With 100 million neurons, the intestinal nervous system contains about as many as the spinal cord. Both are therefore independent nervous systems.
Most of the neurons of the intestinal nervous system neurons are located in:
- Plexus myentericus Auerbach (in the muscle wall)
- Plexus submucosus Meissner (adjacent to the mucosa).
Influence specialized neurons of the intestinal nervous system (promoting or inhibiting depending on the transmitter and receptor):
- Motor skills (different movement patterns)
- Secretion (water, electrolytes, hormones)
- Perfusion (vascular tone, stimulating (vasodilation) or inhibiting (vasoconstriction) blood flow)
- Resorption
- Signal substance formation
The gut-brain axis plays a role in brain development, particularly in infancy, early childhood and childhood. The mother’s microbiome, the type of birth and the environment influence the child’s microbiome. Breastfeeding and a healthy diet provide the child’s gut with important probiotic elements, while antibiotics can disrupt the gut flora.
1. Gut-brain axis¶
The communication of the gut-brain axis is bidirectional. The brain influences the motor, sensory and secretory functions of the gastrointestinal tract top-down via efferent fibers of the vagus nerve. The gut influences the function of the brain bottom-up, in particular the amygdala and hypothalamus, via the afferent vagal fibers.
Intestinal bacteria (intestinal microbiome, intestinal flora) influence the nervous system via various mechanisms:
- Metabolic pathway:
- through modulation of neurotransmitters such as GABA, serotonin, dopamine, noradrenaline
- direct
- indirectly via biosynthetic pathways of the host organism.
- by secretion of short-chain fatty acids (SCFAs). These:
- activate microglial cells
- influence the permeability of the blood-brain barrier
- Immune system: circulating cytokines
- by changing the HPA axis activity
- by stimulation of the vagus nerve:
- The vagus nerve has 80 % afferent fibers, which transmit sensory stimuli from the body to the brain, and 20 % efferent fibers, which transport motor signals from the brain to the body.
Bacteria can synthesize neurotransmitters and hormones and react to them:
| Bacterium |
Dopamine (DA) |
Noradrenaline (NE) |
Serotonin (5-HT) |
GABA |
Acetylcholine (ACh) |
Histamine (Hist) |
Other influences |
| Bacillus species |
produce DA |
produce NE |
|
|
|
|
|
| Bacillus cereus |
produce DA |
|
|
|
|
|
|
| Bacillus mycoides |
produce DA |
produce NE |
|
|
|
|
|
| Bacillus subtilis |
produce DA |
produce NE |
|
|
|
|
|
| Bifidobacterium species |
|
|
|
produce GABA |
|
|
|
| Bifidobacterium adolescentis |
|
|
|
produce GABA |
|
|
|
| Bifidobacterium angulatum |
|
|
|
produce GABA |
|
|
|
| Bifidobacterium dentium |
|
|
|
produce GABA |
|
|
|
| Bifidobacterium infantis |
|
|
|
produce GABA |
|
|
|
| Candida |
|
|
produce 5-HT |
|
|
|
|
| Cirobacter freundii |
|
|
|
|
produce Hist |
|
|
| Enterobacter spp. |
|
|
|
|
produce Hist |
|
|
| Enterococcus |
|
|
produce 5-HT |
|
|
|
|
| Escherichia |
produce DA |
produce NE |
produce 5-HT |
|
|
|
|
| Hafnia alvei (NCIMB, 11999) |
produce DA |
|
produce 5-HT |
|
|
produce Hist |
|
| Klebsiella pneumoniae (NCIMB, 673) |
produce DA |
|
produce 5-HT |
|
|
produce Hist |
|
| L. lactis subsp. lactis (IL1403) |
|
|
produce 5-HT |
|
|
|
|
| Lactobacillus species |
|
|
|
produce GABA |
produce ACh |
|
|
| Lactobacillus brevis (DPC6108) |
|
|
|
produce GABA |
|
|
|
| Lactobacillus buchneri (MS) |
|
|
|
produce GABA |
|
|
|
| Lactobacillus delbrueckiisubsp. bulgaricus (PR1) |
|
|
|
produce GABA |
|
|
|
| Lactobacillus hilgardii |
|
|
|
|
produce Hist |
|
|
