Chronic constipation: modern view on the problem. A review

Chronic constipation is a frequently diagnosed heterogeneous pathology that significantly impairs the quality of life in all population groups and its frequency increases with age. It commonly affects up to 10 — 15 % of the population. There are numerous classifications of constipation due to a great number of disorders that cause it. The types of constipation are identified based on the etiology or mechanism of its development. Different criteria are used to specify the categorization of constipation, but it is still difficult to find one general classification including all types of constipation. The Rome IV criteria categorize disorders of chronic constipation into four subgroups. The treatment depends on the subtype. The significant increase of constipation cases is observed nowadays. This disorder is facilitated by a sedentary lifestyle, insufficient amount of fiber and fluid in the diet, a wide range of diseases that directly lead to the development of chronic constipation, congenital and acquired pathologies, abnormal intake of laxatives and opioids or a combination of these factors. Despite numerous publications on slow transit constipation, the latter is still the subject of research for many specialists. A lot of recent scientific works have been dedicated to the immunohistochemical studies of interstitial pacemaker cells. The numbers of markers they express were found. Consequently, the investigations of modern scientists are aimed to develop and implement new laboratory methods for determining the indications for surgical treatment depending on a diagnosed disorder of the intestinal neurophysiology. These methods will ensure a differentiated selection of patients for surgical treatment. The step approach to the diagnosis of chronic constipation allows choosing an adequate treatment method in order to improve symptoms, the quality of life, and patient satisfaction. The literature review indicates that surgery still remains the most radical treatment method for patients with slow transit constipation.

Paeoniflorin Improved Constipation in the Loperamide-Induced Rat Model via TGR5/TRPA1 Signaling-Mediated 5-Hydroxytryptamine Secretion

Slow transit constipation (STC) is a common type of constipation with a high incidence rate and a large number of patients. We aimed to investigate the therapeutic effects and potential mechanism of paeoniflorin (PAE) on loperamide-induced Sprague Dawley (SD) rat constipation models. Rats with loperamide-induced constipation were orally administered different concentrations of PAE (10, 20, or 40 mg/kg). In vitro, enterochromaffin (EC)-like RIN-14B cells were treated with 20, 40, or 80 μg/ml PAE. We found that PAE treatment significantly improved the symptoms of constipation and increased the intestinal transit rate. Hematoxylin and eosin (H&E) staining showed that PAE alleviated colonic tissue pathological damage. Besides, our results implied that PAE concentration-dependently promoted the content of 5-hydroxytryptamine (5-HT) catalyzed by tryptophan hydroxylase (Tph)-1 in the serum of loperamide-induced rats and in RIN-14B cells. Western blot and immunofluorescence (IF) stain indicated that PAE also promoted the expression of G protein-coupled BA receptor 1 (TGR5), transient receptor potential ankyrin 1 (TRPA1), phospholipase C (PLC)-γ1, and phosphatidylinositol 4,5-bisphosphate (PIP2) in vivo and in vitro. RIN-14B cells were cotreated with a TGR5 inhibitor (SBI-115) to explore the mechanism of PAE in regulating the 5-HT secretion. We observed inhibition of TGR5 reversed the increase of 5-HT secretion induced by PAE in RIN-14B cells. We provided evidence that PAE could promote 5-HT release from EC cells and improve constipation by activating the TRPA1 channel and PLC-γ1/PIP2 signaling. Thus, PAE may provide therapeutic effects for patients with STC.

Effect of fecal microbiota transplantation in patients with slow transit constipation and the relative mechanisms based on the protein digestion and absorption pathway

