Shen-ling-bai-zhu-san, a spleen-tonifying Chinese herbal formula, alleviates lactose-induced chronic diarrhea in rats

In our previous study, we demonstrated that Shen-ling-bai-zhu-san (SL), a classical Chinese herbal formula, could alleviate lactose-induced diarrhea. However, little is known about the mechanism underlying SL action or the efficacy of the polysaccharide (PL) derived from SL. In this study, we investigated the effect of SL and PL on improving the dysregulated luminal and mucosal microbiota in rats with high lactose diet using 16S rRNA analysis. The concentrations of lactose, lactic acid in cecum and short-chain fatty acids (SCFAs) in cecum and portal vein were measured, meanwhile the expression of ion transporters were ascertained. Our data suggest that the SL, PL and cecal microbiota transplantation (CMT) significantly decreased fecal water content and water intake. In the luminal microbiota there was a significant increase in Akkermansia, Bifidobacterium and Blautia and a lower abundance of Lactobacillus, Escherichia-Shigella, and Dubosiella, while the mucosal microbiota showed a significant increase in Bifidobacterium, Akkermansia, Albaculum, Bilophila, and Coriobacteriaceae_UCG-002 and a lower abundance of Enterococcus, Helicobacter, Dubosiella, and Collinsella. Furthermore, the treatments enhanced lactose fermentation and SCFA production, which may be related to the modulation of the luminal microbial community. A lower ratio of phosphorylation Na/H exchanger3/Na/H exchanger3 (pNHE3/NHE3) and a higher sodium monocarboxylate1 (sMCT1) expression were found in the treatment group than in the model group, which may be related to the changes in the mucosal microbial community. Also, the treatments may restore the impacted metabolic pathways of gut microbiota. These results provide an important foundation for mechanism of SL action and developing PL-based treatment for lactose-induced diarrhea.

Jian-Pi-Yin decoction attenuates lactose-induced chronic diarrhea in rats by regulating GLP-1 and reducing NHE3 ubiquitination and phosphorylation

Garcinia buchananii bark extract is an effective anti-diarrheal remedy for lactose-induced diarrhea

1. We set out to ascertain the role of tachykinins, neurokinin A and substance P, in castor oil-induced diarrhoea in rats as disclosed by the inhibitory effect of the non-peptide NK1- and NK2-receptor antagonists. SR 140333 and SR 48968, respectively. 2. SR 48968 (0.02 to 20 micrograms kg-1, s.c. or p.o.), and the opioid receptor agonist loperamide (1-10 mg kg-1, p.o.), dose-dependently prevented castor oil effects: % inhibition vs castor oil, diarrhoea 0 to 100, increase in faecal mass 7 to 90 and water content 16 to 90. SR 140333 (0.02 to 20 micrograms kg-1, s.c.) and the platelet activating factor antagonist SR 27417 (5 to 500 micrograms kg-1, p.o.) did not prevent the increase in faecal water content, but reduced faecal mass (35 to 66%) and diarrhoea (0 to 57%). 3. The R-enantiomers of tachykinin NK1 and NK2 receptor antagonists, SR 140603 and SR 48605 (both at 2 or 20 micrograms kg-1, s.c.) had no effect other than reducing faecal mass at the highest dose tested. 4. SR 48968 (20 micrograms kg-1, p.o.) but not loperamide (10 mg kg-1, p.o.) given 24 h before castor oil, still slightly but significantly reduced by 30% the increase of faecal mass output; both treatments significantly reduced (30 to 70%) the effect of castor oil on faecal water content, although the incidence of diarrhoea was only slightly less than in controls. 5. In castor oil-treated rats, naloxone (2 mg kg-1, s.c.) completely blocked the antidiarrhoeal action of loperamide (10 mg kg-1, p.o.) but not of SR 48968 (20 micrograms kg-1, p.o.): a similar result was obtained on faecal mass and water content. 6. Castor oil strongly increased the occurrence of manometrically recorded propulsive giant contractions (500 to 1000% over control values) of transverse and distal colon, this effect being significantly prevented (80 to 100%) by SR 48968 and loperamide and partially by SR 140333 (35% distal colon, 70% transverse colon). 7. In castor oil free rats, loperamide but not SR 48968 or SR 140333 significantly reduced by 50% the gastrointestinal transit of a charcoal test meal, as well as 24 h faecal mass output. Consistently, loperamide, unlike the tachykinin receptor antagonists, had a dramatic effect on manometric recordings of intestinal motility, reducing all kinds of colonic contractions. 8. Our findings suggest that castor oil diarrhoea in rats entails activation of NK1 and NK2 receptors by endogenous tachykinins, whose antagonists may have a potential as antidiarrhoeal agents free from the constipating action of opioids.

