AQPs are targets of VIP that can change the content of AQPs on the cell membrane through the cellular protein kinase A PKA system to regulate the membrane permeability to water.

VIP up-regulates the expression of AQP3 and its mRNA by activating the cAMP-dependent PKA pathway Itoh et al. PKA also phosphorylates cAMP response element-binding protein CREB ; the phosphorylated CREB then stimulates AQPs gene transcription Ikeda and Matsuzaki, FIGURE 4.

Distribution of AQPs in intestinal tract and signal transduction mechanism of AQP3. AQP1, AQP3, AQP7, AQP10, and AQP11 are highly expressed in the small intestine, while AQP2, AQP3, AQP4, AQP7, and AQP8 are the main subtypes in the colon. In AQP3 expression, there are two pathways: AC-mediated short-time regulation and long-term regulation at the transcriptional level.

AC, adenylate cyclase; AQP, aquaporin; cAMP, cyclic adenosine monophosphate; CREB, cAMP response element-binding protein; PKA, protein kinase A; TNF-α, tumor necrosis factor alpha. The other mechanism refers to the increased AQPs synthesis, mRNA, and protein expression at the transcriptional level, which is termed long-term regulation.

Studies have shown that AQPs promote intestinal function through mechanisms that may involve changes in signaling. NF-κB, a key signal in the long-term regulation of AQP3, down-regulates the expression of AQP3 Zhan et al.

The binding of Sp3 transcription factor to the AQP3 promoter can partially prevent the down-regulation of AQP3 expression induced by TNF-α. IFN-γ, a key factor of impaired epithelial transport and barrier function, can increase epithelial permeability by inhibiting the expression of AQP3.

STAT1 has been shown to partially block the down-regulation of AQP3 expression induced by IFN-γ, while STAT3 and Sp3 can increase AQP3 expression Peplowski et al.

A growing body of studies has investigated the importance of the gastrointestinal water transport system in intestinal function and the effect of AQPs on intestinal fluid secretion and chronic constipation. However, the mechanisms of AQPs action on intestinal fluid and constipation remain unclear.

Further studies on the expression and function of AQPs in the intestinal tract and the mechanism of water transport should provide information for the development of new laxatives. With a better understanding of the mechanisms of chronic constipation and continued advances in pharmaceutical development, an expanding array of treatment approaches have been developed.

At present, drugs are the mainstay for patients with chronic constipation. Many studies have reported the efficacy and safety of laxatives in patients with constipation. The main categories of approved drugs for the treatment of constipation are osmotic laxatives, stimulant laxatives, secretagogues, serotonergic agents, and ileal bile acid transporter inhibitors Black and Ford, Drugs used for the treatment of chronic constipation are listed in Table 1.

However, different drugs act via different pathways, and a further understanding of their mechanisms, combined with that of ion transport and the expression of AQPs, may lead to the development of promising drugs.

The American Gastroenterological Association recommends that use of a fiber supplement should be the initial treatment approach for constipation Bharucha et al.

Fiber is composed of high-molecular weight food components that cannot be degraded by intestinal enzymes thus it remains in the intestinal cavity and increases fecal volume. Insoluble fibers, such as wheat bran, may alter gut motility, thereby accelerating gastrointestinal transit and increasing the frequency of stools.

Soluble fiber, such as psyllium, expands after absorbing water in the intestine, thus softening and increasing the volume of feces. Although fiber supplements are effective in the treatment of constipation, adverse reactions, such as bloating, are becoming a problem with long-term therapy Wald et al.

If patients do not respond to fiber, then osmotic laxatives should be considered. Osmotic laxatives are poorly absorbed or non-absorbed substances, that produce intraluminal osmotic gradients, causing secretion of water and electrolytes into the lumen.

This results in luminal water retention, an increase in stool water content and stool softening, thus facilitates stool passage Krogh et al.

These treatments are useful for patients with mild-to-moderate constipation, and the main side effects are diarrhea and abdominal distention. As an osmotic laxative, lactulose has osmotic activity and can attract water to the colon cavity Jouët et al. Since it is harmless to the human body and can effectively regulate the physiological rhythm of the colon, it is widely used to treat constipation in the elderly, pregnant women, and children.