| Lactobacillus mali |
|
|
|
|
produce Hist |
|
|
| Lactobacillus plantarum (FI8595) |
|
|
produce 5-HT |
(ATCC14917) produce GABA |
produce ACh |
produce Hist |
|
| Lactobacillus reuteri (100-23) |
|
|
|
produce GABA |
|
|
|
| Lactobacillus rhamnosus (JB-1) |
|
|
|
produce GABA; for GABA receptors see * |
|
|
see ** |
| Lactococcus lactis subsp. cremoris (MG 1363) |
|
|
produce 5-HT |
|
|
produce Hist |
|
| Lactococcus lactis subsp. lactis (IL1403) |
|
|
|
|
|
produce Hist |
|
| Monasmus purpureus (CCRC 31615) |
|
|
|
produce GABA |
|
|
|
| Morganella morganii (NCIMB, 10466) |
produce DA |
|
produce 5-HT |
|
|
produce Hist |
|
| Oenococcus oeni |
|
|
|
|
produce Hist |
|
|
| Pediococcus parvulus |
|
|
|
|
produce Hist |
|
|
| Proteus vulgaris |
produce DA |
produce NE |
|
|
|
|
|
| Saccharomyces |
|
produce NE |
|
|
|
|
|
| Serratia |
produce DA |
|
|
|
|
|
|
| Serratia marcescens |
produce DA |
produce NE |
|
|
|
|
|
| Staphylococcus aureus |
produce DA |
|
|
|
|
|
|
| Streptococcus |
|
|
produce 5-HT |
|
|
|
|
| Streptococcus thermophilus (NCFB2392) |
|
|
produce 5-HT |
|
|
produce Hist |
|
| Streptococcus salivarius subsp. thermophilus (Y2) |
|
|
|
produce GABA |
|
|
|
|
|
|
|
|
|
|
|
* Altered the expression of GABA receptors in the brain via the vagus nerve; GABA-B1b receptor mRNA increased in the cortex (cingulate and prelimbic), decreased in the hippocampus, amygdala and locus coeruleus, GABA-Aα2 mRNA reduced in the PFC and amygdala, increased in the hippocampus.
** Reduced stress-related corticosterone secretion; reduced anxiety- and depression-related behavior
The production of dopamine, noradrenaline and serotonin in intestinal neurons does not mean that the neurotransmitters transported in this way reach the brain.
-
Blood-brain barrier
Acetylcholine can cross the blood-brain barrier. However, dopamine, noradrenaline, serotonin and GABA cannot, which means that these latter neurotransmitters produced in the gut do not directly change the levels in the brain.
-
Axonal transport
We wonder whether neurotransmitters synthesized via the vagus nerve in the gut could be transported to the brain. There is evidence that nerve fibers of the vagus nerve contain dopamine.
-
Influencing the prodrug balance
We assume that even if peripherally synthesized or released dopamine, noradrenaline or serotonin from intestinal bacteria could not be directly introduced into the brain via the blood-brain barrier, intestinal bacteria should at least have an influence on the blood level of the precursors that can cross the blood-brain barrier. As a result, the blood level of the precursors could influence the amount of neurotransmitters synthesized from them in the brain.
Treatment options for microbiota problems are probiotics and fecal transplants.
2. Gut bacteria as a possible causal cause of ADHD?¶
One study found evidence of a causal relationship between gut bacteria and ADHD. (Note: Even if causality were confirmed, it should be assumed that this is only one of many different possible ways in which ADHD can develop and would therefore not apply to all sufferers)
One study found that mice whose guts were contaminated with gut bacteria from people with ADHD showed structural changes in the brain (white matter, gray matter, hippocampus, internal capsule), reduced connectivity between motor and visual cortices on the right side of the resting state, and higher anxiety than mice in which gut bacteria from people without ADHD were used.
A single-case study reports an improvement in ADHD symptoms in a young woman following intestinal bacterial replacement related to a recurrent Clostridioides difficile infection.
