Studio interspecie del sistema nervoso enterico e delle patologie ad esso correlate

The enteric nervous system (ENS) modulates a number of digestive functions including well known ones, i.e. motility, secretion, absorption and blood flow, along with other critically relevant processes, i.e. immune responses of the gastrointestinal (GI) tract, gut microbiota and epithelial barrier . The characterization of the anatomical aspects of the ENS in large mammals and the identification of differences and similarities existing between species may represent a fundamental basis to decipher several digestive GI diseases in humans and animals. In this perspective, the aim of the present thesis is to highlight the ENS anatomical basis and pathological aspects in different mammalian species, such as horses, dogs and humans. Firstly, I designed two anatomical studies in horses: “Excitatory and inhibitory enteric innervation of horse lower esophageal sphincter”. “Localization of 5-hydroxytryptamine 4 receptor (5-HT4R) in the equine enteric nervous system”. Then I focused on the enteric dysfunctions, including: A primary enteric aganglionosis in horses: “Extrinsic innervation of the ileum and pelvic flexure of foals with ileocolonic aganglionosis”. A diabetic enteric neuropathy in dogs: “Quantification of nitrergic neurons in the myenteric plexus of gastric antrum and ileum of healthy and diabetic dogs”. An enteric neuropathy in human neurological patients: “Functional and neurochemical abnormalities in patients with Parkinson's disease and chronic constipation”. The physiology of the GI tract is characterized by a high complexity and it is mainly dependent on the control of the intrinsic nervous system. ENS is critical to preserve body homeostasis as reflect by its derangement occurring in pathological conditions that can be lethal or seriously disabling to humans and animals. The knowledge of the anatomy and the pathology of the ENS represents a new important and fascinating topic, which deserves more attention in the veterinary medicine field

La malattia celiaca nel terzo millennio: Nuove prospettive su patogenesi, clinica, diagnosi e terapia

Celiac disease is a disorder triggered by an immune reaction to gluten contained in wheat and related grains, resulting in the atrophy of small intestinal villi and therefore malabsorption. The identification of tissue transglutaminase as the autoantigen of celiac disease has definitely confirmed the autoimmune nature of this condition. This disease, which can occur only in HLA- DQ2/DQ8 positive patients, is very common in the general population (>1%). Female gender is more commonly affected (F/M = 2:1) and the disease can occur at any age with a myriad of symptoms/manifestations. The great variability of the clinical presentation along with a different expression of diagnostic markers led to the identification of a number of phenotypes, i.e. classical, non classical, subclinical, potential, non-responsive and refractory. The identification of celiac disease is challenging since it can occur not only with diarrhoea and weight loss, but also with other gastrointestinal symptoms (such as constipation, bloating, recurrent abdominal pain), extra- intestinal signs (anaemia, raised transaminases, osteoporosis, recurrent miscarriages, aphthous stomatitis and associated autoimmune disorders) or being completely symptomless. Although small intestinal biopsy remains the diagnostic “gold standard”, highly sensitive and specific serological tests such as tissue transglutaminase and anti-endomysial antibodies of IgA class became more and more important in the diagnostic work-up of celiac disease. Currently, the only treatment for celiac disease is still a long-life strict gluten-free diet, which improves the quality of life with disappearance of symptoms and prevents the complications such as ulcerative jejunoileitis as well as small intestinal adenocarcinoma and lymphoma

Seronegative celiac disease: Shedding light on an obscure clinical entity

Background Although serological tests are useful for identifying celiac disease, it is well established that a minority of celiacs are seronegative. Aim To define the prevalence and features of seronegative compared to seropositive celiac disease, and to establish whether celiac disease is a common cause of seronegative villous atrophy. Methods Starting from 810 celiac disease diagnoses, seronegative patients were retrospectively characterized for clinical, histological and laboratory findings. Results Of the 810 patients, fourteen fulfilled the diagnostic criteria for seronegative celiac disease based on antibody negativity, villous atrophy, HLA-DQ2/-DQ8 positivity and clinical/histological improvement after gluten free diet. Compared to seropositive, seronegative celiac disease showed a significantly higher median age at diagnosis and a higher prevalence of classical phenotype (i.e., malabsorption), autoimmune disorders and severe villous atrophy. The most frequent diagnosis in the 31 cases with seronegative flat mucosa was celiac disease (45%), whereas other diagnoses were Giardiasis (20%), common variable immunodeficiency (16%) and autoimmune enteropathy (10%). Conclusions Although rare seronegative celiac disease can be regarded as the most frequent cause of seronegative villous atrophy being characterized by a high median age at diagnosis; a close association with malabsorption and flat mucosa; and a high prevalence of autoimmune disorders

