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Review

A Survey of Methodologies for Assessing Mast Cell Density and Activation in Patients with Functional Abdominal Pain Disorders

1
School of Medicine, University of Kansas, Kansas City, KS 66160, USA
2
Division of Gastroenterology, Hepatology, & Nutrition, Children’s Mercy Kansas City, 2401 Gillham Road, Kansas City, MO 64108, USA
3
Department of Pathology, The University of Texas Southwestern Medical Center, 1935 Medical District Drive, Dallas, TX 75235, USA
4
Department of Pediatrics, School of Medicine, University of Missouri-Kansas City, Kansas City, MO 64108, USA
*
Author to whom correspondence should be addressed.
Academic Editor: Takuji Tanaka
Gastrointest. Disord. 2021, 3(4), 142-155; https://0-doi-org.brum.beds.ac.uk/10.3390/gidisord3040016
Received: 23 July 2021 / Revised: 22 September 2021 / Accepted: 28 September 2021 / Published: 30 September 2021

Abstract

The aim was to assess methods utilized in assessing mast cell involvement in functional abdominal pain disorders (FAPDs), specifically to describe variability in methods utilized to assess both mast cell density and activation and determine if a consensus exists. After a literature search identified 70 manuscripts assessing mast cell density, data were extracted including FAPD diagnosis, site of biopsy, selection of microscopic fields analyzed, selection of mucosal region analyzed, method of mast cell identification, method to assess mast cell density, and if performed, method to assess mast cell activation. There appears to be some consensus favoring inmmunohistochemical stains over histochemical stains for identifying mast cells. Otherwise, considerable variability exists in methodology for assessing mast cell density and activation. Regardless of method, approximately 80% of studies found increased mast cell density and/or activation in comparison to controls with no method being superior. A wide variety of methods have been employed to assess mast cell density and activation with no well-established consensus and inadequate data to recommend specific approaches. The current methodology providing physiologic information needs to be translated to a standard methodology providing clinical information with the development of criteria establishing abnormal density and/or activation, and more importantly, predicting treatment response.
Keywords: mast cells; irritable bowel syndrome; functional dyspepsia mast cells; irritable bowel syndrome; functional dyspepsia

1. Introduction

Functional abdominal pain disorders (FAPDs), particularly irritable bowel syndrome (IBS) and functional dyspepsia (FD), are highly prevalent conditions resulting in significant morbidity and healthcare costs worldwide. IBS is defined by abdominal pain associated with a change in stool frequency, a change in stool form, or a change in pain intensity with stools [1]. FD is defined by the presence of epigastric pain, epigastric burning, early satiety, or postprandial fullness [2]. FAPDs are considered to result from disordered brain-gut axis function with a wide variety of pathophysiologic contributors including altered neural pathways (both peripheral and central), dysmotility, visceral hypersensitivity, inflammation, dysbiosis, and psychologic dysfunction. Mast cells have been implicated in both IBS and FD, in part due to their location at the interface between the patient and the environment and in part due to their functional connectivity to the multiple systems implicated in the generation of gastrointestinal symptoms [3]. Previous studies have shown increased mast cell density and/or evidence of increased mast cell activation in patients with FAPDs in most, but not all, studies. A meta-analysis of adults with FD demonstrated increased mast cells in the stomach and duodenum [4]. Multiple systematic reviews and/or meta-analyses have demonstrated increased mast cells in the ileum and colon of adults with IBS [5,6,7,8]. In the largest of these reviews, Krammer and colleagues reviewed 36 studies with 30 of these studies demonstrating increased mucosal mast cells in adults with IBS [8]. Mast cells have been specifically linked to the development of visceral hypersensitivity, a pathophysiologic process of central importance in FAPDs [9].
A variety of methods have been employed to assess gastrointestinal mast cells, most commonly methods to determine mast cell density. There are a variety of techniques utilized to identify mast cells including histochemical staining (e.g., utilizing toluidine blue or Alcian blue) or immunohistochemical staining (e.g., utilizing antibodies to tryptase or CD 117, also known as c-kit). However, it is well recognized that mast cells exert their biologic functions primarily through the release of mediators and, thus, density does not give a complete picture of mast cell involvement. A variety of methods are available to assess mast cell activation. These include measuring (1) degranulation (e.g., utilizing transmission electron microscopy) [10,11,12,13,14,15,16,17,18,19]; (2) mast cell-derived mediators (e.g., tryptase and histamine) in biologic fluids or intestinal tissue either utilizing techniques such as RNA seq or protein analysis [17,18,20,21,22,23]; and, (3) mediators in the supernatant after tissue incubation [16,17,20,24,25,26,27,28,29,30,31,32,33].
The aim of the current survey was to assess the methods utilized in assessing mast cell involvement in FAPDs in both adults and children, specifically to describe variability in methods utilized to assess both mast cell density and activation and determine if there appears to be any consensus. Ultimately, the transition of the current state implicating mast cells in the pathophysiology of FAPDs to a clinically useful process of assessing mast cell involvement will require some standardization of methods, definitions of abnormal, and proof of an ability to predict response to treatments directed at mast cells or their mediators. Assessment of current practices represents the first step in this transition.

