Table 3 Neurodevelopmental disorders (NDDs) with a clear link to the gut microbiota. This table lists the categories and subcategories of the NDDs included in the diagnostic category of the Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-5) and highlights the main pre-clinical and clinical studies showing empirical evidence of a link between the gut microbiota and these disorders

Specific learning disorders

-below average academic performance after 6 months of adequate instruction. No other sensory, motor, or developmental disorders identified [124]

1. Impairment in reading—dyslexia

2. Impairment in mathematics—dyscalculia

3. Impairment in writing—dysorthography and dysgraphia

Poorly characterized in humans with pure learning disorders

Ascertained in mouse models using proper tests (Hole-board apparatus) [125]

Communication disorders

-deficits in verbal and nonverbal communication skills [127]

1. Language disorders

2. Speech sound disorder

3. Childhood-onset fluency disorder

4. Social (pragmatic) communication disorder (SPCD)^*

5. Unspecified communication disorder

Limited evidence available. L. reuteri can reverse social deficits (comparable to SPCD) but not repetitive behaviors in ASD children [145]

SPCD ascertained in mouse models using the isolation-induced ultrasonic vocalizations test, the 3-chamber social approach and the free social interaction tests [128]

^*SPCD differs from full autism for the absence of repetitive behaviors

Motor disorder

-involuntary or uncontrolled movements or actions of the body [129]

1. Developmental coordination disorder

2. Stereotypic movement disorder

3. Tic disorders

Studies on tic disorders, especially Tourette Syndrome (TS), have shown a reduction of Prevotella spp. and Bifidobacteria at the genus level (130–132)

Different microbial signatures were identified between healthy mice and the TS mouse model established with 3,3’-iminodipropionitrile (i.e., increase in Turicibacteraceae and Ruminococcaceae). Fecal matter transplantation (FMT) of TS mice with the microbiota of healthy mice or probiotics alleviated the TS symptoms at the mice stereotyped behavior score by modulating the microbiota and the levels of 5-HT (133)

Attention-deficit/hyperactivity disorder (ADHD)

-impairing levels of inattention, disorganization, and/or hyperactivity-impulsivity [134]

1. ADHD, primarily inattentive type (ADHD-I)

2. ADHD, primarily hyperactive-impulsive type (ADHD-H)

3. ADHD, combined type (ADHD-C)

In a randomized clinical trial, 10-week dietary micronutrient supplementation leads to an increase in Bifidobacterium and Collinsella and a relative reduction of Actinobacteria (135). Results in cohort studies seem contradictory in identifying changes in specific genera which may derive from different statistical analyses (e.g., unsupervised vs supervised methods) [136, 137]; although, in [136] three differential abundance methods (i.e., LEfSe, DESeq, LADEx2) identified increased Turicibacter in controls compared to adult ADHD individuals. Odoribacter and Butyricimonas were mildly elevated in the ADHD group. [138] demonstrated increased Dialister and Megamonas, and reduced Anaerotaenia and Gracilibacter in over 100 untreated adult ADHD patients. No correlation of these genera with the ADHD rating scale. In children with ADHD, the SNAP-IV parent form and the Child Behavior Checklist (CBCL) were used to identify correlations within the ADHD group. No correlation with the SNAP-IV, but significant association between withdrawal and depression symptoms and Agathobacter and between rule-breaking behavior and Ruminococcus gnavus [139].

Decreased structural integrity of the internal capsule and hippocampus, as well as decreased connectivity between the right motor and right visual cortices and increased anxiety at the open-field test demonstrated in germ-free C57BL/6 JOlaHsd male mice colonized with the gut microbiota from ADHD individuals, compared to those colonized by control microbiota. At the family level mice^ADHD showed increased Clostridiales [unknown] [140]

Autism spectrum disorder (ASD)

-persistent deficits of social communication and interaction; repetitive patterns of behaviors, activities or interests, including sensory issues [129, 177]

No subcategories

The current DSM-V category groups the formerly called “pervasive development disorders”, including autistic disorder; Asperger syndrome; childhood disintegrative disorder; pervasive developmental disorder- not otherwise specified (PDD-NOS) [129]

A recent systematic review (143) identified some common trends between available studies: a decrease of the Bacteroidetes/Firmicutes ratio in ASD children compared to healthy ones; the long-lasting effects of FMT over ASD symptoms severity. Different mixture of both pre- and pro-biotics have also been tested, with reduction of ASD symptoms, anxiety, and systemic inflammatory status [144]

Differential expression of genes (i.e., Daglb) was found in germ-free mice transplanted with gut microbiota (GM) from human donors with ASD, as compared to control mice transplanted with the GM from healthy human donors [117]. Oral supplementation of 5-aminovaleric acid (5 AV) or taurine to BTBR T⁺ tf/J (BTBR) ASD-mouse models significantly reduced repetitive behaviors with the marble burying test and increased social duration with the direct social interaction test [117]. Other works tested whether different pre- or probiotics could reverse the behavioral abnormalities in ASD-mouse models (146, 147). Recently, [148] used oral supplementation of fibers (galacto- and fructo-oligosaccharides, GOS/FOS) in male offspring of BALB/cByJ dams injected with valproate (VPA) during gestation. Fibers restored changes induced by VPA administration, including reduced neuroinflammation in the cerebellum and impairment in behavior and cognition

Intellectual disorders

-childhood onset of intellectual difficulties, defined as an intelligence quotient (IQ) two or more standard deviations below the population mean, associated with difficulties in conceptual, social, and practical areas of living (adaptive functioning) [129]

1. Intellectual developmental disorder

2. Global developmental delay

3. Unspecified intellectual disability

Poorly characterized in humans with pure and isolated intellectual disorders. Mostly associated with other NDDs. [149] demonstrated a positive correlation with Barnesiella and Lachnospiraceae, as well as a negative correlation with Sutterella on different clinic-administered cognitive tests (e.g., the Montreal Cognitive Assessment (MoCA) and Digit Symbol Substitution Test (DSST)) in a cohort of 597 adult patients. Moreover, [150] showed different microbial communities in infants with high or low composite cognition (CC) scores at the Bayley Scale of Infant Development, third edition (BSID-III). Fecal transplant from high or low CC infants to germ-free mice depicted different memory profiles in the two groups, with better results at the open-field test and novel object recognition test for mice transplanted with high CC infant feces. Moreover, the latter group had enrichment with Bacteroides and Bifidobacterium, as well as Phocaeicola (including butyrate-producing species) in the gut microbiota [150]