Attention-Deficit/Hyperactivity Disorder and the Gut Microbiota–Gut–Brain Axis: Closing Research Gaps through Female Inclusion in Study Design
Abstract
:1. Introduction
1.1. The Human Gut Microbiome
1.2. Underrepresentation of Females in Research on ADHD and the Gut Microbiome
2. The Gut Microbiota–Gut–Brain Axis
Microbial Metabolites Relevant in the GMGBA
Metabolite | Category | Metabolite Function | Role of Gut Microbiota | Relevant Microbial Taxa | Example Interaction |
---|---|---|---|---|---|
Phenylalanine and Tyrosine | Amino Acids | Precursors in biosynthetic pathway for norepinephrine and dopamine [43,44,46] | Metabolize to norepinephrine and dopamine [43,44,46]; deplete phenylalanine and tyrosine through use in other biosynthetic pathways [47] | Clostridia and Candida [47] | Clostridia and Candida decrease phenylalanine and tyrosine concentrations for neurotransmitter synthesis through use in non-neurotransmitter biosynthetic pathways [47] |
Tryptophan | Amino Acid | Precursor in biosynthetic pathway for serotonin | Metabolize to serotonin [18,33,46]; indirectly alter blood plasma levels [41] | Bifidobacteria [41] | Bifidobacteria increase plasma tryptophan levels via suppression of IFN-γ production, a cytokine associated with activation of the enzyme that converts tryptophan to the compound kynurenine [41] |
Norepinephrine | Neurotransmitter and Peripheral Hormone | Involved as a neurotransmitter in regulation of memory and attention during cognitive tasks, sleep/wake states, and stress reactions, and as a peripheral hormone in the “fight or flight” response of the sympathetic nervous system [44,45] | Biosynthesis | Escherichia, Bacillus, and Saccharomyces [18,33,48] | Escherichia, Bacillus, and Saccharomyces metabolize phenylalanine and tyrosine to norepinephrine [18,33] |
Dopamine | Neurotransmitter | Involved in learning, memory consolidation, and reward and motivation pathways [43] | Biosynthesis | Bacillus and Escherichia [18,33,36] | Bacillus and Escherichia metabolize phenylalanine and tyrosine to dopamine [18,33,36] |
Serotonin | Neurotransmitter | Involved in the regulation of a wide array of human behaviors and neurological processes, including mood, attention, memory, reward, perception, anger, aggression, and appetite, among other functions [42] | Biosynthesis; ca. 95% of serotonin in the human body is localized in the gut [18] | Candida, Streptococcus, Escherichia, and Enterococcus [18,33] | Candida, Streptococcus, Escherichia, and Enterococcus metabolize tryptophan to serotonin [18,33] |
GABA | Neurotransmitter | Main inhibitory neurotransmitter in the brain and therefore affects many facets of neurological function [49] | Biosynthesis | Lactobacillus and Bifidobacterium [17,18,33,36] | Lactobacillus and Bifidobacterium harbor biosynthetic pathways for GABA production [17,18,33,36] |
ACh | Neurotransmitter | Involved in regulation of attention, cue detection, attentional orienting (default to detection mode shift), and memory encoding [50] | Biosynthesis | Lactobacillus [18,33] | Lactobacillus harbor biosynthetic pathways for ACh production [18,33] |
Short-Chain Fatty Acids (SCFAs—Butyric Acid, Propionic Acid, Acetic Acid, and Lactic Acid) | Fatty acids containing <6 carbon atoms | Energy source for human metabolic activity [12]; also involved in regulating learning and memory processes, enzymes in the biosynthetic pathway for norepinephrine and dopamine, gut inflammation, sympathetic nervous system stimulation, and gut mucosal serotonin release [17,18,33,35,46] | Liberate as byproducts of polysaccharide fermentation | Bacteroidetes and Firmicutes [12] and an incredibly expansive list of additional gut microbial taxa [18,51] | Metabolic activity of Bacteroidetes and Firmicutes liberates SCFAs from food sources, ultimately constituting ca. 10% of human host’s daily energy requirements [12] |