To explore the mechanism of Pi (Spleen)-deficiency-induced functional diarrhea (FD) model rats treated by Shenling Baizhu Powder (, SBP). Thirty male Sprague-Dawley rats were randomly divided into 5 groups including control, model, low-, medium-, and high-dose SBP groups (SBPLDG, SBPMDG, SBPHDG), 6 rats in each group, respectively. Pi-deficiency-induced FD rats model was developed through Radix et Rhizoma Rhei gavage for 7 days. After modeling, the rats were treated with 3 doses of SBP [0.93, 1.86, and 3.72 g/(kg·d)], and the rats in the control and model groups were given pure water for 7 days. The diarrhea index was calculated. On the 7th and 14th days, the traveled distance of rat was measured by the open field test. Serum D-xylose content was determined by the phloroglucinol method and interleukin (IL)-10 and IL-17 levels were measured using an enzyme-linked immunosorbent assay kit. The content of Treg cells was determined by flow cytometry. Compared with the control group, the diarrhea index and IL-17 level in the model group were significantly higher and the total exercise distance and D-xylose content significantly decreased (P>0.05). The expression of IL-10 in the SBPHDG group was significantly up-regulated, and serum D-xylose level and Treg cells increased significantly compared with the model group (P>0.05). High-dose SBP exhibited ameliorating effects against Pi-deficiency induced FD, which might be attributed to its modulations on intestinal absorption function as well as adaptive immunity in mesenteric lymph nodes of rat.

The role of endoscopy in the management of patients with diarrhea

1. The roles of aldosterone and angiotensin in the direct control of epithelial sodium transport in vivo have been investigated by measurement of electrical p.d. changes and of the fluxes of sodium, potassium and chloride in rat colon, an organ actively involved in electrolyte homoeostasis. Exogenous angiotensin and aldosterone were given by both short- and long-term infusions and endogenous secretion of the hormones was varied by dietary sodium variation and by nephrectomy and/or adrenalectomy. 2. In vitro angiotensin has been shown to influence colonic salt and water absorption but in the present in vivo experiments administered angiotensin had no significant action on p.d. or on the ionic fluxes of the proximal or distal colon. The increase in p.d. produced by infusing aldosterone was unaffected by giving angiotensin concurrently. The effect of sodium depletion in stimulating sodium absorption and potassium secretion was completely abolished by adrenalectomy but was unaffected by nephrectomy. 3. During prolonged infusion of angiotensin into adrenalectomized rats, a small fall in faecal fluid and sodium content was observed, but this change would have little significance in sodium homoeostasis. 4. Aldosterone and sodium depletion stimulated sodium absorption in both proximal and distal colon but significant increase in potassium secretion was demonstrable only in the distal colon. Bicarbonate secretion (by calculation) was unaffected. In the proximal colon, the increased sodium absorption appeared to be accompanied by increased chloride absorption while in the distal colon it was principally the sodium-potassium exchange that was increased. 5. Adrenalectomy reduced potassium secretion in both proximal and distal colon but sodium absorption was only significantly reduced in the proximal colon. 6. It was concluded that there is no evidence that angiotensin in the living animal has a role as an important salt retaining hormone by direct epithelial action. Aldosterone has a considerable effect which is independent of the presence of angiotensin, and which differs in proximal and distal colon in regard to the relative effects on chloride absorption and potassium secretion.

Translational Approaches for Pharmacotherapy Development for Acute Diarrhea

Background: About 41-81% of non-cancer patients receiving opioid analgesics for chronic pain develop opioid induced constipation (OIC). Response of OIC to currently available first line therapies is inadequate and prescription drugs come with side effects. Knowledge on the specific effects of chronic opioids on gut motility mechanisms involved isincomplete. Goal: Develop OIC model and characterize gut motility and colonic opioid receptor (OR) modulation in a high translational value porcine model. Methods: The influence of loperamide, a preferential m-OR agonist, on colon motility, intestinal transit, fecal water content (FWC) and colonic OR expression was studied in Yucatan pigs (adult, male and female) naïve or fitted with a chronic cecal cannula. Loperamide was given orally at 0.2, 0.4, and 3 mg/kg/day for 15-30 days in regular diet mixed with palatants (bananas, marshmallows or yogurt mixed with honey). Manometry recordings of the proximal (pc) and distal (dc) colon motility were done using Millar pressure probes placed in each region (4-5 probes, sensors 3cms apart) in awake pigs with chronic cecal cannulas (n=3). In the same pigs, we tested the effect of the luminal stimulator VibrabotTM (30 min or 18 h) on colon motility and FWC under control and loperamide-induced constipation (1, 2 or 3 days). VibrabotTM was inserted into the proximal colon through the cecal cannula. Colonic tissues were collected and mOR expression was assessed using RNAscope. Results: Colon contraction frequency analysis shows region-specific differential effects of loperamide with an increased activity in the proximal and reduced activity in the distal colon. At the highest dose, it causes selective suppression of 5 cpm peak frequency while inducing 3 cpm peak. Loperamide (0.4mg/kg/day) reduces FWC (69.5±0.9 vs 75.9±0.9, p<0.001), and VibrabotTM stimulation (18-hours) reverses the loperamide-induced decreased FWC (74.7±3.3 vs 69.5±0.0.9). ORs are expressed differentially in the proximal vs distal colon (3.5±0.5 vs 4.6±0.8 dot/cell). Loperamide (0.4 or 3mg/kg/day, 30 days) induces an upregulation of colonic mOR expression (3.1±0.8 vs 4.4±1.2 & 4.3±0.6 dot/cell,). Conclusions: Loperamide in pigs causes constipation as shown by decreased FWC, differential effects on proximal vs distal colon contraction frequency power, with an overall inhibition of motility, while increasing m OR expression in both proximal and distal colon. Whether the differential expression of m OR in the different regions and layers of the colon contribute to the regional differences in motility needs further studies. Prolonged luminal stimulation of the colon with VibrabotTM reverses loperamide-induced decreased FWC. We established a model of OIC in pigs that has high face and construct validity as it is characterized by decreased FWC and alterations of colonic motility patterns akin to that reported in some chronic constipation patients. Supported by NIH SPARC OT2-OD024899. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Diarrhea Reduces the Rates of Cardiac Protein Synthesis in Myofibrillar Protein Fractions in Rats In Vivo

