Microbiota treatment of functional constipation: Current status and future prospects

Abstract

Functional constipation (FC) is a common disorder that is characterized by difficult stool passage, infrequent bowel movement, or both. FC is highly prevalent, recurs often, accompanies severe diseases, and affects quality of life; therefore, safe and effective therapy with long-term benefits is urgently needed. Microbiota treatment has potential value for FC treatment. Microbiota treatments include modulators such as probiotics, prebiotics, synbiotics, postbiotics, and fecal microbiota transplantation (FMT). Some probiotics and prebiotics have been adopted, and the efficacy of other microbiota modulators is being explored. FMT is considered an emerging field because of its curative effects; nevertheless, substantial work must be performed before clinical implementation.

Key Words: Functional constipation; Gut microbiota; Microbiota modulators; Fecal microbiota transplantation; Dysbiosis

Core tip: Intestinal microbiota imbalance participates in functional constipation (FC) development. Gut microbiota modulation has potential clinical applications in the treatment of FC. The efficacy of specialized microbiota modulators and fecal microbiota transplantation should be explored.

INTRODUCTION

Functional constipation (FC) is a functional intestinal disease that is characterized by defecation difficulty, hard stool, decreased defecation frequency, or incomplete defecation[1,2]. The prevalence of FC is increasing worldwide owing to changes in diet structure and fast-paced lifestyles. Furthermore, the prevalence of FC increases with age, with rates of 14% and 20% in adults and in individuals over 60, respectively[1-3]. FC causes severe constipation-related symptoms; affects quality of life; and increases the risk of colorectal cancer, cardiovascular and cerebrovascular diseases, and mental and psychological diseases[4]. FC threatens health and increases economic and social burdens. The etiology of FC is unclear; however, genetic, lifestyle, mental, and behavioral factors; colonic motor function; and the intestinal microbiota contribute to FC pathogenesis[1,4]. Several lines of evidence strongly support the link between the intestinal microbiota and FC[5,6]. Intestinal function is influenced by disturbances in the gut microbiota and microbial metabolites, such as short-chain fatty acids (SCFAs), bile acids (BAs), methane, and H₂S[7]. The intestinal microbiota triggers the secretion of enterogenic hormones such as 5-hydroxytryptamine, vasoactive intestinal peptide, and glucagon peptide, which act on the receptors on the intestinal epithelial cells, smooth muscle cells, and neurons; therefore, these hormones affect intestinal sensation, secretion, and motor function[8].

FC treatment includes lifestyle adjustment, traditional medication (e.g., laxatives, prokinetic drugs, secretion-promoting drugs, microecological regulators, and traditional Chinese medicine), psychotherapy, enemas, acupuncture and moxibustion, biofeedback therapy, and surgery[3,4]. These treatment methods (applied alone or in combination) increase the frequency of defecation, improve fecal consistency, and alleviate constipation-related symptoms. Nevertheless, the efficacy of these methods eventually weakens, thus resulting in dependency or recurrence. Intestinal microbiota participates in FC development by interfering with intestinal barrier functions, intestinal secretion, and intestinal motility. Studies have focused on the efficacy of microecological therapies such as probiotics and prebiotics, particularly fecal microbiota transplantation (FMT). These interventions showed encouraging results and have potential for clinical implementation. We searched the MEDLINE and Science Direct databases for research articles on gut microbiota dysbiosis in FC and its microbiota treatment from 2018 to 2024. No other limits on language, author affiliation, or type of study were applied. This review integrates high-quality literature to provide a foundation for future research.