2. Literature Assessment

We conducted a literature search utilizing PubMed, Google, and Google Scholar employing the keywords “gastrointestinal mast cells”, “irritable bowel syndrome”, and “functional dyspepsia” from 2000 to 2021. Additionally, we cross-referenced bibliographies from all identified manuscripts to identify other relevant manuscripts. While the current manuscript was intended to be a methodologic survey and not a systematic review, we did include all relevant manuscripts identified in previous systematic reviews assessing mast cells in patients with FD and/or IBS [4,5,6,7,8]. Manuscripts were included if they reported on any patients with FAPDs and included an assessment of gastrointestinal mast cell density. Manuscripts were excluded if they did not assess density, even if activation was assessed.
Data extractions were performed independently by 2 reviewers (HF and CF). After comparing results, any discrepancies were resolved. Specific data extracted was first author, country where subjects were evaluated, age group, patient FAPD diagnosis, site of biopsy, selection of microscopic fields analyzed, selection of mucosal region analyzed, method of mast cell identification, method to assess mast cell density, and if performed, method to assess mast cell activation (See Figure 1). In addition, whether density and activation differed from a control group was assessed, primarily to determine how frequently findings related to density were discrepant from findings related to activation.

3. Summary of Methods for Mast Cell Evaluation

A total of 11 studies (1 IBS, 5 FD, 2 FAPD, and 3 of endoscopy patients) in children and adolescents and 59 studies (44 IBS, 14 FD, and 1 with both IBS and FD) in adults were identified [8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78]. The primary findings in pediatric patients are shown in Table 1 and in adults are shown in Table 2 and Table 3. In youth, 8/11 (73%) studies identified mast cells with immunohistochemical stains (all utilizing anti-tryptase antibody) and 3/11 studies utilized histochemical stains. In adults, 49/59 (83%) studies identified mast cells with immunohistochemical stains (33 utilizing anti-tryptase, 15 anti-CD117, and one using both) and 10/59 studies utilized histochemical stains, most commonly toluidine blue (7 studies). Mast cell activation was assessed in 2/11 (18%) pediatric studies and 25/59 (43%) of adult studies. The number of microscopic fields assessed varied from 5 to 10 in pediatric studies and 3/20 in adult studies. In pediatric studies, the process for field selection was not stated in 3 studies, random in 2 studies, and through identification of most involved areas in 6 studies. In adult studies, the process for field selection was not stated in 42 studies, random in 11 studies, through identification of most involved areas in 2 studies, and through identification of ‘most representative’ areas in 4 studies. Other selection criteria in some studies included a requirement that the specimen be well-oriented or that villi be cut transversely. Others also avoided lymphoid follicles or lymphoid aggregates. Additional variability was noted in the mucosal layer evaluated with some assessing only the lamina propria and some assessing both the lamina propria and epithelium. There were also a variety of methods for assessing the mast cell density. While most studies involved manual counting of mast cells, others utilized image analysis to report the percentage of the area occupied by mast cells (either overall or lamina propria only). With manual counting, mast cell density was reported per high power field in some studies, per mm2 in others, and as a percentage of total immunocytes in another. Densities were also reported by both quantitative and semi-quantitative (density ranges) methods.
Only 2 pediatric studies compared patients to a control group and both studies demonstrated increased mast cells in the study group [36,39]. Neither assessed activation. Results comparing adult patients to controls are shown in Table 2 and Table 3. Overall, density in comparison to controls was reported in 57 studies. Of these, increased density was reported in 45 studies (79%), no difference in 10 studies (18%), and decreased density in 2 studies (4%). One study reported density as both cell count and area occupied by mast cells demonstrating decreased cell counts and increased area occupied in patients with IBS [26]. Increased mast cells in association with an FAPD was found in 26/33 (79%) of studies staining for tryptase, 12/15 (80%) of studies staining for CD117, and 8/10 (80%) of studies utilizing histochemical staining.
Overall activation in comparison to controls was reported in 24 studies (Table 3). Of these, increased activation was reported in 20 studies (83%), decreased activation in one study (4%), and no difference in 3 studies (13%). Twenty-three of these studies reported both density and activation as compared to controls. In 5 studies, there was a discrepancy between density and activation findings. Three studies showed increased activation with no difference in density and two showed increased density with no difference in activation. One study showed increased density by area occupied but not cell density and activation was increased. Seven studies utilized multiple methods to assess activation and findings were concordant between methods in 6 studies [17,18,20,26,28,29,30]. In the remaining study, supernatant tryptase was increased but degranulation did not differ from controls [28]. Overall activation was assessed by supernatant tryptase in 12 studies, degranulation in 10 studies, tissue tryptase expression or protein analysis in 5 studies, supernatant histamine in 6 studies, assessment of in vitro nerve stimulation in 3 studies, and luminal tryptase in 2 studies.

