Minireviews Open Access
Copyright ©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Clin Cases. Aug 26, 2024; 12(24): 5476-5482
Published online Aug 26, 2024. doi: 10.12998/wjcc.v12.i24.5476
Exploration of the complex origins of primary constipation
Xing-Lin Zeng, Lian-Jun Zhu, School of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu 610075, Sichuan Province, China
Xiang-Dong Yang, Colorectal and Anal Surgery, Chengdu Anorectal Hospital, Chengdu 610015, Sichuan Province, China
ORCID number: Xing-Lin Zeng (0009-0006-8424-5428); Xiang-Dong Yang (0009-0007-5699-1949).
Author contributions: Zeng XL, and Yang XD contributed to the manuscript outline and composed the paper; Zhu LJ was responsible for sourcing and organizing relevant literature; Zeng XL and Yang XD originated the concept for this manuscript; Yang XD provided supervision, reviewed the paper, and finalized the manuscript. All authors have read and approved the final manuscript.
Conflict-of-interest statement: The authors have no conflicts of interest to disclose.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: Https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Xiang-Dong Yang, MM, Professor, Colorectal and Anal Surgery, Chengdu Anorectal Hospital, No. 152 Daqiang East Street, Taisheng South Road, Chengdu 610015, Sichuan Province, China. y-xd@vip.163.com
Received: March 8, 2024
Revised: June 11, 2024
Accepted: June 26, 2024
Published online: August 26, 2024
Processing time: 125 Days and 1.3 Hours

Abstract

Constipation is a common gastrointestinal disorder characterized by infrequent bowel movements and difficulty in passing stools. It can significantly affect an individual's quality of life and overall well-being. Understanding the causes of constipation is important for its effective management and treatment. In this paper, we have reviewed the primary causes of constipation or functional constipation. Primary constipation is a bowel disorder associated with colonic or anorectal sensorimotor or neuromuscular dysfunction. As per the literature, it is multifactorial and involves factors such as decreased interstitial cells of Cajal, altered colonic motility, enteric nervous system dysfunction, intestinal flora disturbances, and psychological influences. Clinical symptoms include difficulty in defecation, decreased frequency of defecation, or a feeling of incomplete evacuation. A comprehensive evaluation and management of constipation require an interdisciplinary approach incorporating dietary modifications, lifestyle changes, pharmacotherapy, and psychological interventions. Further research is imperative to explain the intricate mechanisms underlying constipation and develop targeted therapies for improved patient outcomes.

Key Words: Primary constipation, Pathogenesis factors, Treatment

Core Tip: The etiology of constipation is complex, involving a series of primary and secondary causes. Some of the primary factors reviewed in this paper include decreased interstitial cells of Cajal, altered colonic motility, enteric nervous system dysfunction, intestinal flora disturbances, and psychological influences. Clarifying the etiology of constipation can significantly facilitate the management of this disease through an interdisciplinary approach, incorporating dietary modifications, lifestyle changes, pharmacotherapy, and psychological interventions.



INTRODUCTION

Constipation is a clinical condition with a high incidence rate. It is often difficult to manage and can induce cardiovascular and cerebrovascular diseases, as well as colorectal tumors[1,2]. Epidemiological studies suggest a global prevalence of constipation of 14%-26.8%[3,4], with the incidence continually increasing in parallel with the adoption of unhealthy lifestyle and dietary habits[5,6]. Based on the etiology, constipation can be categorized into primary and secondary types. Primary constipation, or functional constipation (FC), is a bowel disorder associated with colonic or anorectal sensorimotor or neuromuscular dysfunction[7-10]. The clinical symptoms of FC include difficulty in defecation, decreased frequency of defecation, or a feeling of incomplete evacuation. Importantly, the diagnosis of irritable bowel syndrome (IBS) with constipation must be excluded from FC, that is, neither abdominal pain nor abdominal distension should be the main presenting symptom. The clinical symptoms of constipation are generally present for at least 6 months before diagnosis and have occurred within the last 3 months. On the other hand, secondary constipation is linked with organic diseases (e.g., colon stenosis or mass), medication use (e.g., opioids and anticholinergics), or underlying conditions (e.g., metabolic, thyroid, or diabetic disorders). Constipation can lead to the development of psychosomatic problems such as depression, anxiety, schizophrenia, and even suicidal tendencies. Furthermore, several patients with constipation experience sexual dysfunction, urinary retention, anal swelling, and other disorders, which significantly reduce their quality of life and affect their physical and mental health. To better understand constipation and device strategies to manage and cure the underlying causes of constipation, we have extensively reviewed relevant articles on the etiologies of primary constipation.