DISTURBED INTESTINAL MICROBIOTA AND METABOLITES IN FC

Gut microbiota dysbiosis is associated with FC, and characteristic changes occur in the gut microbiota of patients with FC. The relative abundance of Bacteroidetes increases in the intestine of patients with FC, and the relative abundance of Firmicutes and Proteobacteria decreases[9,10]. The abundance of intestinal probiotic genera, such as Bifidobacterium and Lactobacillus, decreases in patients with FC. By contrast, the abundance of Desulfovibrionaceae increases, and its product, namely, H₂S, inhibits colonic motility and promotes inflammation. The abundance of butyric acid–producing bacteria such as Faecalibacterium, Ruminococcus, and Roseburia decreases significantly in patients with FC, and the concentration of butyric acid in feces decreases. Butyrate maintains intestinal barrier integrity, prevents bacterial endotoxin and inflammatory responses, and reduces interference with intestinal motility[11]. One study observed that the abundance of Fusobacterium, which is a butyric acid–producing bacteria, is positively correlated with defecation frequency[12]. Several studies observed the increasing abundance of butyric acid–producing bacteria in the intestine of patients with FC; however, the concentration of butyric acid has yet to be detected[9,10]. In addition, the increased level of Bacteroides in the intestine of patients with FC is associated with the excessive production of γ-aminobutyric acid, which affects intestinal motility[9]. One study showed the increasing abundance of Bacteroides, Parabacteroides, Desulfvibriidae, and Ruminiclostridium and the decreasing abundance of Subdoligranulum accompanied by abnormal BA and lipid metabolism in patients with slow-transit constipation. BA increases intestinal mucosal permeability and the intestinal secretion of electrolytes and water and promotes intestinal motility and defecation by increasing the secretion of 5-hydroxytryptamine[13]. Other studies found that the relative abundance of methanogenic microbes in patients with slow-transit constipation is significantly high and that methane delays peristaltic conduction velocity by enhancing intestinal contraction and participating in the development of constipation[14,15]. Furthermore, extending the colonic transit time in FC facilitates the colonization of slow-growing microbes, and there may be an interaction between gut microbiota and intestinal transit function. Patients with FC have imbalances in intestinal microflora and microbial metabolites, which are involved in intestinal dysfunction and the development of constipation. In-depth studies are needed to clarify the characteristics of the association between intestinal microbiota and FC, as well as the specific microbes contributing to FC. Intestinal microbiota modulation is a potential therapeutic target for FC.

GUT MICROBIOTA MODULATION IN FC

Table 1 Summary of important studies on microecological regulators in the treatment of functional constipation from 2018 to 2024.