BDNF | Neurotrophin | Involved in brain activity and function, including memory, learning, mood regulation, and neuronal growth and survival, specifically differentiation and survival of midbrain dopaminergic neurons [33,35,38,52] | Indirectly alter BDNF levels [21,38] | Preliminary evidence of generalized gut dysbiosis affecting BDNF levels in the brain [21,38] | Altered production of SCFAs by gut microbiota and germ-free and antibiotic-induced changes in gut microbiota composition are associated with changes in brain BDNF levels [21,38] |
3. Neuropsychiatric Disorders and the Gut Microbiota–Gut–Brain Axis
Disease State(s) | Relevant Microbial Taxa | Citation(s) |
---|---|---|
Depression and anxiety | Bifidobacterium infantis, Lactobacillus helveticus, Bifidobacterium longum, Lactobacillus rhamnosus | Desbonnet et al. [41], Sudo et al. [61], Messaoudi et al. [62], Arsenault-Bréard et al. [63], Bravo et al. [64] |
ASDs | L. rhamnosus, Ruminococcus, Bacteroidetes, Firmicutes, Bacteroides, Parabacteroides, Dehalobacterium, Prevotella, Coprobacillus, Sutterella, Akkermansia, Desulfovibrionaceae, Enterobacteraceae, Oscillospira, Rikenellaceae, Saccharibacteria, Lactobacillus, Desulfovibrio, and Helicobacteraceae | Correti et al. [65], Pärtty et al. [66], Mudd et al. [67] |
Obsessive-compulsive disorder (OCD) | Oscillospira, Odoribacter, and Anaerostipes | Turna et al. [68] |
Bipolar disorder | OTU0003 Faecalibacterium, OTU00025 unidentified (Ruminococcaceae family), OTU00024 Anaerostipes, and OTU00022 unidentified (Enterobacteriaceae family) | Evans et al. [69] |
Schizophrenia | Ruminococcus, Roseburia, and Veillonella | Li et al. [70] |
Alzheimer’s disease | 82 operational taxonomic units (OTUs), including species within the Bacteroidetes, Firmicutes, and Actinobacteria phyla | Vogt et al. [71] |
ADHD | Actinobacteria, Firmicutes (order Clostridiales and family Veillonellaceae), Neisseriaceae, Alcaligenaceae, Peptostreptococcaceae, Selenomonadaceae, and additional genera and species (see Section 4.2) | Pärtty et al. [66], Aarts et al. [72], Jiang et al. [73], Prehn-Kristensen et al. [74], Wang et al. [75], Szopinska-Tokov et al. [76], Richarte et al. [77] |
3.1. Depression and Anxiety
3.2. Autism Spectrum Disorders
4. Attention-Deficit/Hyperactivity Disorder and the Gut Microbiota–Gut–Brain Axis
4.1. Etiology of ADHD
4.2. The ADHD Gut Microbiome
4.3. Potential Interactions of ADHD and the GMGBA
5. Host Sex and the Gut Microbiome
6. A Pathway for Future Research
6.1. Foundational Holes in ADHD and GMGBA Research
6.2. Characterizing the ADHD Gut Microbiome
7. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Metabolite(s) | Relevant Findings | Hypothesized Mechanisms of GMGBA–ADHD Interactions |
---|---|---|
Serotonin and Tryptophan |
|
|
Dopamine, Norepinephrine, and Phenylalanine |
| |
GABA |
|
|
SCFAs |
|
|
BDNF |
|
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Schleupner, H.V.; Carmichael, M.J. Attention-Deficit/Hyperactivity Disorder and the Gut Microbiota–Gut–Brain Axis: Closing Research Gaps through Female Inclusion in Study Design. Women 2022, 2, 231-253. https://doi.org/10.3390/women2030023
Schleupner HV, Carmichael MJ. Attention-Deficit/Hyperactivity Disorder and the Gut Microbiota–Gut–Brain Axis: Closing Research Gaps through Female Inclusion in Study Design. Women. 2022; 2(3):231-253. https://doi.org/10.3390/women2030023
Chicago/Turabian StyleSchleupner, Hannah V., and Mary Jane Carmichael. 2022. "Attention-Deficit/Hyperactivity Disorder and the Gut Microbiota–Gut–Brain Axis: Closing Research Gaps through Female Inclusion in Study Design" Women 2, no. 3: 231-253. https://doi.org/10.3390/women2030023