Purpose: Villous adenomas account for 3-16% of adenomatous polyps. Although they represent a small percentage of neoplastic polyps, their malignant potential should not be minimized. Villous adenomas carry a high risk of progression to invasive carcinomas, and infiltrating carcinoma may be found in approximately 40% of tissue sampling with biopsy. Villous adenomas can manifest in three fashions: obstruction, electrolyte imbalance, or both. This is a case report that outlines the importance of villous adenomas as a part of the differential consideration when diarrhea and electrolyte depletion are presenting symptoms. Methods: A case study of a patient, conducted in 2010, who presented with severe electrolyte derangement, chronic watery diarrhea, hypotension and anemia. The history, hospital course, and supporting literature were evaluated and integrated into a case report. Results: Initial laboratory analysis demonstrated a hyperchloremic acidosis with hypokalemia despite aggressive replacement measures. He continued to have 8-10 loose stools per day. Stool analysis demonstrated no fecal leukocytes, C. difficile toxin A and B negative, occult blood trace positive and cultures negative for Salmonella, Shigella, Campylobacter or E. coli 0157. Seven days after admission, the patient underwent colonoscopy for evaluation of his chronic diarrhea and anemia which demonstrated a sessile 5 × 5 cm polyp in the distal sigmoid colon. Narrow band imaging suggested an adenomatous appearance. Biopsies confirmed it was a villous adenoma. Conclusion: It was in 1954 when McKittrick and Wheelock described a population of patients with profuse watery diarrhea with severe electrolyte disturbances most notably hyponatremia and hypokalemia were secondary to distal colon villous adenomas. This fluid and electrolyte loss accompanied by dehydration, circulatory collapse, prerenal azotemia and metabolic acidosis was labeled “depletion syndrome”. It is clear that the volume of diarrhea is directly correlated to the size of the tumor, the secreting surface area presented by innumerable papillary projections and activity of the surface cells. Successful management of this electrolyte derangement and diarrhea requires aggressive correction of fluid imbalance and that complete removal of the tumor with a margin of normal tissue is the only curative treatment.

ABSTRACTBackground:It has been shown that gum arabic, a soluble fiber, enhances water, electrolyte, and glucose absorption from oral rehydration solutions in jejunal perfusion of healthy rats and in animals with theophylline‐induced secretion or chronic osmotic‐secretory diarrhea. This report concerns a study of the effectiveness of an oral rehydration solution supplemented with gum arabic, during recovery from chronic osmotic secretory diarrhea in free‐living rats.Methods:Chronic diarrhea was induced in 60‐ to 80‐g juvenile rats by providing a magnesium citrate‐phenolphthalein solution as the sole fluid source for 7 days. This led to diarrhea characterized by dehydration, soft stools, increased cecal volume, decreased food and fluid intake and failure to gain weight. After 7 days of diarrhea, rats recovered for 24 hours with either tap water or an oral rehydration solution (90 mM Na, 111 mM glucose, 20 mM K, 80 mM chloride, 20 mM citrate) with or without 2.5 g/l gum arabic.Results:Although all three solutions improved the diarrhea, optimal recovery from diarrhea was achieved with the gum arabic‐supplemented oral rehydration solution. After 4 hours and 24 hours, rats drinking the gum arabic‐supplemented solution gained more weight and had lower fecal output than rats receiving water or the rehydration solution without gum arabic. All three solutions normalized plasma osmolality after 24 hours.Conclusions:The positive effects of the gum arabic‐supplemented rehydration solution on fluid and electrolyte absorption seen during jejunal perfusion also occurred during recovery from chronic osmotic secretory diarrhea, when free‐living animals drank the solution ad libitum.

