Nutritional, Gastrointestinal and Endo-Metabolic Challenges in the Management of Children with Spinal Muscular Atrophy Type 1.

The management of patients with spinal muscular atrophy type 1 (SMA1) is constantly evolving. In just a few decades, the medical approach has switched from an exclusively palliative therapy to a targeted therapy, transforming the natural history of the disease, improving survival time and quality of life and creating new challenges and goals. Many nutritional problems, gastrointestinal disorders and metabolic and endocrine alterations are commonly identified in patients affected by SMA1 during childhood and adolescence. For this reason, a proper pediatric multidisciplinary approach is then required in the clinical care of these patients, with a specific focus on the prevention of most common complications. The purpose of this narrative review is to provide the clinician with a practical and usable tool about SMA1 patients care, through a comprehensive insight into the nutritional, gastroenterological, metabolic and endocrine management of SMA1. Considering the possible horizons opened thanks to new therapeutic frontiers, a nutritional and endo-metabolic surveillance is a crucial element to be considered for a proper clinical care of these patients.

Central Neurocircuits Regulating Food Intake in Response to Gut Inputs-Preclinical Evidence.

The regulation of energy balance requires the complex integration of homeostatic and hedonic pathways, but sensory inputs from the gastrointestinal (GI) tract are increasingly recognized as playing critical roles. The stomach and small intestine relay sensory information to the central nervous system (CNS) via the sensory afferent vagus nerve. This vast volume of complex sensory information is received by neurons of the nucleus of the tractus solitarius (NTS) and is integrated with responses to circulating factors as well as descending inputs from the brainstem, midbrain, and forebrain nuclei involved in autonomic regulation. The integrated signal is relayed to the adjacent dorsal motor nucleus of the vagus (DMV), which supplies the motor output response via the efferent vagus nerve to regulate and modulate gastric motility, tone, secretion, and emptying, as well as intestinal motility and transit; the precise coordination of these responses is essential for the control of meal size, meal termination, and nutrient absorption. The interconnectivity of the NTS implies that many other CNS areas are capable of modulating vagal efferent output, emphasized by the many CNS disorders associated with dysregulated GI functions including feeding. This review will summarize the role of major CNS centers to gut-related inputs in the regulation of gastric function with specific reference to the regulation of food intake.

Potential of Electrical Neuromodulation for Inflammatory Bowel Disease.

Inflammatory bowel disease (IBD) is a common chronic inflammatory disease of the digestive tract that is often debilitating. It affects patients' quality of life and imposes a financial burden. Despite advances in treatment with medications such as biologics, a large proportion of patients do not respond to medical therapy or develop adverse events. Therefore, alternative treatment options such as electrical neuromodulation are currently being investigated. Electrical neuromodulation, also called bioelectronic medicine, is emerging as a potential new treatment for IBD. Over the past decade, advancements have been made in electrical neuromodulation. A number of electrical neuromodulation methods, such as vagus nerve stimulation, sacral nerve stimulation, and tibial nerve stimulation, have been tested to treat IBD. A series of animal and clinical trials have been performed to evaluate efficacy with promising results. Although the exact underlying mechanisms of action for electrical neuromodulation remain to be explored, this modality is promising. Further randomized controlled trials and basic experiments are needed to investigate efficacy and clarify intrinsic mechanisms.

Electroacupuncture via chronically implanted electrodes improves gastrointestinal motility by balancing sympathovagal activities in a rat model of constipation.