Adverse reactions are limited to the gastrointestinal system, with bloating and abdominal pain being the most common.

Polyethylene glycol is a non-absorbable macromolecule belonging to the group of osmotic laxatives. Its mechanism of action is physical; it acts through local infiltration, retaining water in the colon cavity, thus softening feces, increasing fecal volume, and leading to unobstructed defecation.

Polyethylene glycol can improve constipation-related symptoms such as stool frequency and stool consistency Chassagne et al. Clinical studies have found that low-dose polyethylene glycol is significantly better than lactulose in improving constipation symptoms, with fewer adverse reactions Attar et al.

Polyethylene glycol can be used for the symptomatic treatment of constipation in children aged 6 months and older and in adults.

Salt laxative MgSO 4 can increase the intestinal osmotic pressure, prevent the absorption of water in the colon, increase the intestinal contents, and stimulate intestinal peristalsis, resulting in rapid and severe catharsis.

The increased cAMP concentration subsequently leads to the activation of PKA, which promotes CREB phosphorylation and AQP3 gene transcription Ikarashi et al. Excessive use of salt laxatives may induce electrolyte disorders and are therefore, not suitable for the elderly and patients with decreased kidney-function.

If the patient does not respond to osmotic laxatives, stimulant laxatives are recommended. Stimulant laxatives stimulate the intestinal mucosa and nerve plexus to secrete water and electrolytes, resulting in peristaltic contraction, thereby accelerating colonic transport.

Stimulant laxatives are effective, and their side effects are known. Chronic use of stimulant laxatives does not seem to cause tolerance or rebound constipation. However, common side effects include diarrhea and abdominal pain Wald, Bisacodyl stimulates the secretion and motility of the small intestine and colon via the following mechanisms: increased secretion of TNF-α and prostaglandin E 2 PGE 2 in the colon following the oral administration of bisacodyl.

TNF-α and PGE 2 , as paracrine factors, act on the colonic mucosal epithelial cells resulting in an immediate reduction in AQP3 expression, thus exerting their laxative effects Ikarashi et al. In a 4-weeks trial, oral bisacodyl was reported to be safe and well-tolerated Kamm et al.

However, bisacodyl is associated with abdominal cramps and diarrhea. Secretagogues are second-line drugs, the effects of which are similar to those of osmotic laxatives. Secretagogues act directly on intestinal epithelial cells, increasing fluid secretion into the intestinal cavity, thereby changing the consistency of stools and reducing the transit time in the colon Luthra et al.

However, these drugs are associated with side effects such as diarrhea when used clinically. Lubiprostone is a prostaglandin E 1 derivative, which can activate the intestinal chloride channel type 2 on the apical surface of small intestinal enterocytes, thereby reducing epithelial permeability and promoting intestinal fluid secretion.

Additionally, sodium and water enter the intestinal cavity passively, increasing the secretion of fluid in the intestinal cavity Gonzalez-Martinez et al. Lubiprostone can significantly increase stool frequency, improve stool consistency, and reduce straining, which makes it effective for the treatment of constipation Nishii et al.

The results of a meta-analysis showed that adverse reactions such as nausea, vomiting, and diarrhea were common incidence rate, 2. This may be related to the rapid flow of fluid into the small intestine after taking the medicine.

Plecanatide and Linaclotide are GC-C receptor agonists that target GC-C receptors on the lumen of the intestinal epithelium, resulting in increased intestinal fluid secretion Shah et al.

By activating colonic epithelial GC-C receptors, the synthesis of intracellular and extracellular cGMP is increased Busby et al. Intestinal dilatation caused by increased intestinal fluid can promote intestinal movement, and therefore treat constipation. The reported efficacy of plecanatide and linaclotide is similar, and the most common side effect is diarrhea Bassotti et al.

Furthermore, increased cGMP can regulate abdominal pain Silos-Santiago et al. The use of osmotic and stimulant laxatives, either alone or in combination, may be considered in first-line drug therapy. Second-line agents, such as prucalopride are indicated in patients with an inadequate response or poor tolerance to a first-line drug.

Studies have reported that exploiting epithelial targets with nonabsorbable serotonergic agents could provide safe and effective therapies.