PRIMARY CONSTIPATION

The causes of primary constipation include factors such as interstitial cells of Cajal (ICCs), enteric nerves and neurotransmitters, intestinal flora, intestinal smooth muscle, age, sex, hormone levels, genetic factors, psychological and behavioral factors, and lifestyle factors (Figure 1; Table 1).

Figure 1
Figure 1 The causes of primary constipation.
Table 1 The causes of constipation.
Classification
Etiology
Primary constipationIntestinal flora
Interstitial cells of Cajal
Intestinal smooth muscle
Enteric nerves and neurotransmitters
Age and sex factors
Hormone levels
Hereditary factors
Psychological and behavioral factors
Lifestyles
Others
Secondary constipationSecondary conditionsMechanical obstruction
Metabolic disorders
Neuropathy
Anorectal disorders
Others
MedicationsAnticholinergics
Antipsychotics
Analgesics
5-HT receptor antagonists
Others
ICCs

ICCs are polymorphic cells located in the smooth muscles of the gastrointestinal tract. They play a crucial role in distributing and regulating the basic electrical activity of the gastrointestinal tract, mediating neural signals, and maintaining rhythmic motility. When ICCs mature to a fusiform or star shape, they develop 2-5 protrusions that form a network[11] whereby they establish tight junctions with the smooth muscles of the gastrointestinal tract through connexin 43[12]. Electron microscopy reveals synapse-like structures on the surface of ICCs that interact with gastrointestinal nerve endings to receive various neurotransmitters[13]. The ICC surface also features several ion channels related to K+, Ca2+, and Cl-. Voltage-dependent Ca2+ channels are categorized into T-type and L-type channels. The T-type Ca2+ channels are closely associated with the generation of slow waves, while the L-type channels facilitate the entry of Ca2+ into the cell and its storage in the endoplasmic reticulum. Changes in the intracellular Ca2+ concentration trigger calcium oscillations, leading to the opening of the chloride channel (anoctamin 1, Ano1) in the plasma membrane, thus generating an inward current. Therefore, ICCs are crucial for regulating the slow-wave plateau phase and conduction[14]. ICCs contain small-conductance calcium-activated K+ channels, large-conductance K + channels, and ATP (triphosadenine) sensitive K+ channels. ATP-sensitive K+ channels regulate K+ inward flow and maintain the cell's resting potential at -70 mV. Changes in the ion channel expression may induce abnormal slow waves and disturbances in the gastrointestinal rhythm. When Ano1 is knocked out in mice, their intestinal rhythmicity, coordination, and contractility are significantly reduced[15]. The activation of K+ channels hyperpolarizes the cell membrane, causing gastrointestinal smooth muscle relaxation and inhibition of the pacing activity. Based on the layering of the intestinal wall, ICCs can be classified into submucosal ICCs, intermuscular ICCs, intramuscular ICCs, and deep muscular plexus ICCs[16]. Among these, intramuscular ICCs generate single potentials and are thus responsible for the relaxation of colonic smooth muscles, whereas intermuscular and submucosal ICCs generate slow waves to promote smooth muscle contraction[17]. Alterations have been noted in the number, morphology, and functions of colonic ICCs in constipation models[18]. The European guidelines state that colonic ICC volume is reduced in patients with constipation, which confirms the relationship between constipation with ICC[7].

Enteric nerves and neurotransmitters

Neuromodulation of the gastrointestinal tract is extraordinarily complex and is subject to regulation by the intrinsic enteric nervous system, central nervous system, and visceral nervous system. ENS is a highly autonomous network composed of neurons, nerve fibers, and supporting cells within the digestive tract[19]. Numerous studies have confirmed abnormalities in the ENS of patients with slow-transit constipation (STC), including decreased neurons and glial cells, ultrastructural changes, and altered neurotransmitters. Furthermore, an enteric neuropathic disorder has been proposed as the essence of STC[20-23]. In the ENS, the excitatory neurotransmitters received by ICCs include neurokinin 1, NK3, acetylcholine, substance P, and 5-hydroxytryptamine, which promote the contraction of the intestinal wall and accelerate intestinal motility. Moreover, inhibitory neurotransmitters, such as nitric oxide, nitric oxide synthase, and vasoactive intestinal peptide, relax the intestinal wall[24-27].