Electroacupuncture (EA) has been reported for treating constipation in clinical studies. However, little is known of the possible mechanisms involved in the prokinetic effect of EA. The aim of this study was to investigate the effects and underlying autonomic mechanisms of EA via chronically implanted electrodes for constipation in rat induced by Loperamide (Lop). Lop was given to regular rats to induce constipation. EA was performed via a pair of electrodes chronically implanted at bilateral acupoint ST-36. Feces characteristics, gastric emptying, small intestinal transit, distal colon transit time (dCTT), and whole gut transit time (WGTT) were measured in various sessions with EA or sham EA in rats with constipation induced by Lop. Heart rate variability (HRV) derived from the electrocardiogram was analyzed to evaluate autonomic functions. The number of fecal pellets was reduced by 27% with Lop (P < 0.01) and normalized by 7-day EA. Similar results were also observed in pellet weight. In normal rats compared with sham EA, EA shortened dCTT by 74% (P < 0.05 vs. sham EA), increased small intestinal transit by 28% (P < 0.01) and gastric emptying by 27% (P < 0.05), and accelerated whole gut transit by 14% (P < 0.05). In Lop-treated rats, the dCTT and WGTT were prolonged by Lop and normalized by EA. Lop significantly decreased vagal activity and increased sympathetic nerve activity; however, EA reversed these effects. EA at ST-36 via chronically implanted electrodes improves Lop-induced constipation by enhancing GI motility via the autonomic mechanisms. NEW & NOTEWORTHY The findings of the present study suggest that the proposed electroacupuncture (EA) may have great therapeutic potential for treating patients with opioid-induced constipation. It was demonstrated that EA at ST-36 improved transit of every organ along the gut mediated via the autonomic mechanisms in normal rats and rats with Lop-induced constipation. It is advised to administrate EA daily instead of two or three times weekly as reported in most of the clinical studies.

Use of Bioelectronics in the Gastrointestinal Tract.

Gastrointestinal (GI) motility disorders are major contributing factors to functional GI diseases that account for >40% of patients seen in gastroenterology clinics and affect >20% of the general population. The autonomic and enteric nervous systems and the muscles within the luminal GI tract have key roles in motility. In health, this complex integrated system works seamlessly to transport liquid, solid, and gas through the GI tract. However, major and minor motility disorders occur when these systems fail. Common functional GI motility disorders include dysphagia, gastroesophageal reflux disease, functional dyspepsia, gastroparesis, chronic intestinal pseudo-obstruction, postoperative ileus, irritable bowel syndrome, functional diarrhea, functional constipation, and fecal incontinence. Although still in its infancy, bioelectronic therapy in the GI tract holds great promise through the targeted stimulation of nerves and muscles.

Bioelectric neuromodulation for gastrointestinal disorders: effectiveness and mechanisms.

The gastrointestinal tract has extensive, surgically accessible nerve connections with the central nervous system. This provides the opportunity to exploit rapidly advancing methods of nerve stimulation to treat gastrointestinal disorders. Bioelectric neuromodulation technology has considerably advanced in the past decade, but sacral nerve stimulation for faecal incontinence currently remains the only neuromodulation protocol in general use for a gastrointestinal disorder. Treatment of other conditions, such as IBD, obesity, nausea and gastroparesis, has had variable success. That nerves modulate inflammation in the intestine is well established, but the anti-inflammatory effects of vagal nerve stimulation have only recently been discovered, and positive effects of this approach were seen in only some patients with Crohn's disease in a single trial. Pulses of high-frequency current applied to the vagus nerve have been used to block signalling from the stomach to the brain to reduce appetite with variable outcomes. Bioelectric neuromodulation has also been investigated for postoperative ileus, gastroparesis symptoms and constipation in animal models and some clinical trials. The clinical success of this bioelectric neuromodulation therapy might be enhanced through better knowledge of the targeted nerve pathways and their physiological and pathophysiological roles, optimizing stimulation protocols and determining which patients benefit most from this therapy.

Silibinin decreases hepatic glucose production through the activation of gut-brain-liver axis in diabetic rats.

Silibinin, a flavonolignan derived from milk thistle (Silybum marianum), has been revealed to have a beneficial effect on improving diabetes-impaired glycemic control. However, the underlying mechanism is still unclear. In the present study, to evaluate whether the gut-brain-liver axis, an important neural pathway for the control of hepatic glucose production, is involved in silibinin-regulated glucose homeostasis, the expression of glucagon-like peptide-1 receptor (GLP1R) in the duodenum, activation of neurons in the nucleus of the solitary tract (NTS), as well as glycogen accumulation and expression of gluconeogenic enzymes in the livers of diabetic SHRSP·Z-Leprfa/IzmDmcr (SP·ZF) rats with 4-week oral administration of silibinin (100 and 300 mg kg-1 day-1) were evaluated. Common hepatic branch vagotomy was further conducted in high-fat diet/streptozotocin (HFD/STZ)-induced diabetic SD rats to confirm the role of the gut-brain-liver axis in silibinin-improved glycemic control. The results revealed a significant inhibition of fasting blood glucose after SP·ZF rats were administrated with silibinin for 4 weeks. The expression of GLP1R in the duodenum and the activation of neurons in the NTS increased, while hepatic glucose production decreased on silibinin administration. However, the hypoglycemic effect of silibinin was reversed by common hepatic branch vagotomy in diabetic SD rats. Our study suggested that silibinin may be useful as a potential functional food ingredient against diabetes by triggering the gut-brain-liver axis.