4. Discussion

A variety of techniques are available for assessing mast cell density in FAPDs and these have been applied with considerable variability. Immunohistochemistry (IHC) staining appears to be the preferred method for identifying mast cells to assess density, with anti-tryptase or anti-CD117 antibodies utilized in 73% of pediatric studies and 83% of adult studies. Histochemical stains for mast cells are known to be less sensitive in identifying mast cells in gastrointestinal mucosa fixed with formalin [80,81]. Not surprisingly, there appears to be a preference for IHC stains. However, these IHC stains are not without limitations and introduce other variability into the literature. For example, 20–30% of tryptase-positive cells in the stomach and colon fail to stain for CD117, creating a challenge in assimilating data obtained utilizing the two different methods [82]. CD117 is present in immature mast cells and a large proportion of mast cells in the stomach and colon do not stain with anti-CD117 [83]. While anti-tryptase appears to identify more mast cells and is the most commonly utilized method, tryptase is expressed late in mast cell maturation and will not identify those mast cells expressing only chymase which are present in the stomach, small bowel, and colon [81,82,83]. This latter limitation can be overcome by also staining for chymase [81]. Variability is also introduced by the selection of microscopic fields to be assessed. While the process for field selection is often not stated, when reported, it varies from random to “most representative” to most involved. The rationale for most involved is that density is often patchy. Most studies assess mast cells per area, either per high power field (hpf) or per mm2. The actual area of a hpf varies between microscopes. Others assess the percentage of area occupied by mast cells utilizing digital imaging. While some studies have found a high correlation between manual cell counts and measurement of the percentage of area occupied by mast cells, another study found discordant results between manual counts and area occupied in comparison to healthy controls [26,52].
There are also a variety of methods for assessing mast cell activation. This may be of particular importance as most biologic functions of mast cells are the result of the release of specific mediators generally acting in a concentration-dependent fashion [84]. There appear to be 3 commonly used approaches for assessing activation: (1) assessing degranulation at a cellular level using light microscopy or at both a cellular and sub-cellular level using electron microscopy, (2) assessing tissue or luminal mast cell mediators, most commonly tryptase and histamine, and (3) functional studies using mucosal supernatants to stimulate enteric nerves in vitro. Regardless of the method, increased activation relative to healthy controls was demonstrated in over 80% of studies. In 22% of studies where activation was assessed by any method, there was a discrepancy between density and activation comparisons to controls. In 2 studies, density alone was increased and in 3 studies, activation alone was increased. Density and activation measurements are not perfectly aligned and both may be needed to get a full picture of mast cell involvement. When multiple methods were utilized to assess activation, these were concordant with each other in 6 of the 7 studies.
While mast cells produce a wide variety of cytokines, chemokines, and other mediators, previous studies have primarily, but not exclusively, focused on tryptase and histamine. This appears justified as both have been implicated in mast cell interactions with sensory nerves. In a series of experiments, Wouters and colleagues established a role for histamine (via H1 receptors) in upregulating TRPV1 which has been highly implicated in visceral hyperalgesia, a central process in FAPDs [9]. Studies have nearly universally found increased tryptase in tissue, tissue supernatants, and luminal fluid. Studies have also demonstrated that supernatants from IBS mucosal biopsies can stimulate submucosal sensory nerves which correlate with serotonin, histamine, and tryptase concentrations and which could be inhibited by H1 receptor antagonists and serine protease inactivation [29,30]. An effect on myenteric nerves is reported to be independent of histamine and serine protease [25]. Mast cell mediators appear to have differential effects on submucosal and myenteric nerves [85]. Methods utilizing sensory nerves are likely a better model for assessing mast cell effects in FAPDs and possibly more representative of effects on pain transmission and visceral hyperalgesia.
There is some evidence to support mast cells as therapeutic targets in IBS and FD utilizing medications to inhibit mediator release (e.g., mast cell stabilizers such as cromolyn or ketotifen or anti-siglec 8) or to inhibit mast cell mediators once released (e.g., histamine or cysteinyl leukotriene inhibitors) [18,32,86,87,88,89,90,91]. One study utilizing cromolyn and one utilizing ketotifen demonstrated evidence of decreased mast cell activation [18,32]. However, no studies have evaluated whether any measures of mast cell density or activation are predictive of response to any of these medications.