Intestinal flora

Intestinal flora affects digestive tract development, participates in the formation of the immune system, and maintains digestive tract homeostasis. Attaluri et al's findings have demonstrated that the prevalence of methanogenic flora was higher (P < 0.05) in the STC group (75%) than in the normal transit constipation (NTC) group (44%) or the control group (28%) (P < 0.05)[28]. The NTC group also produced more methane than the control group (P < 0.05), and the baseline, peak, and area under the curve of the methane response were moderately correlated with colonic transit (P < 0.05)[28]. Ohkusa et al[29] found that patients with IBS-C had reduced Actinobacteria counts in the fecal samples and increased Bacteroides levels in the mucosal samples when compared with healthy subjects. Moreover, treatment with synbiotics, probiotics, prebiotics, antibiotics, and fecal microbiota transplants improved the clinical symptoms in patients with constipation[29]. Gastrointestinal microorganisms, especially their populations, play a crucial role in maintaining the structural integrity of the gastrointestinal mucosal barrier, immune regulation, nutrient metabolism, and resistance to pathogens, mainly by increasing the expression of tight junction proteins (i.e., ZO-1 and occludin), and their dysregulation is associated with FC and IBS-C[30].

Psychological and behavioral factors

The brain-gut axis is a bidirectional pathway linking cognitive and emotional centers to the neuroendocrine, ENS, and immune systems. On one hand, stimuli and intrinsic information connect to advanced nerve centers through the enteric nerve chain to affect gastrointestinal sensation, motility, and secretion. However, gastrointestinal functions can consecutively affect pain, emotions, and behavior in the central nervous system. Thus, psychophysiological abnormalities are the causal factors for gastrointestinal disorders. In Dykes et al's study comprising 28 patients with constipation, 17 (61%) had a current psychiatric disorder and 18 (64%) had a history of psychiatric illness[31]. FC has also been associated with several behavioral factors. For example, Saps et al[32] studied 1334 children with functional gastrointestinal disorders and found that toilet-trained children were more likely to have FC than non-toilet-trained children.

Intestinal smooth muscles

Lesions of the intestinal smooth muscle can trigger altered colonic motility. Sun et al[33] found that the intestinal smooth muscle of STC rats was thinned, with intercellularly separated and disorganized atrophied cytosol. Zhong et al[34] found that drugs can improve constipation by promoting the assembly of actin filaments into tight bundles and stress fibers, thereby enhancing the contractility of intestinal smooth muscle cells. In addition, many studies[35,36] have pointed out that the occurrence of constipation is related to the significant thinning of intestinal smooth muscle and the decrease of intestinal contractility.

Age and sex factors

According to an epidemiological investigation, the ratio of female to male patients with constipation was 2.2:1, with the chances of constipation increasing with age, as has been evidenced in individuals aged > 65 years due to decreased intestinal peristaltic function[37]. Another study reported an overall prevalence of FC of 26.8%, which was significantly higher in women than in men (P = 0.019)[4]; this difference may be attributed to the fact that women are at a higher risk of injury to the pelvic floor muscles and nerves required for defecation[4].

Hereditary factors

Chan et al's survey of first-degree relatives and spouses of adult patients with chronic constipation meeting the Rome II criteria revealed that the prevalence of constipation among relatives of patients with constipation was 16.4%[38], whereas that among the relatives of patients without constipation was 9.1%, suggesting that family members of patients with constipation are at a higher risk of developing constipation.

Lifestyles

It is widely accepted that diet is closely associated with constipation[39,40]. For instance, in Jung et al's study[41], for patients with FC, brown rice-based and wheat-based diets led to improved bowel functions as a result of reduced bowel transit time and increased bowel movements when compared with white rice-based diets. Furthermore, appropriate exercise has been suggested to relieve constipation symptoms[42], although some scholars disagree[43]. Owing to the methodological shortcomings, the actual effect of exercise on constipation cannot be definitively determined, warranting further prospective studies in this direction.