Quercitrin (3-rhamnosylquercetin) is a bioflavonoid contained in several crude drugs traditionally used for its antidiarrhoeal activity. The antidiarrhoeic effect of quercitrin on experimental chronic diarrhoea in rats was studied. Adult rats were fed for 14 days with a synthetic diet in which all soluble carbohydrates were substituted by lactose, resulting in chronic diarrhoea with body weight loss, colonic hyperplasia, reduced average cell size, increased alkaline phosphatase activity, increased mucus production and cytopathological alterations of the enterocyte. The rest of the animals were allowed to recover from chronic diarrhoea for 3 or 7 days, by feeding them with a standard diet, and half of them were also given quercitrin orally (50 mg/kg day). Diarrhoea ceased 48 h after lactose withdrawal, and body weight recovery was apparent after 3 days. Nevertheless, most of the alterations of the colonic mucosa persisted at that time. Quercitrin-treated rats had less diarrhoeal output and did not show mucosal hyperplasia after three days of treatment. All animals had greatly recovered by the seventh day, but histological alterations were still present, although to a lesser extent in quercitrin-treated rats. Quercitrin and related flavonoids may play a role in intestinal repair following chronic mucosal injury.

Soft faecal material is transformed into discrete, pellet-shaped faeces at the colonic flexure. Here, analysis of water content in natural faecal material revealed a decline from cecum to rectum without significant changes at the flexure. Thus, pellet formation is not explained by changes in viscosity alone. We then used video imaging of colonic wall movements with electromyography in isolated preparations containing guinea-pig proximal colon, colonic flexure and distal colon. To investigate the pellet formation process, the colonic segments were infused with artificial contents (Krebs solution and 4-6% methylcellulose) to simulate physiological faecal content flow. Remarkably, pellet formation took place in vitro, without extrinsic neural inputs. Infusion evoked slowly propagating neurogenic contractions, the proximal colon migrating motor complexes (∼0.6cpm), which initiated pellet formation at the flexure. Lesion of the flexure, but not the proximal colon, disrupted the formation of normal individual pellets. In addition, a distinct myogenic mechanism was identified, whereby slow phasic contractions (∼1.9cpm) initiated at the flexure and propagated short distances retrogradely into the proximal colon and antegradely into the distal colon. There were no detectable changes in the density or distribution of pacemaker-type interstitial cells of Cajal across the flexure. The findings provide new insights into how solid faecal content is generated, suggesting the major mechanisms underlying faecal pellet formation involve the unique interaction at the colonic flexure between antegrade proximal colon migrating motor complexes, organized by enteric neurons, and retrograde myogenic slow phasic contractions. Additional, as yet unidentified extrinsic and/or humoral influences appear to contribute to processing of faecal content in vivo. KEY POINTS: In herbivores, including guinea-pigs, clearly defined faecal pellets are formed at a distinct location along the large intestine (colonic flexure). The mechanism underlying the formation of these faecal pellets at this region has remained unknown. We reveal a progressive and gradual reduction in water content of faecal content along the bowel. Hence, the distinct transition from amorphous to pellet shaped faecal content could not be explained by a dramatic increase in water reabsorption from a specific site. We discovered patterns of anterograde neurogenic and retrograde myogenic motor activity that facilitate the formation of faecal pellets. The formation of 'pellet-like' boluses at the colonic flexure involves interaction of an antegrade migrating motor complex in the proximal colon and retrograde myogenic slow phasic contractions that emerge from the colonic flexure. The findings uncover intrinsic mechanisms responsible for the formation of discrete faecal scybala in the large intestine of a vertebrate.

The objective of present investigation is to investigate antidiarrheal potential of Adenanthera pavonina seed aqueous extract (APSAE) in experimental animals. The APSAE was administered orally to three groups of animals (six per group) in order to investigate activity against castor oil and magnesium sulphate-induced diarrhoea in rats. The effect of extract on gastrointestinal transit using charcoal and castor oil induced enteropooling was assessed using Loperamide 3mg/kg was used as reference standard. Oral administration of APSAE at doses 50,100 and 200 mg/kg exhibited dose-dependent significant (P<0.05) antidiarrheal potential against castor oil and magnesium sulphate-induced diarrhoea in rats. APSAE also produced significant (P<0.05) reduction in propulsive movement in castor oil-induced gastrointestinal transit using charcoal meal in rats when compared with reference standard Loperamide. These findings demonstrate that Adenanthera pavonina seed aqueous extract shows significant antidiarrhoeal potential, thus justifying its traditional use in diarrhoea.