The gut microbiota has been found to interact with the brain through the microbiota–gut–brain axis, regulating various physiological processes. In recent years, the impacts of the gut microbiota on neurodevelopment through this axis have been increasingly appreciated. The gut microbiota is commonly considered to regulate neurodevelopment through three pathways, the immune pathway, the neuronal pathway, and the endocrine/systemic pathway, with overlaps and crosstalks in between. Accumulating studies have identified the role of the microbiota–gut–brain axis in neurodevelopmental disorders including autism spectrum disorder, attention deficit hyperactivity disorder, and Rett Syndrome. Numerous researchers have examined the physiological and pathophysiological mechanisms influenced by the gut microbiota in neurodevelopmental disorders (NDDs). This review aims to provide a comprehensive overview of advancements in research pertaining to the microbiota-gut-brain axis in NDDs. Furthermore, we analyzed both the current state of research progress and discuss future perspectives in this field.

Autism Spectrum Disorder (ASD) is a severe neurodevelopmental disorder. To enhance the understanding of the gut microbiota structure in ASD children at different ages as well as the relationship between gut microbiota and fecal metabolites, we first used the 16S rRNA sequencing to evaluate the gut microbial population in a cohort of 143 children aged 2–13 years old. We found that the α-diversity of ASD group showed no significant change with age, while the TD group showed increased α-diversity with age, which indicates that the compositional development of the gut microbiota in ASD varies at different ages in ways that are not consistent with TD group. Recent studies have shown that chronic constipation is one of the most commonly obvious gastrointestinal (GI) symptoms along with ASD core symptoms. To further investigate the potential interaction effects between ASD and GI symptoms, the 30 C-ASD and their aged-matched TD were picked out to perform metagenomics analysis. We observed that C-ASD group displayed decreased diversity, depletion of species of Sutterella, Prevotella, and Bacteroides as well as dysregulation of associated metabolism activities, which may involve in the pathogenesis of C-ASD. Consistent with metagenomic analysis, liquid chromatography-mass spectrometry (LC/MS) revealed some of the differential metabolites between C-ASD and TD group were involved in the metabolic network of neurotransmitters including serotonin, dopamine, histidine, and GABA. Furthermore, we found these differences in metabolites were associated with altered abundance of specific bacteria. The study suggested possible future modalities for ASD intervention through targeting the specific bacteria associated with neurotransmitter metabolism.

The onset of hepatocellular carcinoma (HCC) ranked fifth malignancies all over the world. Increasing evidences showed that the distribution of HCC was related to the incidence of chronic hepatitis B virus (HBV) infection and other factors, such as alcoholism, aflatoxin B1 ingestion and obesity. Recent studies demonstrated that gut dysbiosis plays an important role in liver diseases. However, the researches on gut microbiota of HBV and non-HBV non-HCV related HCC have not been reported. In this study, we investigated the differences between the gut microbiota of HBV related HCC (B-HCC) and non-HBV non-HCV related HCC (NBNC-HCC), finally found some potential bacteria, linking different pathological mechanism of both types of HCCs. We carried out 16S rRNA analyses in a cohort of 33 healthy controls, 35 individuals with HBV related HCC (B-HCC) and 22 individuals with non-HBV non-HCV (NBNC) related HCC (NBNC-HCC). We found that the species richness of fecal microbiota of B-HCC patients was much higher than other two groups. Interestingly, the feces of NBNC-HCC patients harbored more potential pro-inflammatory bacteria (Escherichia-Shigella, Enterococcus) and reduced levels of Faecalibacterium, Ruminococcus, Ruminoclostridium which results in decrease potential of anti-inflammatory short-chain fatty acids. The feces of NBNC-HCC patients had relatively fewer abundance of multiple biological pathways related to amino acid and glucose metabolism, but high level of transport and secretion in some types. However, the B-HCC patients had opposite results of bacterial composition and associated multiple biological pathways versus NBNC-HCC patients. Meanwhile, we found that aberrant network of gut microbiota occurred differently in B-HCC and NBNC-HCC patients. Our study indicated that B-HCC and NBNC-HCC patients showed differential abundance of bacteria involved in different functions or biological pathways. We suggested the modification of specific gut microbiota may provide the therapeutic benefit for B-HCC and NBNC-HCC.

Salmonella infections can become chronic and increase the risk of cancer. The mechanisms by which specific Salmonella organisms contribute to cancer, however, are still unknown. Live and attenuated Salmonella are used as vectors to target cancer cells, but there have been no systematic studies of the oncogenic potential of chronic Salmonella infections in cancer models. AvrA, a pathogenic product of Salmonella, is inserted into host cells during infection and influences eukaryotic cell pathways. In the current study, we colonized mice with Salmonella AvrA-sufficient or AvrA-deficient Salmonella typhimirium strains and induced inflammation-associated colon cancer by azoxymethane/dextran sulfate sodium (AOM/DSS). We confirmed Salmonella persisted in the colon for up to 45 weeks. Salmonella was identified not only in epithelial cells on the colonic luminal surface and base of the crypts but also in invading tumors. Tumor incidence in the AvrA+infected group was 100% compared with 51.4% in the AOM/DSS group without bacterial gavage and 56.3% in mice infected with the AvrA- strain. Infection with AvrA+ strain also altered tumor distribution from the distal to proximal colon that might reflect changes in the microbiome. AvrA-expressing bacteria also upregulated beta-catenin signaling as assessed by decreased beta-catenin ubiquitination, increased nuclear beta-catenin and increased phosphorylated-beta-catenin (Ser552), a marker of proliferating stem-progenitor cells. Other β-catenin targets increased by AvrA included Bmi1, a cancer stem cell marker, matrix metalloproteinase-7, and cyclin D1. In summary, AvrA-expressing Salmonella infection activates β-catenin signals and enhances colonic tumorigenesis. Our findings provide important new mechanistic insights into how a bacterial protein targets proliferating stem-progenitor cells and contributes to cancer development. Our observations also raise a note of caution regarding the use of mutant Salmonella organisms as vectors for anti-cancer therapy. Finally, these studies could suggest biomarkers (such as AvrA level in gut) to assess cancer risk in susceptible individuals and infection-related dysregulation of β-catenin signaling in cancer.