Hormone levels

Ulusoy et al[44] compared 91 children with constipation and 100 healthy controls and found that the serum gastric motility levels were significantly lower in children with constipation than in healthy controls (P = 0.008), suggesting reduced serum gastric motility levels in children with constipation. Cong et al's findings suggest that an impaired STC motor index is the result of abnormal cyclooxygenase and prostaglandin levels[45], possibly due to the overexpression of progesterone receptors resulting in myocytes becoming more sensitive to the circulating progesterone levels. For instance, estrogens have been reported to impair the contraction of colonic smooth muscles, leading to constipation in mice[46,47]. However, evidence regarding the role of estrogens in human constipation is lacking.

TREATMENT

First-line therapies for the treatment of constipation comprise discussing the appropriate and customized diet, exercise, and bowel-management techniques relevant to the patient’s case. Current recommendations suggest that women should consume 20-28 g of fiber and men should consume 30-38 g of fiber in their diets daily, and physical activity should be encouraged in able-bodied patients[48]. Other measures, such as establishing a regular defecation routine and proper toileting habits, are also recommended[49]. If first-line therapies are unsuccessful, pharmacological therapies, such as the use of calcium polycarbophil, psyllium, polyethylene glycol, bisacodyl, and others, should be considered as the next therapeutic option. However, these medications are associated with side effects and may not be always effective[50]. Novel approaches combining several measures need to be explored in larger clinical trials to strategize ways to better manage the disease.

CONCLUSION

Constipation significantly affects the physical and mental health of individuals. The etiology of constipation is complex, involving a series of primary and secondary causes. Some of the primary factors reviewed in this paper include decreased ICC, altered colonic motility, ENS dysfunction, intestinal flora disturbances, and psychological influences. Clarifying the etiology of constipation can significantly facilitate the management of this disease through an interdisciplinary approach, incorporating dietary modifications, lifestyle changes, pharmacotherapy, and psychological interventions.

Footnotes

Provenance and peer review: Unsolicited article; Externally peer reviewed.

Peer-review model: Single blind

Specialty type: Medicine, research and experimental

Country of origin: China

Peer-review report’s classification

Scientific Quality: Grade C, Grade C

Novelty: Grade B, Grade B

Creativity or Innovation: Grade B, Grade C

Scientific Significance: Grade B, Grade C

P-Reviewer: Herrero-Fresneda I; Kwon KA S-Editor: Qu XL L-Editor: A P-Editor: Xu ZH

