There is growing evidence that the gut and the brain are linked. First observation: mental illnesses are commonly associated with gastrointestinal disorders, patients with neurological diseases often experience constipation, abdominal pain, or diarrhoea. Second: the microbiota of patients differs from that of healthy subjects. Third: the maturation of the nervous system and that of the gut microbiota are concomitant, and the brain does not develop normally without gut bacteria.
ADHD and ASD are common neurodevelopmental disorders
Three clues that put scientists on the track of gut-resident microbes as possible culprits of ADHD and ASD… These acronyms refer to common neurodevelopmental disorders that affect children. Attention deficit hyperactivity disorder (ADHD) is one of the most common, with an estimated prevalence around 5% in children and adolescents. Although the main risk factor appears to rely on genetics, the influence of environmental risk factors is non negligible, and the role of gut microbiota is supported by a growing corpus of arguments. Autism spectrum disorders (ASD) cover a wide range of troubles, with common features being deficiencies in social interactions and communication. The estimated prevalence is 1 to 1.5% worldwide, increasing in recent years. Again, genetics and environmental factors are likely to be involved in the disease onset.
So how do the brain and gut interact? The dialogue between those distant organs is established through nerves, hormones, and immunological signals, and is bidirectional. Within the intestines, the population of hosted microorganisms, the so-called microbiota, plays a key role, according to abundant scientific literature. Two recent publications have reviewed knowledge on the microbiota-gut-brain axis in the onset of mental diseases, including ADHD and ASD (1,2). What emerged from their work is that these diseases share common pathophysiological mechanisms, linked to characteristics of the colon microbiota.
The microbiota can interfere with brain functioning via multiple pathways
A dysregulation of several neurotransmitters, i.e. molecules involved in the communication between neurons, underlies the troubles observed in ADHD and ASD. Their names are dopamine, noradrenaline, and serotonin. They all belong to the monoamine family and are involved in the reward process. Interestingly, some bacteria (such as Bifidobacterium) can produce the essential amino acid phenylalanine in the gut lumen, which is absorbed through the intestine wall into the blood, and at the end reaches the central nervous system where it is metabolised into dopamine and noradrenaline. Similarly, the level of serotonin in the brain is potentially modulated by gut microbes, such as strains from the phylum Proteobacteria (including Pseudomonas species), capable of producing the precursor amino acid tyrosine. Another key neurotransmitter, called GABA (gamma-aminobutyric acid), is also produced by bacteria (Bifidobacterium and Lactobacillus); their relative abundance could be involved in the pathogenesis of these neurodevelopmental disorders.
Many papers have described microbial profiles specific to each mental illness, as revealed by metagenomic analyses of patient stools and comparisons with healthy volunteers. More interestingly, a common trait between these various pathological microbial profiles is that they promote inflammation. More Gram-negative bacteria are recovered from patient stools, which trigger an immune reaction at the gut epithelium level. The host’s immune cells, present within the intestinal barrier, are activated by the lipopolysaccharides (LPS, abundant in the external cell membranes of these bacteria), and then produce pro-inflammatory chemical signals called cytokines. Other bacteria have a protective role, such as Lactobacillus which promote tight junctions’ integrity at the gut barrier and influence the permeability of the intestinal epithelium, limiting the effect of LPS and the passage of cytokines. In addition, patients’ microbiota appears less likely to transform dietary fibres into short-chain fatty acids, known to be anti-inflammatory. Altogether, the disease-related microbiota could promote leaky gut and neuroinflammation, which are common disease-related patterns.
Nutritional interventions targeting microbiota could be helpful
For now, therefore, the microbiota is presumed to be guilty, or at least partly responsible for ADHD and ASD… Or is it the other way around: that these disorders could provoke changes in the composition and activities of gut-resident microbes? Both assertions are probably true, and changes in the microbiota are very likely both a cause and a consequence of the pathological process. Some animal models and interventional studies in humans encourage harnessing the causal hypothesis. The good news is that the microbial community is somewhat modifiable, meaning prevention strategies could exist, provided that the dysfunctional microbiota is better described and detected early enough. Diet seems to be the primary driver, as it directly provides nutrients to the gut, and impacts the composition of the microbiota. Nutritional strategies based on diet modification (3,4) or supplementation with probiotics may be helpful. Some promising data have been reported on beneficial effects of Bifidobacterium bifidum 688 (5), or Lactobacillus rhamnosus GG (6) in ADHD children. Similarly, supplementation with probiotics (living microbes with healthy benefits) and/or prebiotics (fibres intended to promote healthy microbes) were found to alleviate ASD symptoms, while favourably modifying the gut microbiota and the metabolism of neurotransmitters (7).
Treatment options based on drugs and behavioural therapy should not be overlooked, as they help some patients with ADHD or ASD. However, they are limited and leave many others without recourse. In this perspective, strategies targeting the microbiota raise great hopes for children and their relatives, deeply impacted by these neurodevelopmental diseases. Beyond that, they could also apply to other mental illnesses occurring later in life, including depression, schizophrenia, Parkinson’s disease, etc.
- Eicher TP, Mohajeri MH. Overlapping Mechanisms of Action of Brain-Active Bacteria and Bacterial Metabolites in the Pathogenesis of Common Brain Diseases. Nutrients. 2022;14(13):2661.
- Iliodromiti Z, Triantafyllou AR, Tsaousi M, Pouliakis A, Petropoulou C, Sokou R, et al. Gut Microbiome and Neurodevelopmental Disorders: A Link Yet to Be Disclosed. Microorganisms. 2023;11(2):487.
- Lawrence K, Myrissa K, Toribio-Mateas M, Minini L, Gregory AM. Trialling a microbiome-targeted dietary intervention in children with ADHD—the rationale and a non-randomised feasibility study. Pilot and Feasibility Studies. 2022;8(1):108.
- Abd El Baaki OM, Abd El Hamid ER, Zaki ST, Alwakkad ASED, Sabry RN, Elsheikh EM. Diet modification impact on ADHD outcome. Bulletin of the National Research Centre. 2021;45(1):15.
- Wang LJ, Yang CY, Kuo HC, Chou WJ, Tsai CS, Lee SY. Effect of Bifidobacterium bifidum on Clinical Characteristics and Gut Microbiota in Attention-Deficit/Hyperactivity Disorder. Journal of Personalized Medicine. 2022;12(2):227.
- Pinto S, Correia-de-Sá T, Sampaio-Maia B, Vasconcelos C, Moreira P, Ferreira-Gomes J. Eating Patterns and Dietary Interventions in ADHD: A Narrative Review. Nutrients. 2022;14(20):4332.
- Wang Y, Li N, Yang JJ, Zhao DM, Chen B, Zhang GQ, et al. Probiotics and fructo-oligosaccharide intervention modulate the microbiota-gut brain axis to improve autism spectrum reducing also the hyper-serotonergic state and the dopamine metabolism disorder. Pharmacological Research. 2020;157:104784.
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