Preventive effects of transcutaneous electrical acustimulation on ischemic stroke-induced constipation mediated via the autonomic pathway.

The aim of this study was to explore the preventive effect and possible mechanisms of transcutaneous electrical acustimulation (TEA) on stroke-induced constipation. A total of 86 ischemic stroke patients were randomly allocated to 2-wk TEA or sham-TEA group. Bowel dairy and Bristol Stool Form Scale were recorded daily. Constipation and dyspeptic symptom assessment was performed at the end of the 14-day treatment. Electrocardiogram was recorded for the assessment of autonomic function. The correlation between autonomic function at admission and stroke severity was assessed. The univariate and multivariate regression analyses were performed to investigate the risk factors for stroke-induced constipation. The cumulative incidence of stroke-induced constipation was 68.2% at the acute stage. Sympathetic nerve activity at admission was positively correlated with stroke severity ( R = 0.47, P < 0.001). Sympathetic nerve activity and stroke severity were independent risk factors for stroke-induced constipation. TEA decreased cumulative incidence of stroke-induced constipation (42.9 vs. 68.2%, P = 0.029). TEA significantly increased frequency of bowel movements (4.5 vs. 5.5, P = 0.001) and spontaneous bowel movements (3.0 vs. 4.5, P = 0.003) per week. TEA decreased straining defecations (0.2 vs. 0, P < 0.001) and laxative use (1 vs. 0, P < 0.001). TEA improved stool consistency and patients' quality of life ( P < 0.05, resp.). TEA increased vagal activity ( P < 0.001 vs. baseline) and decreased sympathetic activity ( P < 0.001 vs. baseline). Ischemic stroke patients are predisposed to autonomic function imbalance. TEA was effective in the prevention of stroke-induced constipation, and the effect was possibly mediated via the autonomic function. NEW & NOTEWORTHY This study illustrated that the brain-gut dysfunction, primarily autonomic function imbalance, was correlated with the stroke-induced constipation. This was the first study to report that transcutaneous electrical acustimulation had a preventive effect on stroke-induced constipation, suggesting a potential novel therapy for bowel problem management. The effect was possibly mediated via the autonomic function.

Electrical therapies for gastrointestinal motility disorders.

INTRODUCTION: Gastrointestinal (GI) motility disorders are common in clinical settings, including esophageal motility disorders, gastroesophageal reflux disease, functional dyspepsia, gastroparesis, chronic intestinal pseudo-obstruction, post-operative ileus, irritable bowel syndrome, diarrhea and constipation. While a number of drugs have been developed for treating GI motility disorders, few are currently available. Emerging electrical stimulation methods may provide new treatment options for these GI motility disorders. Areas covered: This review gives an overview of electrical therapies that have been, and are being developed for GI motility disorders, including gastroesophageal reflux, functional dyspepsia, gastroparesis, intestinal motility disorders and constipation. Various methods of gastrointestinal electrical stimulation are introduced. A few methods of nerve stimulation have also been described, including spinal cord stimulation and sacral nerve stimulation. Potentials of electrical therapies for obesity are also discussed. PubMed was searched using keywords and their combinations: electrical stimulation, spinal cord stimulation, sacral nerve stimulation, gastrointestinal motility and functional gastrointestinal diseases. Expert commentary: Electrical stimulation is an area of great interest and has potential for treating GI motility disorders. However, further development in technologies (devices suitable for GI stimulation) and extensive clinical research are needed to advance the field and bring electrical therapies to bedside.