References
1.  Sumida K, Molnar MZ, Potukuchi PK, Thomas F, Lu JL, Yamagata K, Kalantar-Zadeh K, Kovesdy CP. Constipation and risk of death and cardiovascular events. Atherosclerosis. 2019;281:114-120.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 61]  [Cited by in F6Publishing: 110]  [Article Influence: 18.3]  [Reference Citation Analysis (0)]
2.  Tashiro N, Budhathoki S, Ohnaka K, Toyomura K, Kono S, Ueki T, Tanaka M, Kakeji Y, Maehara Y, Okamura T, Ikejiri K, Futami K, Maekawa T, Yasunami Y, Takenaka K, Ichimiya H, Terasaka R. Constipation and colorectal cancer risk: the Fukuoka Colorectal Cancer Study. Asian Pac J Cancer Prev. 2011;12:2025-2030.  [PubMed]  [DOI]  [Cited in This Article: ]
3.  Suares NC, Ford AC. Prevalence of, and risk factors for, chronic idiopathic constipation in the community: systematic review and meta-analysis. Am J Gastroenterol. 2011;106:1582-91; quiz 1581, 1592.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 499]  [Cited by in F6Publishing: 511]  [Article Influence: 39.3]  [Reference Citation Analysis (0)]
4.  McCrea GL, Miaskowski C, Stotts NA, Macera L, Varma MG. A review of the literature on gender and age differences in the prevalence and characteristics of constipation in North America. J Pain Symptom Manage. 2009;37:737-745.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 97]  [Cited by in F6Publishing: 99]  [Article Influence: 6.6]  [Reference Citation Analysis (0)]
5.  Vazquez Roque M, Bouras EP. Epidemiology and management of chronic constipation in elderly patients. Clin Interv Aging. 2015;10:919-930.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 24]  [Cited by in F6Publishing: 59]  [Article Influence: 6.6]  [Reference Citation Analysis (0)]
6.  Oswari H, Alatas FS, Hegar B, Cheng W, Pramadyani A, Benninga MA, Rajindrajith S. Epidemiology of Paediatric constipation in Indonesia and its association with exposure to stressful life events. BMC Gastroenterol. 2018;18:146.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 9]  [Cited by in F6Publishing: 12]  [Article Influence: 2.0]  [Reference Citation Analysis (0)]
7.  Serra J, Pohl D, Azpiroz F, Chiarioni G, Ducrotté P, Gourcerol G, Hungin APS, Layer P, Mendive JM, Pfeifer J, Rogler G, Scott SM, Simrén M, Whorwell P; Functional Constipation Guidelines Working Group. European society of neurogastroenterology and motility guidelines on functional constipation in adults. Neurogastroenterol Motil. 2020;32:e13762.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 69]  [Cited by in F6Publishing: 90]  [Article Influence: 22.5]  [Reference Citation Analysis (0)]
8.  Serra J, Mascort-Roca J, Marzo-Castillejo M, Delgado Aros S, Ferrándiz Santos J, Rey Diaz Rubio E, Mearin Manrique F. Clinical practice guidelines for the management of constipation in adults. Part 1: Definition, aetiology and clinical manifestations. Gastroenterol Hepatol. 2017;40:132-141.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 10]  [Cited by in F6Publishing: 13]  [Article Influence: 1.6]  [Reference Citation Analysis (0)]
9.  Remes-Troche JM, Coss-Adame E, Lopéz-Colombo A, Amieva-Balmori M, Carmona Sánchez R, Charúa Guindic L, Flores Rendón R, Gómez Escudero O, González Martínez M, Icaza Chávez ME, Morales Arámbula M, Schmulson M, Tamayo de la Cuesta JL, Valdovinos MÁ, Vázquez Elizondo G. The Mexican consensus on chronic constipation. Rev Gastroenterol Mex (Engl Ed). 2018;83:168-189.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 2]  [Cited by in F6Publishing: 3]  [Article Influence: 0.5]  [Reference Citation Analysis (0)]
10.  Andrews CN, Storr M. The pathophysiology of chronic constipation. Can J Gastroenterol. 2011;25 Suppl B:16B-21B.  [PubMed]  [DOI]  [Cited in This Article: ]
11.  Faussone-Pellegrini MS, Thuneberg L. Guide to the identification of interstitial cells of Cajal. Microsc Res Tech. 1999;47:248-266.  [PubMed]  [DOI]  [Cited in This Article: ]
12.  Wang XY, Sanders KM, Ward SM. Intimate relationship between interstitial cells of cajal and enteric nerves in the guinea-pig small intestine. Cell Tissue Res. 1999;295:247-256.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 112]  [Cited by in F6Publishing: 125]  [Article Influence: 5.0]  [Reference Citation Analysis (0)]