5. Conclusions

A wide variety of methods have been employed to assess mast cell density and activation in patients with FAPDs with no well-established consensus and not enough data to recommend a specific approach. Given that differences in mast cell density and activation between patients with FAPDs and healthy controls are demonstrated in a strong majority of studies, regardless of methodology, this variability may make a more compelling case for mast cells in the pathophysiology of FAPDs in general. Whether this evidence is strong enough to warrant empiric treatment aimed at mast cell stabilization or mediators is up to clinical interpretation. Ideally though, the methodology providing physiologic information would be translated to a standard methodology providing clinical information with the development of criteria establishing abnormal density and/or activation, and more importantly, predicting response to treatment.

Author Contributions

Conceptualization, H.F., M.S., V.S. and J.V.S.; methodology, H.F., M.S., V.S., J.V.S. and C.A.F.; data curation, H.F. and C.A.F.; writing—original draft preparation, H.F. and C.A.F.; writing—review and editing, H.F., M.S., V.S., J.V.S. and C.A.F. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Lacy, B.E.; Pimentel, M.; Brenner, D.M.; Chey, W.D.; Keefer, L.A.; Long, M.D.; Moshiree, B. ACG clinical guidelines: Management of irritable bowel syndrome. Am. J. Gastroenterol. 2021, 116, 17–44. [Google Scholar] [CrossRef] [PubMed]
  2. Moayyedi, P.M.; Lacy, B.E.; Andrews, C.N.; Enns, R.A.; Howden, C.W.; Vakil, N. ACG and CAG clinical guideline: Management of dyspepsia. Am. J. Gastroenterol. 2017, 112, 988–1013. [Google Scholar] [CrossRef] [PubMed]
  3. Albert-Bayo, M.; Paracuellos, I.; González-Castro, A.M.; Rodríguez-Urrutia, A.; Rodríguez-Lagunas, M.J.; Alonso-Catoner, C.; Santos, J.; Vicario, M. Intestinal mucosal mast cells: Key modulators of barrier function and homeostasis. Cells 2019, 8, 135. [Google Scholar] [CrossRef] [PubMed]
  4. Du, L.; Chen, B.; Kim, J.J.; Chen, X.; Dai, N. Micro-inflammation in functional dyspepsia: A systematic review and meta-analysis. Neurogastroenterol. Motil. 2018, 30, e13304. [Google Scholar] [CrossRef]
  5. Robles, A.; Ingles, D.P.; Myneedu, K.; Deoker, A.; Sarosiek, I.; Zuckerman, M.J.; Schmulson, M.J.; Bashashati, M. Mast cells are increased in the small intestinal mucosa of patients with irritable bowel syndrome: A systematic review and meta-analysis. Neurogastroenterol. Motil. 2019, 31, e13718. [Google Scholar] [CrossRef]
  6. Bashashati, M.; Moossavi, S.; Cremon, C.; Barbaro, M.R.; Moraveji, S.; Talmon, G.; Rezaei, N.; Hughes, P.A.; Bian, Z.X.; Choi, C.H.; et al. Colonic immune cells in irritable bowel syndrome: A systematic review and meta-analysis. Neurogastroenterol. Motil. 2018, 30, e13192. [Google Scholar] [CrossRef]
  7. Burns, G.; Carroll, G.; Mathe, A.; Horvat, J.; Foster, P.; Walker, M.M.; Talley, N.J.; Keely, S. Evidence for local and systemic immune activation in functional dyspepsia and the irritable bowel syndrome: A systematic review. Am. J. Gastroenterol. 2019, 114, 429–436. [Google Scholar] [CrossRef]