Features and Progression of Potential Celiac Disease in Adults

Background & Aims: Individuals with potential celiac disease have serologic and genetic markers of the disease with little or no damage to the small intestinal mucosa. We performed a prospective study to learn more about disease progression in these people. Methods: We collected data from 77 adults (59 female; median age, 33 years) diagnosed with potential celiac disease (on the basis of serology and HLA type) at Bologna University in Italy from 2004 through 2013. The subjects had normal or slight inflammation of the small intestinal mucosa. Clinical, laboratory, and histologic parameters were evaluated at diagnosis and during a 3-year follow-up period. Results: Sixty-one patients (46 female; median age, 36 years) showed intestinal and extraintestinal symptoms, whereas the remaining 16 (13 female; median age, 21 years) were completely asymptomatic at diagnosis. All subjects tested positive for immunoglobulin A endomysial antibody and tissue transglutaminase antibody, except for 1 patient with immunoglobulin A deficiency; 95% of patients were carriers of HLA-DQ2. Duodenal biopsies from 26% patients had a Marsh score of 0, and 74% had a Marsh score of 1. A higher proportion of symptomatic patients had autoimmune disorders (36%) and antinuclear antibodies (41%) than asymptomatic patients (5% and 12.5%, respectively), and symptomatic patients were of older age at diagnosis (P <.05). Gluten withdrawal led to significant clinical improvement in all 61 symptomatic patients. The 16 asymptomatic patients continued on gluten-containing diets, and only 1 developed mucosal flattening; levels of anti-endomysial and tissue transglutaminase antibodies fluctuated in 5 of these patients or became undetectable. Conclusions: In a 3-year study of adults with potential celiac disease, we found most to have symptoms, but these improved on gluten withdrawal. Conversely, we do not recommend a gluten-free diet for asymptomatic adults with potential celiac disease because they do not tend to develop villous atrophy

Effects of Chronic Enteropathies on VIPergic and Nitrergic Immunoreactive Neurons in the Dog Ileum

Introduction: The enteric nervous system (ENS) comprises a huge amount of neurons and nerve fibers interposed between the two muscular layers of the tunica muscularis and in the submucosa. Neuropeptides produced by the ENS neurons act as neurotransmitters/neuromodulators, which control intestinal motility and mucosal functions, and play a crucial role also in the regulation of inflammatory processes via cross talk with the local immune system. A growing body of evidence indicates that the gastrointestinal inflammatory response damages the enteric neurons themselves, thus resulting in deregulations in gut motility and mucosal functions. Keywords: Enteric Nervous System; Ileum; Immunohistochemistry; Neuronal Nitric Oxide Synthase; Vasoactive Intestinal Peptide Objective: The purpose of this study was to evaluate quantitatively enteric neurons immunoreactive for the vasoactive intestinal polypeptide (VIP) and neuronal nitric oxide synthase (nNOS) in the myenteric (MP) and submucosal (SMP) plexus of the ileum of dogs without (CTRL-dogs) and with spontaneous chronic enteritis (inflamed dogs, INF). In addition, the percentage of nNOS immunoreactive neurons co-expressing VIP immunoreactivity (and vice versa) was evaluated. Methods and Material: Animal tissues were collected from the ileum of six control (CTRL) dogs (none had evident gastrointestinal disorders) and ten INF-dogs with chronic enteritis of the ileum. All the enteric neurons, VIPergic and nitrergic neurons were immunohistochemically identified with the anti-HuC/HuD, anti-VIP, and anti-nNOS antibodies, respectively. VIP- and nNOS-immunoreactive neurons were immunohistochemically quantified as a relative percentages, in consideration of the total number of HuC/HuD neurons. Data were expressed as mean \ub1 standard deviation. Results: In the myenteric plexus of INF-dogs, the percentage of VIPergic neurons (16 \ub1 7%) was significantly greater than that observed in the CTRL-dogs (8 \ub1 3%) (P = 0,022). Conversely, in the submucosal plexus of CTRL- and INF-dogs the percentages of VIPergic neurons were similar (31 \ub1 9% and 30 \ub1 11%, respectively; P = 0,786). In the myenteric plexus of INF-dogs, the percentage of nitrergic neurons (24 \ub1 5%) showed only a tendency to decrease in comparison to that evaluated in the CTRL-dogs (29 \ub1 5%) (P = 0.138); also in the submucosal plexus the percentages of nitrergic neurons of CTRL-dogs (8 \ub1 5%) and INF-dogs (7 \ub1 2%) did not show meaningful differences (P = 0.884). Co-localization studies indicated that also the percentages of nitrergic neurons co-expressing VIP immunoreactivity did not change between CTRL- and INF-dogs in the MP (23 \ub1 12% and 24 \ub1 10%, respectively; P = 0.935) and SMP (26 \ub1 16% and 23 \ub1 15%, respectively; P = 0.810). Conclusion: This is the first quantitative study about the VIPergic and nitrergic neurons harbored in the in MP and SMP of the canine ileum and the first comparison between these subclasses of neurons in dogs with and without chronic enteritis. Our findings showed significan