13.  Klein S, Seidler B, Kettenberger A, Sibaev A, Rohn M, Feil R, Allescher HD, Vanderwinden JM, Hofmann F, Schemann M, Rad R, Storr MA, Schmid RM, Schneider G, Saur D. Interstitial cells of Cajal integrate excitatory and inhibitory neurotransmission with intestinal slow-wave activity. Nat Commun. 2013;4:1630.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 147]  [Cited by in F6Publishing: 155]  [Article Influence: 14.1]  [Reference Citation Analysis (0)]
14.  Strege PR, Gibbons SJ, Mazzone A, Bernard CE, Beyder A, Farrugia G. EAVK segment "c" sequence confers Ca(2+)-dependent changes to the kinetics of full-length human Ano1. Am J Physiol Gastrointest Liver Physiol. 2017;312:G572-G579.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 6]  [Cited by in F6Publishing: 6]  [Article Influence: 0.9]  [Reference Citation Analysis (0)]
15.  Park CG, Kim YD, Kim MY, Kim JS, Choi S, Yeum CH, Parajuli SP, Park JS, Jeong HS, So I, Kim KW, Jun JY. Inhibition of pacemaker currents by nitric oxide via activation of ATP-sensitive K+ channels in cultured interstitial cells of Cajal from the mouse small intestine. Naunyn Schmiedebergs Arch Pharmacol. 2007;376:175-184.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 13]  [Cited by in F6Publishing: 13]  [Article Influence: 0.8]  [Reference Citation Analysis (0)]
16.  Zhou J, O'Connor MD, Ho V. The Potential for Gut Organoid Derived Interstitial Cells of Cajal in Replacement Therapy. Int J Mol Sci. 2017;18.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 10]  [Cited by in F6Publishing: 15]  [Article Influence: 2.1]  [Reference Citation Analysis (0)]
17.  Huizinga JD, Martz S, Gil V, Wang XY, Jimenez M, Parsons S. Two independent networks of interstitial cells of cajal work cooperatively with the enteric nervous system to create colonic motor patterns. Front Neurosci. 2011;5:93.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 75]  [Cited by in F6Publishing: 83]  [Article Influence: 6.4]  [Reference Citation Analysis (0)]
18.  Wang YB, Ling J, Zhang WZ, Li G, Qiu W, Zheng JH, Zhao XH. Effect of bisacodyl on rats with slow transit constipation. Braz J Med Biol Res. 2018;51:e7372.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 6]  [Cited by in F6Publishing: 6]  [Article Influence: 1.0]  [Reference Citation Analysis (0)]
19.  Gariepy CE. Developmental disorders of the enteric nervous system: genetic and molecular bases. J Pediatr Gastroenterol Nutr. 2004;39:5-11.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 35]  [Cited by in F6Publishing: 33]  [Article Influence: 1.7]  [Reference Citation Analysis (0)]
20.  Bassotti G, Villanacci V. Slow transit constipation: a functional disorder becomes an enteric neuropathy. World J Gastroenterol. 2006;12:4609-4613.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in CrossRef: 68]  [Cited by in F6Publishing: 67]  [Article Influence: 3.7]  [Reference Citation Analysis (1)]
21.  Bassotti G, Villanacci V. Can "functional" constipation be considered as a form of enteric neuro-gliopathy? Glia. 2011;59:345-350.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 38]  [Cited by in F6Publishing: 40]  [Article Influence: 2.9]  [Reference Citation Analysis (0)]
22.  Bassotti G, Villanacci V, Maurer CA, Fisogni S, Di Fabio F, Cadei M, Morelli A, Panagiotis T, Cathomas G, Salerni B. The role of glial cells and apoptosis of enteric neurones in the neuropathology of intractable slow transit constipation. Gut. 2006;55:41-46.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 127]  [Cited by in F6Publishing: 139]  [Article Influence: 7.7]  [Reference Citation Analysis (0)]
23.  Wedel T, Roblick UJ, Ott V, Eggers R, Schiedeck TH, Krammer HJ, Bruch HP. Oligoneuronal hypoganglionosis in patients with idiopathic slow-transit constipation. Dis Colon Rectum. 2002;45:54-62.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 75]  [Cited by in F6Publishing: 79]  [Article Influence: 3.6]  [Reference Citation Analysis (0)]
24.  Han Y, Wang JM. Effects of Jianpiyiqitongbian Formula on the quality of life evaluation and related enteric neurotransmitters in slow-transmitting constipation with lung and spleen qi deficiency type. Zhongyiyao Linchuang Zazhi. 2018;30:518-520.  [PubMed]  [DOI]  [Cited in This Article: ]
25.  Israelyan N, Del Colle A, Li Z, Park Y, Xing A, Jacobsen JPR, Luna RA, Jensen DD, Madra M, Saurman V, Rahim R, Latorre R, Law K, Carson W, Bunnett NW, Caron MG, Margolis KG. Effects of Serotonin and Slow-Release 5-Hydroxytryptophan on Gastrointestinal Motility in a Mouse Model of Depression. Gastroenterology. 2019;157:507-521.e4.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 65]  [Cited by in F6Publishing: 88]  [Article Influence: 17.6]  [Reference Citation Analysis (0)]
