Slow Gut Transit Research Articles

Slow gut transit increases the risk of Alzheimer’s disease: An integrated study of the bi-national cohort in South Korea and Japan and Alzheimer’s disease model mice

IntroductionAlthough the association between Alzheimer's disease (AD) and constipation is controversial, its causality and underlying mechanisms remain unknown. ObjectivesTo investigate the potential association between slow gut transit and AD using epidemiological data and a murine model. MethodsWe conducted a bi-national cohort study in South Korea (discovery cohort, N=3,130,193) and Japan (validation cohort, N=4,379,285) during the pre-observation period to determine the previous diagnostic history (2009–2010) and the follow-up period (2011–2021). To evaluate the causality, we induced slow gut transit using loperamide in 5xFAD transgenic mice. Changes in amyloid-beta (Aβ) and other markers were examined using ELISA, qRT-PCR, RNA-seq, and behavioral tests. ResultsConstipation was associated with an increased risk of AD in the discovery cohort (hazard ratio, 2.04; 95% confidence interval [CI], 2.01–2.07) and the validation cohort (hazard ratio; 2.82; 95% CI, 2.61–3.05). We found that loperamide induced slower gut transit in 5xFAD mice, increased Aβ and microglia levels in the brain, increased transcription of genes related to norepinephrine secretion and immune responses, and decreased the transcription of defense against bacteria in the colonic tissue. ConclusionImpaired gut transit may contribute to AD pathogenesis via the gut-brain axis, thus suggesting a cyclical relationship between intestinal barrier disruption and Aβ accumulation in the brain. We propose that gut transit or motility may be a modifiable lifestyle factor in the prevention of AD, and further clinical investigations are warranted.

Effect of wheat bran derived prebiotic supplementation on gastrointestinal transit, gut microbiota, and metabolic health: a randomized controlled trial in healthy adults with a slow gut transit

ABSTRACT Acute intake of the wheat bran extract Arabinoxylan-Oligosaccharide (AXOS) modulates the gut microbiota, improves stool characteristics and postprandial glycemia in healthy humans. Yet, little is known on how long-term AXOS intake influences gastrointestinal (GI) functioning, gut microbiota, and metabolic health. In this randomized, placebo-controlled, double-blind study, we evaluated the effects of AXOS intake on GI function and metabolic health in adults with slow GI transit without constipation. Forty-eight normoglycemic adults were included with whole-gut transit time (WGTT) of >35 h receiving either 15 g/day AXOS or placebo (maltodextrin) for 12-wks. The primary outcome was WGTT, and secondary outcomes included stool parameters, gut permeability, short-chain fatty acids (SCFA), microbiota composition, energy expenditure, substrate oxidation, glucose, insulin, lipids, gut hormones, and adipose tissue (AT) function. WGTT was unchanged, but stool consistency softened after AXOS. 12-wks of AXOS intake significantly changed the microbiota by increasing Bifidobacterium and decreasing microbial alpha-diversity. With a good classification accuracy, overall microbiota composition classified responders with decreased WGTT after AXOS. The incretin hormone Glucagon-like protein 1 was reduced after AXOS compared to placebo. Energy expenditure, plasma metabolites, AT parameters, SCFA, and gut permeability were unchanged. In conclusion, intake of wheat bran extract increases fecal Bifidobacterium and softens stool consistency without major effects on energy metabolism in healthy humans with a slow GI transit. We show that overall gut microbiota classified responders with decreased WGTT after AXOS highlighting that GI transit and change thereof were associated with gut microbiota independent of Bifidobacterium. NCT02491125

Clinical science workshop: targeting the gut-liver-brain axis.

A clinical science workshop was held at the ISHEN meeting in London on Friday 11th September 2014 with the aim of thrashing out how we might translate what we know about the central role of the gut-liver-brain axis into targets which we can use in the treatment of hepatic encephalopathy (HE). This review summarises the integral role that inter-organ ammonia metabolism plays in the pathogenesis of HE with specific discussion of the roles that the small and large intestine, liver, brain, kidney and muscle assume in ammonia and glutamine metabolism. Most recently, the salivary and gut microbiome have been shown to underpin the pathophysiological changes which culminate in HE and patients with advanced cirrhosis present with enteric dysbiosis with small bowel bacterial overgrowth and translocation of bacteria and their products across a leaky gut epithelial barrier. Resident macrophages within the liver are able to sense bacterial degradation products initiating a pro-inflammatory response within the hepatic parenchyma and release of cytokines such as tumour necrosis factor alpha (TNF-α) and interleukin-8 into the systemic circulation. The endotoxemia and systemic inflammatory response that are generated predispose both to the development of infection as well as the manifestation of covert and overt HE. Co-morbidities such as diabetes and insulin resistance, which commonly accompany cirrhosis, may promote slow gut transit, promote bacterial overgrowth and increase glutaminase activity and may need to be acknowledged in HE risk stratification assessments and therapeutic regimens. Therapies are discussed which target ammonia production, utilisation or excretion at an individual organ level, or which reduce systemic inflammation and endotoxemia which are known to exacerbate the cerebral effects of ammonia in HE. The ideal therapeutic strategy would be to use an agent that can reduce hyperammonemia and reduce systemic inflammation or perhaps to adopt a combination of therapies that can address both.