Background Fecal microbiota transplantation (FMT) is considered an effective treatment for slow transit constipation (STC); nevertheless, the mechanism remains unclear. Methods In this study, eight patients with STC were selected according to the inclusion and exclusion criteria; they then received three treatments of FMT. The feces and serum of STC patients were collected after each treatment and analyzed by integrating 16 s rRNA microbiome and metabolomic analyses. Results The results showed that the percentage of clinical improvement reached 62.5% and the rates of patients’ clinical remission achieved 75% after the third treatment. At the same time, FMT improved the Wexner constipation scale (WCS), the Gastrointestinal Quality-of-Life Index (GIQLI) and Hamilton Depression Scale (HAMD). Fecal microbiome alpha diversity and beta diversity altered significantly after FMT. Analysis of the 16 s rRNA microbiome showed that the numbers of Bacteroidetes (Prevotell/Bacteroides) and Firmicute (Roseburia/Blautia) decreased, whereas Actinobacteria (Bifidobacterium), Proteobacteria (Escherichia), and Firmicute (Lactobacillus) increased after FMT. The metabolomics analyses showed that the stool of FMT-treated patients were characterized by relatively high levels of N-Acetyl-L-glutamate, gamma-L-glutamyl-L-glutamic acid, Glycerophosphocholine, et al., after FMT. Compared with baseline, the serum of treated patients was characterized by relatively high levels of L-Arginine, L-Threonine, Ser-Arg, Indoleacrylic acid, Phe-Tyr, 5-L-Glutamyl-L-alanine, and lower levels of Erucamide after the treatment. The correlation analysis between the metabolites and gut microbiota showed a significant correlation. For example, L-Arginine was positively correlated with lactobacillus, et al. L-Threonine was positively correlated with Anaerovibrio, Sediminibacterium but negatively correlated with Phascolarctobacterium. Erucamide had significant negative correlations with Sediminibacterium and Sharpea, while being positively correlated with Phascolarctobacterium. Enriched KEGG pathways analysis demonstrated that the protein digestion and absorption pathways gradually upregulated with the increase of FMT frequency. The L-Arginine and L-Threonine were also involved in the pathway. A large amount of Na + was absorbed in the pathway, so that it might increase mucus secretion and electrical excitability of GI smooth muscle. Conclusions Therefore, we speculated that FMT changed the patients’ gut microbiota and metabolites involved in the protein digestion and absorption pathways, thereby improving the symptoms of STC. Study on the effectiveness and safety of FMT in the treatment of STC. The study was reviewed and approved by Ethics Committee of Tianjin People's Hospital (ChiCTR2000033227) in 2020.

Unusual cause of low abdominal pain

A 53-year-old woman, G2P2, was referred to the outpatient clinic because of chronic abdominal pain. Abdominal examination revealed tenderness in the right lower quadrant without peritoneal signs and blood analysis was normal. To exclude slow transit constipation a pellet study was performed: plain abdominal radio-graphy showed the presence of all ingested pellets and an abnormal, slightly lateralized and angulated position of the intrauterine device, a levonorgestrel intrauterine system called Mirena® which was placed five years earlier (figure 1). Subsequently an abdominal computed tomography was executed.

Justification of the diagnostic algorithm and treatment strategies in patients with severe chronic slow-transit constipation

Surgical treatment of patients with chronic slow-transit constipation leads to unsatisfactory results in almost a third of cases. It appears relevant to the search for the causes of unsatisfactory results of surgical interventions in such patients and the need to develop a rational diagnostic algorithm; its implementation will allow us to determine the indications for surgical treatment and justify the volume of colon resection. For this purpose, the results of the examination and treatment of 53 patients with constipation were analyzed. The median disease duration was 15 years, and the median duration of constipation was 6.2 1.6 days. Patients were divided into a group with a positive effect of conservative treatment and a group without the expected effect. The symptoms, results of laboratory tests of blood and feces, and instrumental studies of the colon were analyzed. A balloon expulsion test was used to exclude proctogenic constipation. The evacuation function of the colon was studied by X-ray examination, while the transit time of barium sulfate or X-ray contrast markers through the gastrointestinal tract was estimated. Twenty-four patients underwent surgery for chronic slow-transit constipation, while the sigmoid colon was removed in one patient, including 7-left-sided hemicolectomy and 16-subtotal resection of the colon. Long-term results were examined in the period from 3 to 6 months after surgery. In the total examination of the semiotics of chronic slow-transit constipation, the results did not show significant differences between the groups of patients and did not allow us to justify the stratification into severe and non-severe disease course by its specific symptoms. The use of X-ray contrast markers for the assessment of the state of the evacuation function of the colon makes it possible to quantify the severity of various motor disorders and justify the choice of the volume of its resection. The analysis of the long-term results of the treatment of patients with chronic slow-transit constipation allows us to conclude that segmental resections of the colon (left-sided hemicolectomy, resection of the sigmoid colon) have a good therapeutic effect if the preoperative examination revealed a segmental type of failure of the evacuation function of the colon, and subtotal resection of the colon is appropriate for the common type. The absence of negative results of surgical treatment of patients with chronic slow-transit constipation, in which the formation of a colonic anastomosis was performed with a short stump of the sigmoid colon, indicates the possibility of using this option to complete the surgical intervention.