26.  King SK, Sutcliffe JR, Ong SY, Lee M, Koh TL, Wong SQ, Farmer PJ, Peck CJ, Stanton MP, Keck J, Cook DJ, Chow CW, Hutson JM, Southwell BR. Substance P and vasoactive intestinal peptide are reduced in right transverse colon in pediatric slow-transit constipation. Neurogastroenterol Motil. 2010;22:883-892, e234.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 45]  [Cited by in F6Publishing: 49]  [Article Influence: 3.5]  [Reference Citation Analysis (0)]
27.  Singh RD, Gibbons SJ, Saravanaperumal SA, Du P, Hennig GW, Eisenman ST, Mazzone A, Hayashi Y, Cao C, Stoltz GJ, Ordog T, Rock JR, Harfe BD, Szurszewski JH, Farrugia G. Ano1, a Ca2+-activated Cl- channel, coordinates contractility in mouse intestine by Ca2+ transient coordination between interstitial cells of Cajal. J Physiol. 2014;592:4051-4068.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 76]  [Cited by in F6Publishing: 84]  [Article Influence: 8.4]  [Reference Citation Analysis (0)]
28.  Attaluri A, Jackson M, Valestin J, Rao SS. Methanogenic flora is associated with altered colonic transit but not stool characteristics in constipation without IBS. Am J Gastroenterol. 2010;105:1407-1411.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 184]  [Cited by in F6Publishing: 167]  [Article Influence: 11.9]  [Reference Citation Analysis (0)]
29.  Ohkusa T, Koido S, Nishikawa Y, Sato N. Gut Microbiota and Chronic Constipation: A Review and Update. Front Med (Lausanne). 2019;6:19.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 106]  [Cited by in F6Publishing: 159]  [Article Influence: 31.8]  [Reference Citation Analysis (0)]
30.  Carco C, Young W, Gearry RB, Talley NJ, McNabb WC, Roy NC. Increasing Evidence That Irritable Bowel Syndrome and Functional Gastrointestinal Disorders Have a Microbial Pathogenesis. Front Cell Infect Microbiol. 2020;10:468.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 30]  [Cited by in F6Publishing: 49]  [Article Influence: 12.3]  [Reference Citation Analysis (0)]
31.  Dykes S, Smilgin-Humphreys S, Bass C. Chronic idiopathic constipation: a psychological enquiry. Eur J Gastroenterol Hepatol. 2001;13:39-44.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 33]  [Cited by in F6Publishing: 30]  [Article Influence: 1.3]  [Reference Citation Analysis (0)]
32.  Saps M, Velasco-Benitez CA, Fernandez Valdes L, Mejia J, Villamarin E, Moreno J, Ramirez C, González MJ, Vallenilla I, Falcon AC, Axelrod C. The impact of incorporating toilet-training status in the pediatric Rome IV criteria for functional constipation in infant and toddlers. Neurogastroenterol Motil. 2020;32:e13912.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 4]  [Cited by in F6Publishing: 6]  [Article Influence: 1.5]  [Reference Citation Analysis (0)]
33.  Sun J, Guo H, Chen L, Wu XL, Li H, Pei LX, Peng YJ, Lu B. Effects of electroacupuncture on the structure of colonic smooth muscle and Cajal mesenchymal stromal cells in rats with slow-transmitting constipation. Zhenci Yanjiu. 2011;36:171-175.  [PubMed]  [DOI]  [Cited in This Article: ]
34.  Zhong W, Sun B, Ruan H, Yang G, Qian B, Cao H, He L, Fan Y, Roberts AG, Liu X, Hu X, Liang Y, Ye Q, Yin T, Wang B, Yang C, Sun T, Zhou H. Deglycosylated Azithromycin Targets Transgelin to Enhance Intestinal Smooth Muscle Function. iScience. 2020;23:101464.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 5]  [Cited by in F6Publishing: 7]  [Article Influence: 1.8]  [Reference Citation Analysis (0)]
35.  Yamaji M, Mahmoud M, Evans IM, Zachary IC. Neuropilin 1 is essential for gastrointestinal smooth muscle contractility and motility in aged mice. PLoS One. 2015;10:e0115563.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 22]  [Cited by in F6Publishing: 22]  [Article Influence: 2.4]  [Reference Citation Analysis (0)]
36.  Kim JE, Go J, Lee HS, Hong JT, Hwang DY. Spicatoside A in red Liriope platyphylla displays a laxative effect in a constipation rat model via regulating mAChRs and ER stress signaling. Int J Mol Med. 2019;43:185-198.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 5]  [Cited by in F6Publishing: 7]  [Article Influence: 1.2]  [Reference Citation Analysis (0)]
