvement in neurodevelopmental disorders.

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Environmental Chemical Diethylhexyl Phthalate Alters Intestinal Microbiota Community Structure and Metabolite Profile in Mice

mSystems ◽

10.1128/msystems.00724-19 ◽

2019 ◽

Vol 4 (6) ◽

Cited By ~ 3

Author(s):

Ming Lei ◽

Rani Menon ◽

Sara Manteiga ◽

Nicholas Alden ◽

Carrie Hunt ◽

...

Keyword(s):

Gut Microbiota ◽

Neurodevelopmental Disorders ◽

Developmental Disorders ◽

Chemical Exposure ◽

Metabolite Profile ◽

Environmental Chemicals ◽

Toxic Metabolite ◽

Environmental Chemical ◽

Diethylhexyl Phthalate

ABSTRACT Exposure to environmental chemicals during windows of development is a potentially contributing factor in gut microbiota dysbiosis and linked to chronic diseases and developmental disorders. We used a community-level model of microbiota metabolism to investigate the effects of diethylhexyl phthalate (DEHP), a ubiquitous plasticizer implicated in neurodevelopmental disorders, on the composition and metabolite outputs of gut microbiota in young mice. Administration of DEHP by oral gavage increased the abundance of Lachnoclostridium, while decreasing Clostridium sensu stricto. Addition of DEHP to in vitro-cultured cecal microbiota increased the abundance of Paenibacillus and Lachnoclostridium. Untargeted metabolomics showed that DEHP broadly altered the metabolite profile in the culture. Notably, DEHP enhanced the production of p-cresol while inhibiting butyrate synthesis. Metabolic model-guided correlation analysis indicated that the likely sources of p-cresol are Clostridium species. Monoculture of Lachnoclostridium bolteae confirmed that it is capable of producing p-hydroxyphenylacetic acid, the immediate precursor of p-cresol, and that the species’ growth is enhanced upon DEHP exposure. Taken together, these findings suggest a model where DEHP increases production of p-cresol, a bacterial metabolite linked with neurodevelopmental disorders, by expanding the abundance of species that synthesize the metabolite’s precursor. IMPORTANCE Several previous studies have pointed to environmental chemical exposure during windows of development as a contributing factor in neurodevelopmental disorders and correlated these disorders with microbiota dysbiosis; however, little is known about how the chemicals specifically alter the microbiota to interfere with development. The findings reported in this paper unambiguously establish that a pollutant linked with neurodevelopmental disorders can directly modify the microbiota to promote the production of a potentially toxic metabolite (p-cresol) that has also been correlated with neurodevelopmental disorders. Furthermore, we used a novel modeling strategy to identify the responsible enzymes and bacterial sources of this metabolite. To the best of our knowledge, the present study is the first to characterize the functional consequence of phthalate exposure on a developed microbiota. Our results suggest that specific bacterial pathways could be developed as diagnostic and therapeutic targets against health risks posed by ingestion of environmental chemicals.

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Microbiome-Gut-Brain Interactions in Neurodevelopmental Disorders: Focus on Autism and Schizophrenia

10.1017/9781108539623.014 ◽

2021 ◽

pp. 258-291

Author(s):

Kiran V. Sandhu ◽

Eoin Sherwin ◽

Ted G. Dinan ◽

John F. Cryan

Keyword(s):

Neurodevelopmental Disorders ◽

Brain Interactions

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Gut microbiota‐immune‐brain interactions in chemotherapy‐associated behavioral comorbidities

Cancer ◽

10.1002/cncr.31584 ◽

2018 ◽

Vol 124 (20) ◽

pp. 3990-3999 ◽

Cited By ~ 17

Author(s):

Kelley R. Jordan ◽

Brett R. Loman ◽

Michael T. Bailey ◽

Leah M. Pyter

Keyword(s):

Gut Microbiota ◽

Brain Interactions

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A Revolutionizing Approach to Autism Spectrum Disorder Using the Microbiome

Nutrients ◽

10.3390/nu12071983 ◽

2020 ◽

Vol 12 (7) ◽

pp. 1983

Author(s):