Serotonin agonists stimulate intestinal secretion and motility by activating 5-HT receptors in the gastrointestinal nervous system.

Unlike other older non-selective 5-HT 4 receptor agonists e. Prucalopride is a high-affinity 5-HT 4 receptor agonist with colonic prokinetic activity Vijayvargiya and Camilleri, Prucalopride functions by activating 5-HT 4 receptors in myenteric plexus neurons and stimulates HAPCs to increase colonic motility Miner et al.

This significantly increases intestinal muscle contraction, as well as stool frequency and consistency in patients with chronic constipation. Some studies have also found that prucalopride can increase the expression of c-kit mRNA in colonic tissue of rats with constipation, and then improve the function of ICCs, so as to promote colonic motility.

It is effective at improving stool frequency, stool consistency and straining. The most common side effects include diarrhea, headache, nausea, and abdominal pain Daniali et al. Multicenter, double-blind, randomized, placebo-controlled trials have demonstrated that prucalopride is superior to placebo in the short to medium term and can improve constipation in both men and women across a broad spectrum of ages and ethnicities Camilleri et al.

Nevertheless, this drug is considerably more expensive than conventional therapy. With knowledge that 5-HT 3 receptors can participate in the activation of propulsive motility and secretory responses in the gut, 5-HT 3 agonists have been developed and tested for the treatment of constipation Mawe and Hoffman, Bile acid can activate the secretory activity of colonic epithelial cells Mekjian et al.

Therefore, up-regulation of the colonic bile acid concentration can be used to treat patients with constipation. Bile acid, a natural laxative in the human body, has garnered attention for the treatment of chronic constipation because of its ability to promote colonic epithelial secretion Keely et al.

However, its efficacy and safety need to be further confirmed in large scale studies. Elobixibat can block the enterohepatic circulation of bile acid, up-regulate the synthesis of bile acid reaching the colon, and stimulate the secretion of fluid and electrolytes, thereby increasing fecal water content and gut motility Mekjian et al.

Increased gut motility facilitates stool passage. Few adverse reactions have been associated with this drug and they include abdominal pain and diarrhea. Abdominal pain with elobixibat may be related to its ability to induce dilatation and contraction Taniguchi et al.

As a motilin receptor agonist, mitemcinal GM can stimulate and promote peristalsis of the gastrointestinal tract by acting on the motilin receptor Sudo et al. This effect has been observed in animal models; however, due to a lack of clinical outcome data, the clinical significance of these studies has not been clearly demonstrated.

Therefore, further clinical trials are required to confirm the efficacy and safety of mitemcinal in this population Mozaffari et al. Probiotic consumption can regulate the intestinal microbiota of patients with constipation, which in turn, can improve gut motility.

Some studies have shown that probiotics can be helpful for treating patients with constipation improved stool frequency and stool consistency with very few side effects Ohkusa et al. These studies have mainly involved the bacteroides , bifidobacterial, and lactobacilli. Recently, the positive impacts of SCFAs on gut motility and constipation were established Chu et al.

Nevertheless, since the effects of probiotics may be strain-specific and the exact mechanism of action remains unknown, more studies and randomized controlled trials are needed to confirm the effects of probiotics in patients with constipation Dimidi et al.

Traditional Chinese Medicine TCM has a role in promoting gastrointestinal motility and has been used to treat constipation for more than 1, years in China. In recent years, there have been many reports about TCM in the treatment of constipation and the improvement of gastrointestinal function Cirillo and Capasso, Therefore, TCM has garnered increasing attention as a promising alternative treatment for constipation.

However, few studies have investigated its therapeutic mechanisms. Thus, the long-term efficacy and side-effect profiles of these medicines in modern medicine need to be determined. Further studies are needed to determine the exact mechanism for the observed recovery of intestinal function.

Importantly, the composition of TCM is complex. Senna and rhubarb are anthraquinone laxatives used widely in the treatment of intestinal constipation. Sennoside A exerts a laxative effect through its main bioactive component. Rheinanthrone, the active metabolite of sennoside A, can increase the production of PGE 2 Kon et al.