Ref.	Study type	Agent in the treatment group	Study population	Daily dosage and duration	Conclusion
Yoon et al[16], 2018	RCT	S. thermophilus MG510 and L. plantarum LRCC5193	171 patients (88 probiotics, 83 placebo)	MG510 7.8 × 109 CFU and LRCC5193 2.6 × 109 CFU; 4 wk	Probiotics ameliorated stool consistency
Ibarra et al[17], 2018	RCT	B. animalis subsp. lactis HN019	228 patients (76 high dose HN019, 76 low dose HN019, 76 placebo)	1 × 109 CFU or 1 × 1010 CFU; 4 wk	HN019 improved bowel movement frequency in adults with fewer than 3 stools per week
Lim et al[18], 2018	RCT	L.plantarum LP01, B. lactis BB12, and inulin-oligofructose	85 patients (43 synbiotics, 42 placebo)	1 × 1010 CFU, 2.5 g; 12 wk	Synbiotics improved constipation symptoms but failed to demonstrate benefits over the controls
Dimidi et al[19], 2019	RCT	B.lactis NCC2818	75 patients (37 NCC2818, 38 placebo)	1.5 × 1010 CFU; 4 wk	NCC2818 was not effective in the management of mild chronic constipation
Riezzo et al[20], 2019	RCT	L. reuteri DSM17938	56 patients (28 DSM17938, 28 placebo)	4 × 108 CFU for 15 d and then 2 × 108 CFU for 90 d	DSM17938 improved functional constipation by affecting 5-HT and brain-derived neurotrophic factor serum concentrations
Ou et al[21], 2019	Before–after study	L. casei strain Shirota	16 patients with constipation and 22 patients without constipation	1 × 1010 CFU; 4 wk	Shirota improved defecation frequency, stool consistency, and constipation-related symptoms
Kasugai et al[22], 2019	RCT	A crystalline lactulose preparation (SK-1202)	250 patients (63 SK-1202 at 13 g, 63 SK-1202 at 26 g, 62 SK-1202 at 39 g, 62 placebo)	13, 26, or 39 g; 2 wk	SK-1202 increased SBMs, and the optimal dose was 26 g/d
Chu et al[23], 2019	RCT	Prebiotic UG1601 (inulin, lactitol, and aloe vera gel)	40 patients (20 UG1601, 20 placebo)	13 g; 4 wk	Prebiotic failed to demonstrate benefits over the controls in symptom improvement but helped alleviate endotoxemia
Wang et al[24], 2022	RCT	B.bifidum CCFM16	103 patients (53 CCFM16, 50 placebo)	2 × 109 CFU; 4 wk	CCFM16 improved stool consistency and SBMs by regulating the gut microbiota and SCFA metabolism
Schoemaker et al[25], 2022	RCT	GOS	132 patients (45 GOS at 5.5 g, 44 GOS at 11 g, 43 placebo)	5.5 or 11 g; 3 wk	GOS at 11 g increased stool frequency in subjects with low stool frequency at baseline and in adults with self-reported constipation
Takeda et al[26], 2023	RCT	B. longum BB536	79 patients (38 BB536, 41 placebo)	5 × 1010 CFU; 4 wk	BB536 improved the bowel movements and upper abdominal symptoms of elderly patients
Patch et al[27], 2023	RCT	B. subtilis BG01-4TM	67 participants (34 BG01-4™, 33 placebo)	5 × 109 CFU; 4 wk	BG01-4™ improved specific symptoms of constipation and related gastrointestinal dysfunction
Ma et al[28], 2023	RCT	L. plantarum P9	163 patients (78 P9, 85 placebo)	1 ×1011 CFU; 6 wk	P9 improved the frequency of bowel movements and enriched potentially beneficial bacteria
Venkataraman et al[29], 2023	RCT	B. coagulans Unique IS2 and lactulose	150 patients (50 Unique IS2 with lactulose, 50 lactulose, 50 placebo)	Unique IS2 2 × 109 spores, lactulose at 10 g; 4 wk	Unique IS2 with lactulose was more effective than lactulose alone in relieving symptoms of constipation in a short period
Erhardt et al[30], 2024	RCT	A prebiotic formulation with PHGG and acacia gum as main ingredients	61 participants (31 prebiotics, 30 placebo)	PHGG at 6000 mg, acacia gum at 2000 mg, and other formulations; 3 wk	Prebiotics significantly increased CSBMs and were associated with a decrease in species richness and Shannon diversity

SBMs: Spontaneous bowel movements; GOS: Galactooligosaccharides; PHGG: Partially hydrolyzed guar gum; CSBMs: Complete spontaneous bowel movements.

The changes and functions of intestinal microflora in patients with FC provide a theoretical basis for microecological intervention in the treatment of FC. Intestinal microecological therapy includes microecological regulators such as probiotics, prebiotics, synbiotics, and postbiotics, which have proven therapeutic effects on FC (Table 1[16-30]). FMT is critical for treating diseases related to intestinal microecological imbalance. The literature suggests that intestinal microecological therapy can improve constipation symptoms by promoting the recovery of intestinal flora, which is safe and has advantages over traditional treatment.