Dinyadarshini Johnson ◽

Vengadesh Letchumanan ◽

Sivakumar Thurairajasingam ◽

Learn-Han Lee

Keyword(s):

Autism Spectrum Disorder ◽

Side Effects ◽

Gut Microbiota ◽

Neurodevelopmental Disorders ◽

Autism Spectrum ◽

Spectrum Disorder ◽

Health Conditions ◽

Maternal Influence ◽

Research Gaps ◽

The Relationship

The study of human microbiota and health has emerged as one of the ubiquitous research pursuits in recent decades which certainly warrants the attention of both researchers and clinicians. Many health conditions have been linked to the gut microbiota which is the largest reservoir of microbes in the human body. Autism spectrum disorder (ASD) is one of the neurodevelopmental disorders which has been extensively explored in relation to gut microbiome. The utilization of microbial knowledge promises a more integrative perspective in understanding this disorder, albeit being an emerging field in research. More interestingly, oral and vaginal microbiomes, indicating possible maternal influence, have equally drawn the attention of researchers to study their potential roles in the etiopathology of ASD. Therefore, this review attempts to integrate the knowledge of microbiome and its significance in relation to ASD including the hypothetical aetiology of ASD and its commonly associated comorbidities. The microbiota-based interventions including diet, prebiotics, probiotics, antibiotics, and faecal microbial transplant (FMT) have also been explored in relation to ASD. Of these, diet and probiotics are seemingly promising breakthrough interventions in the context of ASD for lesser known side effects, feasibility and easier administration, although more studies are needed to ascertain the actual clinical efficacy of these interventions. The existing knowledge and research gaps call for a more expanded and resolute research efforts in establishing the relationship between autism and microbiomes.

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Environmental chemical diethylhexyl phthalate alters intestinal microbiota community structure and metabolite profile in mice

10.1101/581975 ◽

2019 ◽

Author(s):

Ming Lei ◽

Rani Menon ◽

Sara Manteiga ◽

Nicholas Alden ◽

Carrie Hunt ◽

...

Keyword(s):

Gut Microbiota ◽

Neurodevelopmental Disorders ◽

Developmental Disorders ◽

Chemical Exposure ◽

Metabolite Profile ◽

Environmental Chemicals ◽

Toxic Metabolite ◽

Environmental Chemical ◽

Diethylhexyl Phthalate

AbstractExposure to environmental chemicals during windows of development is a potentially contributing factor in gut microbiota dysbiosis, and linked to chronic diseases and developmental disorders. We used a community-level model of microbiota metabolism to investigate the effects of diethylhexyl phthalate (DEHP), a ubiquitous plasticizer implicated in neurodevelopmental disorders, on the composition and metabolite outputs of gut microbiota in young mice. Administration of DEHP by oral gavage increased the abundance ofLachnoclostridum, while decreasingAkkermansia, Odoribacter, andClostridium sensu stricto. Addition of DEHP toin vitrocultured cecal microbiota increased the abundance ofAlistipes, Paenibacillus, andLachnoclostridium. Untargeted metabolomics showed that DEHP broadly altered the metabolite profile in the culture. Notably, DEHP enhanced the production ofp-cresol, while inhibiting butyrate synthesis. Metabolic model-guided correlation analysis indicated that the likely sources ofp-cresol areClostridiumspecies. Our results suggest that DEHP can directly modify the microbiota to affect production of bacterial metabolites linked with neurodevelopmental disorders.ImportanceSeveral previous studies have pointed to environmental chemical exposure during windows of development as a contributing factor in neurodevelopmental disorders, and correlated these disorders with microbiota dysbiosis, little is known about how the chemicals specifically alter the microbiota to interfere with development. The findings reported in this paper unambiguously establish that a pollutant linked with neurodevelopmental disorders can directly modify the microbiota to promote the production of a potentially toxic metabolite (p-cresol) that has also been correlated with neurodevelopmental disorders. Further, we use a novel modeling strategy to identify the responsible enzymes and bacterial sources of this metabolite. To the best of our knowledge, the present study is the first to characterize the functional consequence of phthalate exposure on a developed microbiota. Our results suggest that specific bacterial pathways could be developed as diagnostic and therapeutic targets against health risks posed by ingestion of environmental chemicals.