37.  Higgins PD, Johanson JF. Epidemiology of constipation in North America: a systematic review. Am J Gastroenterol. 2004;99:750-759.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 692]  [Cited by in F6Publishing: 651]  [Article Influence: 32.6]  [Reference Citation Analysis (0)]
38.  Chan AO, Hui WM, Lam KF, Leung G, Yuen MF, Lam SK, Wong BC. Familial aggregation in constipated subjects in a tertiary referral center. Am J Gastroenterol. 2007;102:149-152.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 13]  [Cited by in F6Publishing: 15]  [Article Influence: 0.9]  [Reference Citation Analysis (0)]
39.  Yang J, Wang HP, Zhou L, Xu CF. Effect of dietary fiber on constipation: a meta analysis. World J Gastroenterol. 2012;18:7378-7383.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in CrossRef: 165]  [Cited by in F6Publishing: 150]  [Article Influence: 12.5]  [Reference Citation Analysis (5)]
40.  Yurtdaş G, Acar-Tek N, Akbulut G, Cemali Ö, Arslan N, Beyaz Coşkun A, Zengin FH. Risk Factors for Constipation in Adults: A Cross-Sectional Study. J Am Coll Nutr. 2020;39:713-719.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 9]  [Cited by in F6Publishing: 21]  [Article Influence: 5.3]  [Reference Citation Analysis (0)]
41.  Jung SJ, Oh MR, Park SH, Chae SW. Effects of rice-based and wheat-based diets on bowel movements in young Korean women with functional constipation. Eur J Clin Nutr. 2020;74:1565-1575.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 2]  [Cited by in F6Publishing: 2]  [Article Influence: 0.5]  [Reference Citation Analysis (0)]
42.  Simrén M. Physical activity and the gastrointestinal tract. Eur J Gastroenterol Hepatol. 2002;14:1053-1056.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 47]  [Cited by in F6Publishing: 50]  [Article Influence: 2.3]  [Reference Citation Analysis (0)]
43.  Gao R, Tao Y, Zhou C, Li J, Wang X, Chen L, Li F, Guo L. Exercise therapy in patients with constipation: a systematic review and meta-analysis of randomized controlled trials. Scand J Gastroenterol. 2019;54:169-177.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 25]  [Cited by in F6Publishing: 28]  [Article Influence: 5.6]  [Reference Citation Analysis (0)]
44.  Ulusoy E, Arslan N, Küme T, Ülgenalp A, Çirali C, Bozkaya Ö, Ercal D. Serum motilin levels and motilin gene polymorphisms in children with functional constipation. Minerva Pediatr (Torino). 2021;73:420-425.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in F6Publishing: 5]  [Reference Citation Analysis (0)]
45.  Cong P, Pricolo V, Biancani P, Behar J. Abnormalities of prostaglandins and cyclooxygenase enzymes in female patients with slow-transit constipation. Gastroenterology. 2007;133:445-453.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 47]  [Cited by in F6Publishing: 51]  [Article Influence: 3.0]  [Reference Citation Analysis (0)]
46.  Wang Y, Jiang Y, Jiang L, Xiong W, Wang Y, Gao X, Chen Q, Lin L, Yu T, Tang Y. Estrogen increases the expression of BKCa and impairs the contraction of colon smooth muscle via upregulation of sphingosine kinase 1. J Cell Physiol. 2023;238:2390-2406.  [PubMed]  [DOI]  [Cited in This Article: ]  [Reference Citation Analysis (0)]
47.  Oh JE, Kim YW, Park SY, Kim JY. Estrogen rather than progesterone cause constipation in both female and male mice. Korean J Physiol Pharmacol. 2013;17:423-426.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 18]  [Cited by in F6Publishing: 20]  [Article Influence: 1.8]  [Reference Citation Analysis (0)]
48.  Shams-White MM, Pannucci TE, Lerman JL, Herrick KA, Zimmer M, Meyers Mathieu K, Stoody EE, Reedy J. Healthy Eating Index-2020: Review and Update Process to Reflect the Dietary Guidelines for Americans,2020-2025. J Acad Nutr Diet. 2023;123:1280-1288.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 7]  [Cited by in F6Publishing: 38]  [Article Influence: 38.0]  [Reference Citation Analysis (0)]
49.  Lucak S, Lunsford TN, Harris LA. Evaluation and Treatment of Constipation in the Geriatric Population. Clin Geriatr Med. 2021;37:85-102.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 3]  [Cited by in F6Publishing: 11]  [Article Influence: 2.8]  [Reference Citation Analysis (0)]
50.  Locke GR 3rd, Pemberton JH, Phillips SF. American Gastroenterological Association Medical Position Statement: guidelines on constipation. Gastroenterology. 2000;119:1761-1766.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 179]  [Cited by in F6Publishing: 184]  [Article Influence: 7.7]  [Reference Citation Analysis (0)]