Exploration of the complex origins of primary constipation

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 The causes of primary constipation.

Table 1 The causes of constipation.

Classification	Etiology
Primary constipation	Intestinal 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 constipation	Secondary conditions	Mechanical obstruction
		Metabolic disorders
		Neuropathy
		Anorectal disorders
		Others
	Medications	Anticholinergics
		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.