Pathohistological study of the ganglion plexuses of the sigmoid colon in patients with chronic slow-transit constipation

The morphological study of the resected sections of the colon obtained at the S.P. Fedorov Department of Faculty Surgery of S.M. Kirov Military Medical Academy, as a result of surgical treatment of patients with severe chronic slow-transit constipation, included an assessment of the changes in the structures of ganglion plexuses. Three cases were considered (women, aged 3740 years). Various degrees of pathological changes were detected in the ganglion plexuses (Auerbach and Meissner) of the sigmoid colon from patients with chronic slow-transit constipation using Nissls toluidine blue staining. In all cases, reactive, dystrophic, severe degenerative-necrotic changes of ganglion cells, as well as the details of their death, were described in detail. Along with pathological changes in nerve cells in the myenteric nerve plexus and gliosis, features of neuronglial relationships were described, and the death of ganglion cells in the human colon with the active participation of specialized astrocyte-like glial cells was also established for the first time. In the third case, a pattern of pronounced dysplasia and dysgangliogenesis was revealed in the myenteric ganglion plexus of the sigmoid colon, and the presence of diffuse lymphmonocytic infiltrates was noted in the circular muscle layer. Pathological changes in the enteral nervous system in chronic slow-transit constipation reflect neuropathy, which can serve as the main cause of impaired intestinal functions and of some symptoms.

The Fecal Microbiota Transplantation: A Remarkable Clinical Therapy for Slow Transit Constipation in Future

Slow transit constipation is a common condition that would be difficult to treat in clinical practice with a widespread incidence in the population. Pharmacotherapy and surgery are common treatment modalities. However, the clinical effect is limited, and patients still suffer from it. As the researchers strived in this field for decades, the profound relationship between slow transit constipation and fecal microbiota transplantation has comprehensively been sustained. It is very pivotal to maintain intestinal homeostasis, the structure function and metabolic function of symbiotic bacteria, which can inhibit the engraftment of intestinal pathogens. This mini review explains the treatment effects and possible mechanisms of the fecal microbiota transplantation in treating slow transit constipation. Simultaneously, it is found that there is significant improvement in the disease by adjusting the intestinal microbes like fecal microbiota transplantation. Fecal microbiota transplantation has efficient therapeutic effects in slow transit constipation compared with traditional therapies.

Effect of Fecal Microbiota Transplantation in Patients With Slow Transit Constipation and the Relative Mechanisms Based On the Protein Digestion and Absorption Pathway

Background: Fecal microbiota transplantation (FMT) is considered an effective treatment for slow transit constipation (STC); nevertheless, the mechanism remains unclear. Methods: In this study, eight patients with STC were selected according to the inclusion and exclusion criteria; they then received three treatments of FMT. The feces and serum of STC patients were collected after each treatment and analyzed by integrating 16s rRNA microbiome and metabolomic analyses. Results: The results showed that the percentage of clinical improvement reached 62.5% and the rates of patients’ clinical remission achieved 75% after the third treatment. At the same time, FMT improved the Wexner constipation scale (WCS), the Gastrointestinal Quality-of-Life Index (GIQLI) and Hamilton Depression Scale (HAMD). Fecal microbiome alpha diversity and beta diversity altered significantly after FMT. Analysis of the 16s rRNA microbiome showed that the numbers of Bacteroidetes (Prevotell/Bacteroides) and Firmicute (Roseburia/Blautia) decreased, whereas Actinobacteria (Bifidobacterium), Proteobacteria (Escherichia), and Firmicute (Lactobacillus) increased after FMT. The metabolomics analyses showed that the stool of FMT-treated patients were characterized by relatively high levels of N-Acetyl-L-glutamate, gamma-L-Glutamyl-L-glutamic acid, Glycerophosphocholine, et al, after FMT. Meanwhile, the serum of treated patients was characterized by relatively high levels of L-Arginine, L-Threonine, Ser-Arg, Indoleacrylic acid, Phe-Tyr, 5-L-Glutamyl-L-alanine, and lower levels of Erucamide after the treatment. The correlation analysis between the metabolites and gut microbiota showed a significant correlation. For example, L‐Arginine was positively correlated with lactobacillus, et al. L-Threonine was positively correlated with Anaerovibrio, Sediminibacterium but negatively correlated with Phascolarctobacterium. Erucamide had significant negative correlations with Sediminibacterium and Sharpea, while being positively correlated with Phascolarctobacterium. Enriched KEGG pathways analysis demonstrated that the protein digestion and absorption pathways gradually upregulated with the increase of FMT frequency. The L‐Arginine and L-Threonine were also involved in the pathway. A large amount of Na+ was absorbed in the pathway, so that it might increase mucus secretion and electrical excitability of GI smooth muscle. Conclusions: Therefore, we speculated that FMT changed the patients’ gut microbiota and metabolites involved in the protein digestion and absorption pathways, thereby improving the symptoms of STC.Study on the effectiveness and safety of FMT in the treatment of STC. The study was reviewed and approved by Ethics Committee of Tianjin People's Hospital (ChiCTR2000033227) in 2020.