Microecological regulators

Probiotics: Supplementation with probiotics such as Bifidobacterium and Lactobacillus is the primary common intestinal microbial intervention for FC. B. bifidum CCFM16 improves the stool consistency of patients with FC; increases the frequency of spontaneous defecation; changes the composition of gut microbiota; and increases the concentration of acetic acid, butyric acid, and total SCFA in feces[24]. B. longum BB536 increases the frequency of defecation and improves abdominal symptoms in older adults with FC, and its therapeutic effect can be maintained four weeks after discontinuation[26]. However, the effect of B. lactis NCC2818 on intestinal transit time, defecation frequency, and constipation symptoms in patients with mild FC was not observed[19]. Several studies on other probiotic strains showed that L. reuteri DSM-17938 or Bacillus subtilis improves constipation, abdominal distension, discomfort, and indigestion[20,27]. The therapeutic effect of L. casei Shirota on constipation might be associated with piperidic acid, which improves intestinal motility by increasing the concentrations of 5-hydroxytryptamine and acetylcholine in the colon[21]. L. plantarum P9 increases the frequency of defecation in patients with FC, which is achieved by regulating functional bacteria and microbial metabolites[28]. The addition of B. coagulans Unique IS2 to lactulose relieves constipation symptoms in a shorter period than lactulose alone[29]. Compared with single-strain probiotics, mixed probiotics might be more effective in increasing defecation frequency and relieving abdominal symptoms[16,31]. The dosage and duration time of probiotics might influence this effect[17,32,33]. High-quality studies are needed to evaluate the therapeutic effect of supplementary probiotics on FC.

Prebiotics: Prebiotics are not digested by humans but can be fermented by intestinal microflora, including oligofructose, inulin, galactooligosaccharides, and lactulose, which play a therapeutic role by positively influencing gut microbiota[34,35]. Several studies showed that prebiotics are similar to probiotics in terms of improving the defecation frequency and constipation symptoms of patients with FC[36]. In constipation-related guidelines and consensus statements, lactulose is recommended as a first-line treatment[3]. Lactulose dose-dependently increases the frequency of spontaneous defecation and has a good safety profile[22]. Lactulose exerts its therapeutic effect by acting as an osmotic laxative; increasing the abundance of beneficial intestinal microbes, such as Bifidobacterium; and improving the balance of intestinal microbiota and metabolites, thus inhibiting intestinal inflammatory response and promoting intestinal movement[37,38].

Regarding other prebiotics, several studies showed that galactooligosaccharides increase the defecation frequency of patients with FC and are associated with increased levels of Bifidobacterium and Anaerostipes hadrus, which produce SCFA[25]. A meta-analysis confirmed the efficacy of galactooligosaccharides in increasing stool frequency and relieving the abdominal symptoms of patients with FC[34]. The prebiotic UG1601, which is composed of inulin, aloe vera gel, and lactitol, decreases the serum concentration of lipopolysaccharide and CD14, which cause prolonged intestinal transit time and sphincter dysfunction; this prebiotic can also improve the composition of intestinal microflora by decreasing Firmicutes and increasing butyric acid–producing microbes[23]. A prebiotic formulation with partially hydrolyzed guar gum and acacia gum as its main ingredients increases bowel movements associated with decreased species richness and Shannon diversity[30]. The therapeutic effect of lactulose on FC has been fully affirmed, and other prebiotics also show therapeutic potential for FC. However, most prebiotics are currently used as food ingredients, and clinical studies must be conducted to clarify their therapeutic effects on FC.

Synbiotics and postbiotics: Synbiotics containing fructooligosaccharides or pectin can increase stool frequency, improve stool consistency, decrease colonic transit time, and improve constipation-related symptoms[18,34,36,39]. Synbiotics containing probiotics and xylooligosaccharides increase the abundance of Prevotella and Lactococcus and reduce the abundance of Escherichia and Shigella in the intestine of patients with FC. The efficacy of synbiotics on constipation might be achieved by restoring the intestinal microbiota[40]. Synbiotics are added to healthy food and formula milk, but the clinical application of synbiotics is limited. Therefore, the efficacy of synbiotics on FC needs to be explored.