3. Microbiome and short-chain fatty acids in ADHD¶
The primary functions of the microbiota include
- Protection against pathogens by increasing mucus production and thus stabilizing the intestinal-blood barrier
- Support for the immune system
- Production of vitamins
- Production of short-chain fatty acids (SCFAs) from indigestible carbohydrates
Short-chain fatty acids are:
|
|
|
|
|
|
| C1:0 (no SCFA) |
Formic acid |
Methanoic acid |
Formates |
Methanoates |
HCOOH |
| C2:0 |
Acetic acid |
Ethanoic acid |
Acetate |
Ethanoate |
CH3COOH |
| C3:0 |
Propionic acid |
Propanoic acid |
Propionates |
Propanoates |
CH3CH2COOH |
| C4:0 |
Butyric acid |
Butanoic acid |
Butyrate |
Butanoate |
CH3(CH2)2COOH |
| C4:0 |
Isobutyric acid |
2-Methylpropanoic acid |
Isobutyrate]] |
2-Methylpropanoate |
(CH3)2CHCOOH |
| C5:0 |
Valeric acid |
Pentanoic acid |
Valerate |
Pentanoate |
CH3(CH2)3COOH |
| C5:0 |
Isovaleric acid |
3-Methylbutanoic acid |
Isovalerate |
3-Methylbutanoate |
(CH3)2CHCH2COOH |
| C6:0 |
Caproic acid |
Hexanoic acid |
Capronate |
Hexanoate |
CH3(CH2)4COOH |
A study on short-chain fatty acids in the blood serum of ADHD compared to healthy family members found:
- Adults with ADHD
- Formic acid reduces
- Acetic acid reduces
- Propionic acid reduces
- Succinic acid reduced (C4H6O, an aliphatic dicarboxylic acid; food additive number E 363)
- Children with ADHD
- Formic acid lower than in adults
- Propionic acid lower than in adults
- Isovaleric acid lower than in adults
- Antibiotic medication in the last 2 years caused
- Formic acid reduces
- Propionic acid reduces
- Succinic acid reduces
- current stimulant use in children caused
- Acetic acid reduces
- Propionic acid reduces
4. Gut microbiota in ADHD¶
Studies found abnormalities in the intestinal flora of children with ADHD
ADHD correlated with leaky gut, neuroinflammation and overactivated microglial cells. The colonic microbiota exhibits a pro-inflammatory shift and harbors more gram-negative bacteria that contain immune-triggering lipopolysaccharides in their cell walls.
Adults with ADHD had lower plasma concentrations of formic, acetic, propionic and succinic acid than their healthy family members. When ADHD patients were adjusted for SCFA-influencing factors, children had lower concentrations of formic, propionic, and isovaleric acids than adults, and those who had taken more antibiotic medications in the past two years had lower concentrations of formic, propionic, and succinic acids. After adjusting for antibiotic medication, we found that among children, those currently taking stimulant medications had lower acetic and propionic acid concentrations, and adults with ADHD had lower formic and propionic acid concentrations than adult healthy family members.
Early disruptions to the developing gut microbiota can affect neurological development and potentially lead to adverse mental health outcomes later in life.
4.1. Reduced intestinal bacteria in ADHD¶
- Bacteroides coprocola (B. coprocola)
- Butyricicoccus
- Desulfovibrio
- Dial register
- Dialister level increased after ADHD treatment
- Enterococcus
- Eubacterium
- Eubacterium rectale
- Enterococcus
- Faecalibacterium prausnitzii
- Faecalibacterium
- Anti-inflammatory
- Faecalibacterium (Firmicutes strain)
- Reduced Faecalibacterium (Firmicutes strain) correlated with increased hyperactivity / impulsivity
- LachnospiraceaeNC2004group
- Lachnospiraceae bacterium
- Peptostreptococcaceae
- Prevotella
- produce short-chain fatty acids (SCFAs)
- anti-inflammatory
- Romboutsia
- Ruminococcus gnavus
- Increased against: RuminococcaceaeUCG013
4.2. Increased intestinal bacteria in ADHD¶
- Agathobacter
- correlated with withdrawal symptoms and depression
- Bacillota (synonym: Firmicutes)
- Coprococcus
- Subdoligranulum
- Bacteroidetes
- Bacteroides
- Correlated with hyperactivity / impulsivity in ADHD
- Bacteroides uniformis (B. uniformis)
- Bacteroides ovatus (B. ovatus)
- Increase correlated with ADHD symptoms
- Bacteroides caccae
- Bacteroides faecis (OR: 1.09)
- Bacteroides eggerthii correlated with PTSD (OR: 1.11), not with ADHD
- Bacteroides thetaiotaomicron correlated with PTSD (OR: 1.11), not with ADHD
- Bacteroidota
- Bifidobacterium
- Anti-inflammatory
- Increases
- A slight increase in Bifidobacterium in the gut is thought to be associated with increased production of cyclohexadienyl dehydratase, which is a precursor to phenylanaline, which is a precursor to dopamine. At the same time, the increase in Bifidobacterium is thought to be associated with reduced reward anticipation, which may indicate reduced dopamine levels in the striatum. How these two seemingly contradictory pathways fit together is not yet clear to us.
