Ulcerative colitis (UC) is a chronic autoimmune disorder affecting the colonic mucosa. UC is a subtype of inflammatory bowel disease along with Crohn’s disease and presents with varying extraintestinal manifestations. No single etiology for UC has been found, but a combination of genetic and environmental factors is suspected. Research has focused on the role of intestinal dysbiosis in the pathogenesis of UC, including the effects of dysbiosis on the integrity of the colonic mucosal barrier, priming and regulation of the host immune system, chronic inflammation, and progression to tumorigenesis. Characterization of key microbial taxa and their implications in the pathogenesis of UC and colitis-associated cancer (CAC) may present opportunities for modulating intestinal inflammation through microbial-targeted therapies. In this review, we discuss the microbiota-immune crosstalk in UC and CAC, as well as the evolution of microbiota-based therapies.

Introduction: Critical phases of neurodevelopment and gut microbiota diversification occur in early life and both processes are impacted by genetic and environmental factors. Recent studies have shown the presence of gut microbiota alterations in neurodevelopmental disorders. Here we performed a systematic review of alterations of the intestinal microbiota composition and function in pediatric and adult patients affected by autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), and Rett syndrome (RETT).Methods: We searched selected keywords in the online databases of PubMed, Cochrane, and OVID (January 1980 to December 2021) with secondary review of references of eligible articles. Two reviewers independently performed critical appraisals on the included articles using the Critical Appraisal Skills Program for each study design.Results: Our systematic review identified 18, 7, and 3 original articles describing intestinal microbiota profiles in ASD, ADHD, and RETT, respectively. Decreased Firmicutes and increased Bacteroidetes were observed in the gut microbiota of individuals affected by ASD and ADHD. Proinflammatory cytokines, short-chain fatty acids and neurotransmitter levels were altered in ASD and RETT. Constipation and visceral pain were related to changes in the gut microbiota in patients affected by ASD and RETT. Hyperactivity and impulsivity were negatively correlated with Faecalibacterium (phylum Firmicutes) and positively correlated with Bacteroides sp. (phylum Bacteroidetes) in ADHD subjects. Five studies explored microbiota-or diet-targeted interventions in ASD and ADHD. Probiotic treatments with Lactobacillus sp. and fecal microbiota transplantation from healthy donors reduced constipation and ameliorated ASD symptoms in affected children. Perinatal administration of Lactobacillus sp. prevented the onset of Asperger and ADHD symptoms in adolescence. Micronutrient supplementation improved disease symptomatology in ADHD without causing significant changes in microbiota communities’ composition.Discussion: Several discrepancies were found among the included studies, primarily due to sample size, variations in dietary practices, and a high prevalence of functional gastrointestinal symptoms. Further studies employing longitudinal study designs, larger sample sizes and multi-omics technologies are warranted to identify the functional contribution of the intestinal microbiota in developmental trajectories of the human brain and neurobehavior.Systematic review registration: https://clinicaltrials.gov/, CRD42020158734.

Steroid hormones are essential biomolecules for human physiology as they modulate the endocrine system, nervous function and behaviour. Recent studies have shown that the gut microbiota is directly involved in the production and metabolism of steroid hormones in the periphery. However, the influence of the gut microbiota on levels of steroids acting and present in the brain (i.e., neuroactive steroids) is not fully understood. Therefore, using liquid chromatography–tandem mass spectrometry, we assessed the levels of several neuroactive steroids in various brain areas and the plasma of germ-free (GF) male mice and conventionally colonized controls. The data obtained indicate an increase in allopregnanolone levels associated with a decrease in those of 5α-androstane-3α, 17β-diol (3α-diol) in the plasma of GF mice. Moreover, an increase of dihydroprogesterone and isoallopregnanolone in the hippocampus, cerebellum, and cerebral cortex was also reported. Changes in dihydrotestosterone and 3α-diol levels were also observed in the hippocampus of GF mice. In addition, an increase in dehydroepiandrosterone was associated with a decrease in testosterone levels in the hypothalamus of GF mice. Our findings suggest that the absence of microbes affects the neuroactive steroids in the periphery and the brain, supporting the evidence of a microbiota-mediated modulation of neuroendocrine pathways involved in preserving host brain functioning.

Perturbations of the gastrointestinal (GI) microbiota (i.e. dysbiosis) in early life may induce vulnerability of the enteric nervous system (ENS), contributing to early onset GI disorders, such as irritable bowel syndrome (IBS). Probiotics, such as Lacticaseibacillus rhamnosus GG (LGG), may improve pediatric digestive disorders; however, the mechanisms involved, including effects on the ENS, are not yet fully understood. In this study, the long-lasting consequences of antibiotic-induced dysbiosis on intestinal neuromuscular function, as well as the effect of LGG, were evaluated in juvenile female and male mice. One week after antibiotic treatment cessation, broad-spectrum antibiotic treatment induced significant taxonomic changes in both sexes compared to untreated control animals. These changes appeared earlier and involved more potentially harmful bacterial taxa in females than in males. LGG effectively prevented alterations in microbial communities in both sexes, with a more pronounced protective effect in males. Dysbiosis reduced transit efficiency, nitrergic relaxations, and tachykinergic contractions only in females, with no significant effect of LGG in this group. In both sexes, dysbiosis decreased cholinergic contractions; however, LGG restored the excitatory responses to control levels only in males. In summary, early antibiotic-induced dysbiosis in juvenile mice leads to persistent effects during late adolescence on both gut microbiota composition and neuromuscular function. These alterations are more pronounced and less responsive to LGG treatment in females. The findings underscore the critical role of the enteric microbiota in early-life development of functional gastrointestinal disorders with sex-specific features, such IBS.

Obesity is associated with enteric dysfunctions, including gut dysmotility and neurodegeneration, which may involve Toll-like receptor 4 (TLR4) signaling. To investigate this relationship, we examined the impact of TLR4 deficiency on the enteric nervous system (ENS) of the small intestine in a mouse model of high-fat diet (HFD)-induced obesity. Male TLR4^−/− and wild-type (WT) C57BL/6J mice were fed either a standard diet (SD; 18% kcal fat) or an HFD (60% kcal fat) for 8 weeks. ENS alterations were evaluated using real-time qPCR and confocal immunofluorescence microscopy on longitudinal muscle–myenteric plexus (LMMP) whole-mount preparations. Alterations in gut motility were evaluated by assessing stool frequency, transit of a fluorescent-labeled marker, and isometric motor responses of ileal preparations to receptor- and non-receptor-mediated stimuli. In WT mice, HFD induced delayed gastrointestinal transit, impaired cholinergic and nitrergic responses, and altered 5-HT-mediated concentration–response curves. These functional deficits were accompanied by neuroglial network disruption, myenteric neurodegeneration, loss of ChAT⁺ and nNOS⁺ neurons, and increased 5-HT ileal tissue levels. In contrast, TLR4 deficiency mitigated body weight gain and largely prevented HFD-induced structural and functional alterations. Overall, our findings highlight a key role for TLR4 signaling in modulating small intestine inflammation and ENS remodeling associated with obesity.