Furthermore, postbiotics, as a derivative of probiotics, refer to inanimate microorganisms or their beneficial components to the host[41]. Only a few animal experiments showed that postbiotics could improve constipation-related symptoms by increasing intestinal motility, protecting intestinal barrier functions, and regulating intestinal microbiota and SCFA metabolism[42,43]. Clinical studies are needed to define the role of postbiotics on FC.

FMT

FMT involves the transplantation of fecal matter from healthy donors into a recipient’s digestive tract to modulate tissue and organ functions and intestinal microecology and achieve therapeutic effects for dysbiosis disorders[44,45]. FMT has been proposed as a therapeutic approach for FC[46,47]. Recently, clinical studies on FC treatment with FMT have been increasing. A retrospective study from China showed the efficacy of FMT via nasointestinal tube, oral capsule, or colonoscopy on constipation; the overall effectiveness rates after 3 and 36 months were 70.3% and 60.5%, respectively[48]. One study showed that FMT via nasointestinal tube for six consecutive days every two weeks led to a remission rate of 75% in patients with slow-transit constipation after the third treatment[49]. Regular and multiple FMT treatments for FC might effectively relieve constipation-related symptoms and maintain therapeutic efficacy and intestinal homeostasis[46].

Moreover, the combination of FMT and laxatives, such as lactulose, might be a safe and effective treatment for FC[50]. FMT combined with biofeedback therapy increased defecation frequency and improved fecal consistency and quality of life[51]. Moreover, FMT might improve the depression and anxiety of patients with constipation[52,53]; therefore, FMT might have multiple therapeutic functions via the regulation of the brain–gut–microbiota axis.

FMT could restore the disturbed intestinal microbiota in patients with FC. After FMT treatment, the α-diversity of gut microflora increases, and the abundance of Clostridia, Fusicatenibacter, and Paraprevotella increases; these results are consistent with the improvement of constipation-related symptoms[54]. Another study showed that the levels of Bacteroides, Prevotell, Roseburia, and Blautia in the gut of patients with FC decreased after FMT, whereas Bifidobacterium, Escherichia, and Lactobacillus increased[49]. This study found that the increase in protein metabolites was significantly correlated with intestinal bacterial genera such as Lactobacillus and Anaerovibrio. FMT was speculated to regulate disturbed gut microbiota and influence protein metabolism by stimulating intestinal water and Na⁺ secretion and relieving constipation[49].

The effect of FMT on dysbiosis disorders is influenced by factors such as donor selection; fecal sample preparation; transplantation route; and transplantation frequency, dosage, and duration[44-47]. Data regarding FMT in FC are somewhat limited, although several observational studies have shown promising clinical application prospects. Regarding the use of FMT in the management of FC, the following should first be validated by high-quality basic studies and clinical trials: donor–recipient microbial profiling, evaluation, and matching; preparation of fecal samples (fresh or frozen); identification of the most appropriate route of administration (oral capsule, nasointestinal tube, or colonoscopy); use of single or multiple interventions; and analysis of the efficacy of FMT or combination therapy.

CONCLUSION

FC is associated with gut microbiota dysbiosis. Microbial metabolites affect the intestinal neuroendocrine system, movement, and secretion functions. An in-depth evaluation is needed to clarify the microbial-related mechanisms in FC. Generally, recent studies showed that gut microbiota interventions can promote the recovery of intestinal microbiota, increase defecation frequency, and improve stool consistency and constipation-related symptoms. Several probiotic strains, such as Bifidobacterium. sp. and Lactobacillus. sp., and some prebiotics, such as lactulose, have been widely used in treating FC. However, the best strain, dosage, and duration of use of microecological agents should be verified. FMT might be the most effective gut microbiota intervention method for FC. Nevertheless, the best therapeutic strategies; the best technical schemes; the role of next-generation FMT such as transplant bacteriome, virome, or mycobiome; and the potential mechanisms of FMT require further study. It is anticipated that in-depth studies will promote the formation of consensus on the microecological therapy of FC.