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The Gut–Brain–Microbiome Axis in Bumble Bees

Insects ◽

10.3390/insects11080517 ◽

2020 ◽

Vol 11 (8) ◽

pp. 517

Author(s):

Laura Leger ◽

Quinn S. McFrederick

Keyword(s):

Gut Microbiota ◽

Gut Microbiome ◽

Neurodevelopmental Disorders ◽

Bumble Bees ◽

Bombus Impatiens ◽

Initial Test ◽

Sucrose Reward ◽

Future Studies ◽

Bee Health ◽

The Brain

The brain-gut–microbiome axis is an emerging area of study, particularly in vertebrate systems. Existing evidence suggests that gut microbes can influence basic physiological functions and that perturbations to the gut microbiome can have deleterious effects on cognition and lead to neurodevelopmental disorders. While this relationship has been extensively studied in vertebrate systems, little is known about this relationship in insects. We hypothesized that because of its importance in bee health, the gut microbiota influences learning and memory in adult bumble bees. As an initial test of whether there is a brain-gut–microbiome axis in bumble bees, we reared microbe-inoculated and microbe-depleted bees from commercial Bombus impatiens colonies. We then conditioned experimental bees to associate a sucrose reward with a color and tested their ability to learn and remember the rewarding color. We found no difference between microbe-inoculated and microbe-depleted bumble bees in performance during the behavioral assay. While these results suggest that the brain-gut–microbiome axis is not evident in Bombus impatiens, future studies with different invertebrate systems are needed to further investigate this phenomenon.

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Kismet/CHD7/CHD8 affects gut biomechanics, the gut microbiome, and gut-brain axis in Drosophila melanogaster

10.1101/2021.12.17.473216 ◽

2021 ◽

Author(s):

Angelo Niosi ◽

Nguyên Henry Võ ◽

Punithavathi Sundar ◽

Chloe Welch ◽

Aliyah Penn ◽

...

Keyword(s):

Drosophila Melanogaster ◽

Gut Microbiota ◽

Gut Microbiome ◽

Neurodevelopmental Disorders ◽

Courtship Behavior ◽

Gastrointestinal Symptoms ◽

Tissue Mechanics ◽

Metagenomic Sequencing ◽

Risk Genes ◽

And Behavior

The gut-brain axis may contribute to the pathophysiology of neurodevelopmental disorders, yet it is often unclear how risk genes associated with these disorders affect gut physiology in a manner that could impact microbial colonization. We addressed this question using Drosophila melanogaster with a null mutation in kismet, the ortholog of chromodomain helicase DNA-binding protein ( CHD ) family members CHD7 and CHD8. In humans, CHD7 and CHD8 are risk genes for neurodevelopmental disorders with co-occurring gastrointestinal symptoms . We found kismet mutant flies have a significant increase in gastrointestinal transit time, indicating functional homology of kismet with CHD7/CHD8 in vertebrates. To measure gut tissue mechanics, we used a high-precision force transducer and length controller, capable of measuring forces to micro-Newton precision, which revealed significant changes in the mechanics of kismet mutant guts, in terms of elasticity, strain stiffening, and tensile strength. Using 16S rRNA metagenomic sequencing, we also found kismet mutants have reduced diversity of gut microbiota at every taxonomic level and an increase in pathogenic taxa. To investigate the connection between the gut microbiome and behavior, we depleted gut microbiota in kismet mutant and control flies and measured courtship behavior. Depletion of gut microbiota rescued courtship defects of kismet mutant flies, indicating a connection between gut microbiota and behavior. In striking contrast, depletion of gut microbiome in the control strain reduced courtship activity. This result demonstrated that antibiotic treatment can have differential impacts on behavior that may depend on the status of microbial dysbiosis in the gut prior to depletion. We propose that Kismet influences multiple gastrointestinal phenotypes that contribute to the gut-brain axis to influence behavior. Based on our results, we also suggest that gut tissue mechanics should be considered as an element in the gut-brain communication loop, both influenced by and potentially influencing the gut microbiome and neuronal development.

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