Gastrointestinal Involvement in Anderson-Fabry Disease: A Narrative Review

Anderson-Fabry disease (FD) is an X-linked lysosomal storage disorder leading to a wide array of clinical manifestations. Among these, gastrointestinal (GI) symptoms such as abdominal pain, bloating, and diarrhea affect about half of the FD adults and more than half of FD children. GI symptoms could be the first manifestation of FD; however, being non-specific, they overlap with the clinical picture of other conditions, such as irritable bowel syndrome and inflammatory bowel disease. This common overlap is the main reason why FD patients are often unrecognized and diagnosis is delayed for many years. The present narrative review is aimed to promote awareness of the GI manifestations of FD amongst general practitioners and specialists and highlight the latest findings of this rare condition including diagnostic tools and therapies. Finally, we will discuss some preliminary data on a patient presenting with GI symptoms who turned to be affected by a variant of uncertain significance of alpha-galactosidase (GLA) gene

Nutritional Treatment in Crohn’s Disease

Crohn’s disease (CD) is a chronic inflammatory bowel disease (IBD) which can affect any part of the whole gastrointestinal tract (from mouth to anus). Malnutrition affects 65–75% of CD patients, and it is now well acknowledged that diet is of paramount importance in the management of the disease. In this review, we would like to highlight the most recent findings in the field of nutrition for the treatment of CD. Our analysis will cover a wide range of topics, from the well-established diets to the new nutritional theories, along with the recent progress in emerging research fields, such as nutrigenomics

LPAR1 regulates enteric nervous system function through glial signaling and contributes to chronic intestinal pseudo-obstruction

Gastrointestinal motility disorders involve alterations to the structure and/or function of the enteric nervous system (ENS) but the causal mechanisms remain unresolved in most cases. Homeostasis and disease in the ENS are processes that are regulated by enteric glia. Signaling mediated through type I lysophosphatidic acid receptors (LPAR1) has recently emerged as an important mechanism that contributes to disease, in part, through effects on peripheral glial survival and function. Enteric glia express LPAR1 but its role in ENS function and motility disorders is unknown. We used a combination of genetic, immunohistochemical, calcium imaging, and in vivo pharmacological approaches to investigate the role of LPAR1 in enteric glia. LPAR1 was enriched in enteric glia in mice and humans and LPA stimulated intracellular calcium responses in enteric glia, subsequently recruiting activity in a subpopulation of myenteric neurons. Blocking LPAR1 in vivo with AM966 attenuated gastrointestinal motility in mice and produced marked enteric neuro- and gliopathy. Samples from humans with chronic intestinal pseudo-obstruction (CIPO), a severe motility disorder, showed reduced glial LPAR1 expression in the colon and ileum. These data suggest that enteric glial LPAR1 signaling regulates gastrointestinal motility through enteric glia and could contribute to severe motility disorders in humans such as CIPO

Autoimmune enteropathy: not all flat mucosa mean coeliac disease

A 62-year-old woman complaining of severe malabsorption was diagnosed with celiac disease based on the findings of flat, small intestinal mucosa and HLA-DQ2 positivity, although celiac serology was negative. This diagnosis was questioned due to the lack of clinical and histological improvement after a long period of strict gluten-free diet. The detection of enterocyte autoantibodies guided to the correct diagnosis of autoimmune enteropathy, leading to a complete recovery of the patient following an appropriate immunosuppressive treatment. Autoimmune enteropathy should be considered in the differential diagnosis of malabsorption with severe villous atrophy, including those cases with negative celiac-related serology