Evaluation of bidirectional gut-brain axis and anorectal function in Parkinson's disease with constipation.

BACKGROUND: Parkinson's disease (PD) is a neurodegenerative movement disorder with prodromal and highly prevalent gastrointestinal (GI) symptoms, especially constipation. Although PD models suggest gut-brain axis dysfunction, the mechanistic underpinnings and their correlation with GI symptoms are poorly understood. AIM: To examine the bidirectional gut-brain axis function in PD and correlate it with constipation severity, PD duration, and severity. METHODS: Rectal sensory thresholds and afferent cortical evoked potentials (CEP) were assessed using a 4-ring EMG electrode probe. Efferent anal and rectal motor evoked potentials (MEPs) were obtained following transcranial and lumbosacral magnetic stimulation. Bowel symptoms were assessed by prospective stool diary. The CEP and MEP latencies, rectal sensory thresholds, and anorectal sensorimotor data were compared between PD subjects and age-adjusted healthy subjects. KEY RESULTS: Twenty-five PD subjects with constipation (F/M = 6/19) and 20 healthy subjects (F/M = 14/6) were enrolled. The first and pain sensation thresholds were higher in PD subjects than healthy subjects (p < 0.002) but lost significance after adjustment for age. Age-adjusted rectal CEP and right-sided cortico-anal MEP latencies were prolonged in PD subjects compared to healthy subjects (p < 0.04). Also, half (4 of 8) age-adjusted spino-anal and rectal MEP latencies in PD subjects were significantly longer. In multivariate linear analysis, first rectal sensation and right-sided MEP latencies showed moderate correlation with constipation severity. CONCLUSIONS & INFERENCES: Parkinson's disease is associated with significant bidirectional gut-brain axis dysfunction as evidenced by prolonged afferent and efferent neuronal signaling. Constipation severity in PD is correlated to abnormal rectal sensation and lateralized disturbance of efferent brain-gut signaling.

Step on the accelerator: modern treatment of constipation.

PURPOSE OF REVIEW: This review aims to explore effective management of constipation, examine challenges in making a positive diagnosis, and highlights the significance of a positive patient-provider relationship and emerging treatments. RECENT FINDINGS: Less than one-fifth of patients feel satisfied with treatment of their constipation. Sixty percent of patients with functional dyspepsia and gastroparesis have severe to very severe constipation that correlates with their upper gastrointestinal symptom severity. Two gold kiwifruits are noninferior to 10 g of psyllium in the treatment of constipation. More than 40% of patients undergoing lumbar fusion continue to fill opioid prescriptions 90 days after surgery, contributing to 80 000 chronic opioid users annually. Most patients are using over-the-counter (OTC) treatments for constipation with greater than 60% dissatisfied. Pharmacologic management involves the use of GCC agonists and emerging drug classes such as bile acid transport inhibitors and sodium hydrogen exchanger isoform 3 (NHE3) inhibitors. Nonpharmacologic treatments, including neuromodulation and FDA-approved vibrating capsule, show promise in improving symptoms and quality of life. SUMMARY: Constipation significantly impacts patients' quality of life and well being and the majority of patients are refractory to conservative measures and OTC treatments. Both pharmacologic and nonpharmacologic treatments hold promise for improving constipation and quality of life.

Tenapanor in the Treatment of Irritable Bowel Syndrome with Constipation: Discovery, Efficacy, and Role in Management.

Irritable bowel syndrome (IBS) is a common disorder of gut-brain interaction (DGBI). IBS significantly impacts the quality of life of patients. Since its pathogenesis is unclear and can be multifactorial, it highlights the need for new and improved pharmaceutical drugs that not only improve bowel symptoms, but also address global IBS symptoms, such as abdominal pain. Tenapanor, a recently Food & Drug Administration (FDA)-approved medication for IBS with constipation (IBS-C), is a small molecule inhibitor of the sodium/hydrogen exchanger isoform 3 (NHE3) that inhibits the absorption of sodium and phosphate in the gastrointestinal tract, resulting in fluid retention and softer stool. Furthermore, tenapanor reduces intestinal permeability to improve visceral hypersensitivity and abdominal pain. Due to its recent approval, tenapanor was not included in the recent IBS guidelines, however, it may be considered for IBS-C patients failing first-line treatment of soluble fiber. In this review article, we aim to provide in-depth information to the reader regarding the design of tenapanor, its development through Phase I, II and III randomized clinical trials, and its role in the treatment of IBS-C.

Parkinson's Disease and Diabetes Mellitus: Synergistic Effects on Pathophysiology and GI Motility.

PURPOSE OF REVIEW: Parkinson's disease and diabetes affect an increasing proportion of the aging global population. Both conditions extensively affect gastrointestinal (GI) motility with similar and differing clinical symptoms. Nonetheless, GI symptoms in Parkinson's disease and diabetes pose significant morbidity and impairment of quality of life. Their pathophysiology is poorly understood, and therefore, effective treatment options are lacking. RECENT FINDINGS: Parkinson's disease patients have oropharyngeal dysphagia and constipation. They also have mild or absent upper GI symptoms associated with delayed gastric emptying, which is prevalent in 70% of patients. Delayed gastric emptying in Parkinson's disease leads to erratic medication absorption and fluctuating motor symptoms. Half of diabetics have upper GI symptoms, which correlate to gastric emptying and changes in brain activity of the insular cortex. The majority of diabetics also have constipation. Diabetics have an increased risk for developing Parkinson's disease and anti-diabetic medications are associated with risk reduction of developing Parkinson's disease. Hyperglycemia is associated with advanced glycated end products formation and acceleration of α-synuclein aggregation. GLP-1 receptor agonists have also demonstrated efficacy in improving motor symptoms and cognition in Parkinson's disease patients with diabetes. Parkinson's disease and diabetes are pan-enteric disorders with significant GI symptoms and impairment of gut motility. Both conditions have synergistic pathophysiologies that propagate neurodegenerative changes. Treatment options for GI symptoms in diabetic and Parkinson's disease patients are lacking. Anti-diabetic treatment improves motor symptoms in Parkinson's disease, however, its effect on GI symptoms is unclear.