- Bifidobacterium codes for the enzyme arenate dehydratase (ADT), which is important for the production of phenylalanine. Phenylalanine can cross the blood-brain barrier and is a precursor of tyrosine, which is required for DA and NE synthesis. However, a small study found no systematic phenylalanine or tyrosine_abnormalities in children with ADHD.
- Eggerthella
- Eubacteriumhalliigroup
- Flavonifractor
- Odoribacter splanchnicus
- Odoribacter
- Different a study according to which Odoribacter were reduced
- Paraprevotella xylaniphila
- Phascolarctobacterium
- Prevotella_2,
- Proteobacteria (Phylum)
- Roseburia
- Ruminococcus gnavus
- correlated with rule-breaking behavior
- Ruminococcustorquesgroup
- Sutterella stercoricanis (S. stercoricanis)
- Increase correlated with intake of dairy products, nuts, seeds, legumes, iron, magnesium
- Increase correlated with ADHD symptoms
- Veillonella parvula
- Veillonellaceae
No significant difference was found in the alpha diversity of intestinal bacteria in ADHD.
75 infants were randomly assigned to receive either Lactobacillus rhamnosus GG or a placebo in the first 6 months of life. After 13 years, ADHD or ASD was found in 17% of the placebo group and in none of the probiotic group. Bifidobacteria were significantly reduced in the intestinal microbiome of the affected children in the first 6 months of life.
A study of urine and fecal samples using 1H nuclear magnetic resonance spectroscopy and liquid chromatography-mass spectrometry found gender-specific patterns in the metabolic phenotype of ADHD
- Urine profile
- Hippurate (a product of microbial host co-metabolism that can cross the blood-brain barrier)
- increased (men only)
- correlated negatively with IQ (in men)
- correlated with fecal metabolites associated with microbial metabolism in the gut.
- Fecal profile (independent of ADHD medication, age and BMI)
- Stearoyl-linoleoyl-glycerol increased
- 3,7-Dimethylurate increased
- FAD increased
- Glycerol-3-phosphate reduced
- Thymine reduced
- 2(1H)-quinolinone reduced
- Aspartate reduced
- Xanthine reduces
- Hypoxanthine reduces
- Orotate reduced
5. Gut microbiota similar in ADHD and ASD¶
The intestinal microbiota in ADHD and ASD are quite similar in both alpha and beta diversity and differ significantly from non-affected individuals.
In addition, a subgroup of ADHD and ASD cases showed an increased concentration of lipopolysaccharide-binding protein, which correlated positively with interleukin IL-8, IL-12 and IL-13, compared to unaffected children. This indicates a disturbance of the intestinal barrier and a dysregulation of the immune system in a subgroup of children with ADHD or ASD.
6. Urinary microbiota in ADHD¶
A study of the urinary microbiota in ADHD found:
- a lower alpha diversity in the urine bacteria of the ADHD group
- reduced Shannon and Simpson indices (p < 0.05)
-
significant differences in beta diversity
- were common in ADHD:
- Phyla Firmicutes
- Actinobacteriota
- Ralstonia (genus)
- Afipia (genus)
- less frequently with ADHD:
- Phylum Proteobacteria
- Corynebacterium (genus)
- Peptoniphilus (genus)
- Afipia correlated significantly with the results of the Child Behavior Checklist Attention Problems and the DSM-oriented ADHD subscale