Relationship between gut-specific autonomic testing and bowel dysfunction in spinal cord injury patients

Investigation of bowel function in 55 patients and 26 healthy volunteers using radiological, anorectal physiological and laser Doppler blood flow monitoring. Bowel dysfunction is common after spinal cord injury (SCI). We aimed to determine whether hindgut testing of autonomic innervation provides insight into presence of symptoms, altered motor function (transit) and level of injury. St Mark's Hospital, UK and The Spinal Injuries Unit, Royal National Orthopaedic Hospital, UK. A total of 55 patients with chronic complete SCI and 26 healthy volunteers were studied. Twenty-four patients had lesions above T5 and 31 had lesions below T5. Thirty-five patients complained of constipation: 75% (18/24) of patients with lesions above T5 and 55% (17/31) of those with lesions below T5. Gut transit, rectal electrosensitivity and rectal blood flow were measured. Slow gut transit occurred in 65% of patients and in all the 35 patients complaining of constipation. Delay was pancolonic. All patients had an elevated sensory threshold. The threshold was significantly higher in those with subjective constipation (P<0.01), slow transit (P<0.04) and high SCI (P=0.046). Mucosal blood flow was lower in SCI patients with constipation (P<0.04) and slow transit (P<0.03). It was higher than normal in high-SCI volunteers (P=0.056), reflecting loss of sympathetic inhibition. In SCI, subjective constipation correlates closely with slow gut transit. Delay is pancolonic, regardless of the site of lesion. Sensory testing provides evidence for completeness of lesion, offering further evidence for pain transmission through sympathetic pathways. Studies in SCI patients provide further evidence of mucosal blood flow as a marker of altered autonomic innervation.

Ingested placenta blocks the effect of morphine on gut transit in Long–Evans rats

Opioids produce antinociception, and ingested placenta or amniotic fluid modifies that antinociception. More specifically, ingested placenta enhances the antinociception produced by selective activation of central κ-opioid or δ-opioid receptors but attenuates that produced by activation of central μ-opioid receptors. Opioids also slow gut transit by acting on central or peripheral μ-opioid receptors. Therefore, we hypothesized that ingested placenta would reverse the slowing of gut transit that is produced by morphine, a preferential μ-opioid-receptor agonist. Rats were injected with morphine either centrally or systemically and fed placenta, after which gastrointestinal transit was evaluated. We report here that ingested placenta reversed the slowing of gut transit produced by centrally administered morphine but did not affect the slowing of gut transit produced by systemically administered morphine. These results suggest another likely consequence of placentophagia at parturition in mammals—reversal of opioid-mediated, pregnancy-based disruption of gastrointestinal function—as well as an important consideration in opioid-based treatments for pain in humans—enhancement of desirable effects with attenuation of adverse effects.

Effect of a novel prokinetic drug, R093877, on gastrointestinal transit in healthy volunteers

Background—Stronger prokinetic agents which specifically enhance transit in different parts of the gut are required. R093877 is a novel 5-HT4 agonist prokinetic compound which is chemically related to cisapride but...

Clinical Management of Intractable Constipation

To review current management of intractable constipation. Original articles and reviews published in the English-language literature between 1965 and 1993 identified by MEDLINE search. Verbal feedback from attendees after presentation of the document as a clinical symposium at the 14th International Symposium on Gastrointestinal Motility in September 1993. Key words included constipation, epidemiology, colonic inertia, pseudo-obstruction, pelvic floor dysfunction, and results of therapeutic interventions, particularly the effects of biofeedback training and subtotal colectomy. In most patients, constipation is usually due to lack of dietary fiber and responds to simple measures to correct these factors, often without consulting a physician. In some, probably fewer than 10% of patients who consult their physicians, structural diseases of the colon and rectum, systemic disease, or medications that slow gut transit should be excluded, and regular exercise, dietary fiber, and an osmotic laxative prescribed. In a series of 277 highly selected patients from a tertiary referral center who had intractable constipation, only 29% had a definable abnormality; identification of abnormal transit facilitates selection of patients for further investigations identifying colonic inertia or pelvic floor dysfunction. An algorithmic approach can carefully select patients with intractable constipation for behavioral modification and biofeedback; the long-term outcome is excellent, with at least 75% success in several series. In a minority of patients with slow transit constipation unresponsive to medical treatment, subtotal colectomy with ileorectostomy is indicated and effective.

Loperamide effects on hepatobiliary function, intestinal transit and analgesia in mice

Loperamide effects on hepatobiliary function, analgesia and gut transit were studied in mice. Varying doses of the antidiarrheal drug, loperamide, were administered to mice by intracerebroventricular, intravenous, subcutaneous and intragastric routes. Gut motility was determined by intestinal transit of India ink, analgesia by warm water tail flick latency, and hepatobiliary function by retention of the anionic dye, sulfobromophthalein in plasma and liver. When given by all routes at modest doses, loperamide slowed intestinal transit. Analgesia, a centrally mediated opiate effect, wa only detected after intracerebroventricular or subcutaneous loperamide at high, near-toxic doses. Elevations of plasma and liver sulfobromopthalein were noted at routes and doses which slowed gut transit, well below those needed for analgesia. Intragastric loperamide at one fortieth its LD50 caused marked elevation of sulfobromophthalein levels and gut slowing, but no analgesia. Sulfobromopthalein elevation and gut slowing by intragastric loperamide were not affected by spinal cord transection but were reversed by naltrexone, an opiate antagonist. Non-toxic doses of loperamide slow gut transit and modify hepatobiliary function in mice by opiate actions at peripheral sites.