Owing to its toxicity to the kidney and liver, we suggest that special attention should be paid to patients with kidney and liver diseases when using Senna drugs for a long period Cao et al. Total glucosides of paeony TGP are extracted from the root of Paeonia Lactiflora Pall.

Studies have shown that TGP can improve the function of ICCs, block inhibitory neurotransmitters such as NO, NOS, and VIP, and increase the fecal volume and water content, as well as intestinal transit rate Zhu et al.

As a common disease that seriously impacts the quality of life and mental health of patients, chronic constipation has attracted widespread attention.

Further studies on the abnormal changes of the ENS, ANS, CNS, endocrine signaling, and microbiota would aid our understanding of constipation from the perspective of gut motility. Intestinal fluid and electrolyte transport are also strongly correlated with chronic constipation.

As a subject for future research, ion channels and AQPs play critical roles in the transport of fluid. At present, studies on ion transport and AQPs in constipation are limited, and many complex mechanisms have not been clarified.

Further experiments are warranted to demonstrate this mechanism. With extended symptom duration, severity, and frustration, the occurrence of additional symptoms will also increase.

Therefore, patients with chronic constipation usually require active treatment. The choice of therapeutic drugs should focus on the effectiveness of relieving the symptoms of constipation, the improvement of the intestinal environment, and the effectiveness and safety of long-term use.

If these measures fail, prescription laxatives with different mechanisms of action may be used. Modifying the gut luminal environment through gut motility, fluid, and electrolytes will affect transit and secretion in the gut, thereby benefiting patients with chronic constipation. Intestinal fluid transport mediated by ion channels and AQPs is the key mechanism through which many laxatives exert their effects.

Nevertheless, further studies are still required to resolve the problem. Recently, the action of probiotics on gut motility was shown to be beneficial for constipation. However, the positive effects of probiotics depend on the specific probiotics used and the level applied. Therefore, the use of probiotics in the treatment of chronic constipation is promising and further studies are required.

We hope that a better understanding of the pathogenesis of constipation and the mechanism of drug action may create new targets for the treatment of diseases that remain a major scourge worldwide.

Y-YC and Y-PT conceived and designed the review. QZ searched the literature and drafted the manuscript. D-QX and S-JY additions and revisions in manuscript. JY and L-MX examined the literature and made the figures.

R-JF edited the manuscript. Y-YC and Y-PT made a critical revision of the review. All authors approved the final version of the manuscript.

This work was supported by the National Natural Science Foundation of China , Cultivation Plan of Young Scientific and Technological Stars in Shaanxi Province , The Youth Innovation Team of Shaanxi Universities , Natural Science Foundation of Shaanxi Provincial Department of Education 17jk , and Subject Innovation Team of Shaanxi University of Chinese Medicine YL The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers.

Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher. Ahmed, M. Functional, Diagnostic and Therapeutic Aspects of Gastrointestinal Hormones. CrossRef Full Text Google Scholar.

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Lacy, B. Bowel Disorders. Gastroenterology , — Laforenza, U. Expression and Immunolocalization of Aquaporin-7 in Rat Gastrointestinal Tract. Cel 97 8 , — A week after starting the Mag Citrate, use the beets measurement test again to see if your transit time has improved.

If there is still no improvement, increase the dosage to six capsules twice a day. Note: Be VERY careful to keep hydrating and supplementing with electrolytes like Dynamic Hydrate.

Talk to your practitioner before starting the Mag Citrate recommendations in order to get their input on the process and how it may affect you personally.

Purchase a high-quality, highly-alkalized, powdered vitamin C such as C Aspa Scorb in order to best affect bowel motility. When you wake up and before you eat, take mg. Record the time and amount. Every half hour, take an additional mg dose of vitamin C in at least two ounces of water and record the amount.

You may eat and drink lightly after the first dose, but eating or drinking too much during the flush procedure may cause discomfort. Make sure to drink the required amount of liquid to avoid dehydration. Keep drinking fluids throughout the day and supplementing with electrolytes like Dynamic Hydrate.

After eight doses, you may begin to hear gurgling or rumbling in your gut. This is a good sign that the vitamin C is doing its job. every 15 minutes. Be sure to record the time and amount of each dose.

