Background and Purpose: Inflammatory bowel disease (IBD) patients display genetic polymorphisms in toll‐like receptor 4 (TLR4) genes, contributing to dysregulate enteric nervous system (ENS) circuits with increased levels of 5‐HT and alteration of the neuroimmune crosstalk. In this study, we investigated the impact of TLR4 signalling on mouse ENS dysfunction caused by dextran sulphate sodium (DSS)‐induced ileitis.Experimental Approach: Male C57BL/6J (wild‐type [WT]) and TLR4^−/− mice (10 ± 2 weeks old) received 2% DSS in drinking water for 5 days and then were switched to 3‐day regular drinking water. Histological analysis and proinflammatory cytokine mRNA levels were assessed in ileal samples. Gut motility was evaluated by changes in transit of a fluorescent‐labelled marker and isometric neuromuscular responses of ileal full‐thickness segments to receptor and non‐receptor‐mediated stimuli. Alterations in ENS architecture were assessed by confocal immunohistochemistry in longitudinal muscle–myenteric plexus whole‐mount preparations.Key Results: In WT mice, DSS treatment caused delayed gastrointestinal transit, ileal myenteric neurodegeneration, reactive gliosis and release of proinflammatory cytokines. Enhanced cholinergic and tachykinergic excitatory tone, increased inducible nitric oxide synthase (iNOS)‐mediated relaxation, and changes in 5‐HT_2A and 5‐HT₃ receptor‐mediated responses were observed during ileitis in WT mice. TLR4 deficiency reversed most of the functional and morphological abnormalities.Conclusion and Implications: Our results demonstrate that TLR4 activity influences the severity of ileitis, neuroglial plasticity, gut motility, and nitrergic and 5‐HTergic neurotransmissions. The neuroimmune interaction between TLR4 and 5‐HT observed in our study appears to be a potential pharmacological target to treat ENS dysfunction implicated in IBD onset/progression.

Proton pump inhibitors (PPIs) are the first-line treatment for gastroesophageal reflux disease (GERD). However, due to their intrinsic limitations, there are still unmet clinical needs that have fostered the development of potassium-competitive acid blockers (p-CABs). Currently, four different drugs (vonoprazan, tegoprazan, fexuprazan, keverprazan) are marketed in some Asian countries, whereas only vonoprazan and tegoprazan are available in Western countries (U.S.A. and Brazil or Mexico, respectively). This review summarizes the current knowledge on p-CABs acute and long-term safety in GERD treatment compared to that of PPIs. Full-text articles and abstracts were searched in PubMed. p-CABs proved to address some of the unmet clinical needs in GERD, with a favorable risk-benefit ratio compared to conventional PPIs. Preclinical and clinical findings have highlighted p-CAB safety to be superimposable, to that of PPIs, in short-term treatments, although further studies are warranted to monitor their effects in long-term therapy. From an epidemiological point of view, the paucity of rigorous data for many variables (e.g. age, ethnicity, drug interactions, comorbidities, genetic polymorphisms, interindividual susceptibility, microbial dysbiosis) deserves a worldwide framework of continuous pre/post-marketing pharmacovigilance programs to reduce potential confounding factors and accurately link acute and chronic p-CAB therapy to adverse outcomes.

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.

Researchers are increasingly focusing on understanding the microbiota’s influence on disease susceptibility and overall health. The vast number of microorganisms in our gastrointestinal tract and their extensive surface area underscore their undeniable impact on well-being. Viewing the gut microbiome as a distinct pool of microbial genetic information that interacts with the human genome highlights its pivotal role in genetically predisposed diseases. Investigating this complex crosstalk may lead to the development of novel therapeutic strategies—such as targeting dysbiosis—to complement conventional treatments and improve patient care. Parkinson’s disease (PD) is a multifactorial condition originating from a combination of genetic and environmental risk factors. Compelling evidence points to the enteric nervous system as an initial site of pathological processes that later extend to the brain—a pattern known as the ‘body-first’ model. Furthermore, most patients with PD exhibit both qualitative and quantitative alterations in the composition of the gut microbiota, including dysbiosis and small intestinal overgrowth. Nonetheless, the existing literature predominantly addresses fecal microbiota, while knowledge of upper intestinal sections, like the duodenum, remains scarce. Given the potential for microbiota modulation to impact both motor and gastrointestinal symptoms, further research exploring the therapeutic roles of balanced diets, probiotics, and fecal transplants in PD is warranted.

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.

Researchers are increasingly focused on understanding how the microbiota influences disease susceptibility and contributes to overall health. Given the vast number of microorganisms inhabiting our gastrointestinal tract and the extensive surface area they occupy, their impact on our well-being is undeniable. For example, when we consider the gut microbiota's collective genetic information—referred to as the microbiome—and view our genetic profile as a blend of both microbial and human genes, it becomes evident that the microbiota may play a pivotal role in the development of genetically predisposed diseases. Investigating these complex interactions could pave the way for new therapeutic strategies, such as targeting dysbiosis, to complement conventional treatments and enhance patient care. Parkinson's disease (PD) is a multifactorial condition characterized by various genetic and environmental factors that collectively increase the risk of developing the disease. There is strong evidence of the involvement of the enteric nervous system where the pathological processes may start initially and to proceed later to the brain. Moreover, it has been observed that most of PD patients exhibit qualitative and quantitative alterations in the composition of the intestinal microbiota, such as dysbiosis and increased proliferation in the small intestine. Despite this evidence, the available literature largely focuses on information regarding the fecal microbiota, while knowledge of the microbiota in the upper sections of the intestine, such as the duodenum, remains limited. Since modulation of the microbiota may have an effect on both motor and gastrointestinal symptoms, further research exploring how a balanced diet, probiotics, and/or fecal transplants may have a role in PD therapy is warranted.