  8. Krammer, L.; Sowa, A.S.; Lorentz, A. Mast cells in irritable bowel syndrome: A systematic review. J. Gastrointestin. Liver Dis. 2019, 28, 463–472. [Google Scholar] [CrossRef]
  9. Wouters, M.M.; Balemans, D.; Van Wanrooy, S.; Dooley, J.; Cibert-Goton, V.; Alpizar, Y.A.; Valdez-Morales, E.E.; Nasser, Y.; Van Veldhoven, P.P.; Vanbrabant, W.; et al. Histamine receptor H1-mediated sensitization of TRPV1 mediates visceral hypersensitivity in patients with irritable bowel syndrome. Gastroenterology 2015, 150, 875–887.e9. [Google Scholar] [CrossRef]
  10. Park, C.H.; Joo, Y.E.; Choi, S.K.; Rew, J.S.; Kim, S.J.; Lee, M.C. Activated mast cells infiltrate in close proximity to entric nerves in diarrhea-predominant irritable bowel syndrome. J. Korean Med. Sci. 2003, 18, 204–210. [Google Scholar] [CrossRef]
  11. Liu, D.R.; Xu, X.J.; Yao, S.K. Increased intestinal mucosal leptin levels in patients with diarrhea-predominant irritable bowel syndrome. World J. Gastroenterol. 2018, 24, 46–57. [Google Scholar] [CrossRef]
  12. Xu, X.J.; Zhang, Y.L.; Liu, L.; Pan, L.; Yao, S.K. Increased expression of nerve growth factor correlates with visceral hypersensitivity and impaired gut barrier function in diarrhoea-predominant irritable bowel syndrome: A preliminary explorative study. Aliment. Pharmacol. Ther. 2017, 45, 100–114. [Google Scholar] [CrossRef]
  13. Yuan, H.P.; Li, Z.; Zhang, Y.; Li, X.P.; Li, F.K.; Li, Y.Q. Anxiety and depression are associated with increased counts and degranulation of duodenal mast cells in functional dyspepsia. Int. J. Clin. Exp. Med. 2015, 8, 8010–8014. [Google Scholar]
  14. Yuan, H.P.; Li, X.P.; Yang, W.R.; Li, F.K.; Li, Y.Q. Inducible nitric oxide synthase in the duodenal mucosa is associated with mast cell degranulation in patients with functional dyspepsia. Ann. Clin. Lab. Sci. 2015, 45, 522–527. [Google Scholar]
  15. Wang, X.; Li, X.; Ge, W.; Huang, J.; Li, G.; Cong, Y.; Li, F.; Liu, Z.; Liu, Z.; Li, Y.; et al. Quantitative evaluation of duodenal eosinophils and mast cells in adult patients with functional dyspepsia. Ann. Diagn. Pathol. 2015, 19, 50–56. [Google Scholar] [CrossRef]
  16. Foley, S.; Garsed, K.; Singh, G.; Duroudier, N.P.; Swan, C.; Hall, I.P.; Zaitoun, A.; Bennett, A.; Marsden, C.; Holmes, G.; et al. Impaired uptake of serotonin by platelets from patients with irritable bowel syndrome correlates with duodenal immune activation. Gastroenterology 2011, 140, 1434–1443.e1. [Google Scholar] [CrossRef]
  17. Barbara, G.; Stanghellini, V.; De Giorgio, R.; Cremon, C.; Cottrell, G.S.; Santini, D.; Pasquinelli, G.; Morselli-Labate, A.M.; Grady, E.F.; Bunnett, N.W.; et al. Activated mast cells in proximity to colonic nerves correlate with abdominal pain in irritable bowel syndrome. Gastroenterology 2004, 126, 693–702. [Google Scholar] [CrossRef]