Continue taking vitamin C in water until you have a watery bowel movement. Then discontinue taking vitamin C for the remainder of the day and proceed to step 8. Repeat step 5 the next day. Calculate the quantity of vitamin C used.

Add up all the dosages to determine how many milligrams you consumed. Beginning the day after the flush, take that amount each day in four divided doses.

As you continue to take this level of vitamin C, your transit time should normalize. After a week, you can do the beets test again to confirm that your food is being digested and eliminated in a timely manner.

If at any point your stools start to become too loose, back off the vitamin C a bit. Your vitamin C needs change with your stress and general health status. Illness, exercise, exposure to toxins, emotional stress, chronic disease, and chronic inflammation can all increase your need for vitamin C.

If you need or want to stop taking it, taper the dosage downward over a period of several days. Note: it is normal to experience some mild bloating and gas and mild discomfort during the process..

Russell Jaffe, MD, PhD, CCN. The above strategy is adjusted for easier bowel tolerance, but some people may need a stronger approach. Talk to your health practitioner before starting the vitamin C strategy in order to get their input and advice on whether or not the protocol may be right for your body.

This strategy is definitely not recommended for everyone. When you get to know your body better, you can tweak your vitamin C or magnesium citrate dosage every so often to help keep your digestive tract performing well.

Whole grains, fruits, and vegetables can shorten your transit time. Sugar and refined carbohydrates, on the other hand, can slow it down. Also, move! your body. in whatever way you are physically able. Do things, go places, and laugh with friends and family.

Let your body be free to do what it does best. Home About About Us Contact Us Subscribe to the Global Wellness Lab today!

Regulation of the MMC is complex, requiring the release of many hormones and neurotransmitters, as well as activity of the enteric and autonomic nervous system 2. This contraction moves through the stomach and small intestine, towards the ileocecal valve.

These waves occur in cycles, playing a housekeeping role, clearing the small intestine of remnants of food left behind during peristalsis and segmentation contraction, as well as bacteria 3. A small amount of bile and enzymes are released with each MMC. If there is dysfunction within any of these movement patterns, gut motility may be decreased, leading to constipation, changes in the gut microbiome, pain, and other digestive symptoms.

Particularly, a decrease in Phase III activity of the MMC, the most active phase of its four phases, has been shown to be absent in cases of IBS and SIBO 2. Additionally, conditions that affect motility predispose toward development of SIBO.

A significant amount of patients with SIBO have motility issues, particularly decreased MMC activity 3,5. While motility issues predispose patients to bacterial overgrowth, once overgrowth occurs, the methane gas that is produced in certain cases of SIBO What is SIBO? further slows the activity of the gastrointestinal tract 6.

In turn, treating dysbiosis has an effect on dysmotility 7. It is essential to treat the dysmotility that contributed to development of SIBO, while also treating the bacterial overgrowth.

Depending on the root cause of decreased gut motility, treatments vary greatly. For example, in cases of intestinal blockage, patients may have to undergo surgery to remove the blockage.

However, if gut motility is decreased due to dysfunction within any of the digestive movement patterns , certain substances and lifestyle habits that increase and coordinate intestinal motility may be helpful.

Maya Kuczma Empowering Your Gut: The Role of Motility in Digestive Wellness Wellness , Health , Gut Health. Understanding Gut Motility In a well-functioning digestive tract, there are three movement patterns to ensure food is digested and propelled through the gut, and the gut is cleared of food and bacteria once digestion is complete.

These patterns, known as segmentation contraction, peristalsis, and the migrating motor complex MMC , decrease the potential for small intestinal bacterial overgrowth by ensuring that food particles and bacteria are moved through the digestive tract, rather than accumulating in the small intestine.

However, if there is dysfunction within any of these mechanisms, or imbalances within the digestive hormones that control them, gut motility is reduced, increasing the likelihood of SIBO 1. What Causes Reduced Gut Motility?

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Deep cleansing of the intestine Once the digestive process has finished, food residues can be found in our colon, the purpose of which is to eliminate them through transmission. This fragile mechanism can be altered by additional toxic molecules resulting in inflammatory reactions which will have an impact on the entire system.

Cleansing the digestive system thoroughly offers the dual benefit of…. Read the article.