  18. Lobo, B.; Ramos, L.; Martínez, C.; Guilarte, M.; González-Castro, A.M.; Alonso-Cotoner, C.; Pigrau, M.; de Torres, I.; Rodiño-Janeiro, B.K.; Salvo-Romero, E.; et al. Downregulation of mucosal mast cell activation and immune response in diarrhoea-irritable bowel syndrome by oral disodium cromoglycate: A pilot study. United Eur. Gastroenterol. J. 2017, 5, 887–897. [Google Scholar] [CrossRef]
  19. Du, L.; Shen, J.; Kim, J.J.; Yu, Y.; Ma, L.; Dai, N. Increased duodenal eosinophil degranulation in patients with functional dyspepsia: A prospective study. Sci. Rep. 2016, 6, 34305. [Google Scholar] [CrossRef]
  20. Li, X.; Chen, H.; Lu, H.; Li, W.; Chen, X.; Peng, Y.; Ge, Z. The study on the role of inflammatory cells and mediators in post-infectious functional dyspepsia. Scand. J. Gastroenterol. 2010, 45, 573–581. [Google Scholar] [CrossRef]
  21. Martínez, C.; Lobo, B.; Pigrau, M.; Ramos, L.; González-Castro, A.M.; Alonso, C.; Guilarte, M.; Guilá, M.; de Torres, I.; Azpiroz, F.; et al. diarrhoea-predominant irritable bowel syndrome: An organic disorder with structural abnormalities in the jejunal epithelial barrier. Gut 2013, 62, 1160–1168. [Google Scholar] [CrossRef]
  22. Guilarte, M.; Santos, J.; de Torres, I.; Alonso, C.; Vicario, M.; Ramos, L.; Martínez, C.; Casellas, F.; Saperas, E.; Malagelada, J.R. Diarrhoea-predominant IBS patients show mast cell activation and hyperplasia in the jejunum. Gut 2007, 56, 203–209. [Google Scholar] [CrossRef]
  23. Martínez, C.; Vicario, N.; Ramos, L.; Lobo, B.; Mosquera, J.L.; Alonso, C.; Sánchez, A.; Guilarte, M.; Antolín, M.; de Torres, I.; et al. The jejunum of diarrhea-predominant irritable bowel syndrome shows molecular alterations in the tight junction signaling pathway that are associated with mucosal pathobiology and clinical manifestations. Am. J. Gastroenterol. 2012, 107, 736–746. [Google Scholar] [CrossRef]
  24. Lee, H.; Park, J.H.; Park, D.I.; Kim, H.J.; Cho, Y.K.; Sohn, C.I.; Jeon, W.K.; Kim, B.I.; Chae, S.W. Mucosal mast cell count is associated with intestinal permeability in patients with diarrhea predominant irritable bowel syndrome. J. Neurogastroenterol. Motil. 2013, 19, 244–250. [Google Scholar] [CrossRef]
  25. Balestra, B.; Vicini, R.; Cremon, C.; Zecchi, L.; Dothel, G.; Vasina, V.; De Giorgio, R.; Paccapelo, A.; Pastoris, O.; Stanghellini, V.; et al. Colonic mucosal mediators from patients with irritable bowel syndrome excite enteric cholinergic motor neurons. Neurogastroenterol. Motil. 2012, 24, 1118–e570. [Google Scholar] [CrossRef]
  26. Han, W.; Wang, Z.; Lu, X.; Guo, C. Protease activated receptor 4 status of mast cells in post infectious irritable bowel syndrome. Neurogastroenterol. Motil. 2012, 24, 113–119. [Google Scholar] [CrossRef]
  27. Cremon, C.; Stanghellini, V.; Barbaro, M.R.; Cogliandro, R.F.; Bellacosa, L.; Santos, J.; Vicario, M.; Pigrau, M.; Alonso Cotoner, C.; Lobo, B.; et al. Randomised clinical trial: The analgesic properties of dietary supplementation with palmitoyletholamide and polydatin in irritable bowel syndrome. Aliment. Pharmacol. Ther. 2017, 45, 909–922. [Google Scholar] [CrossRef]
  28. Bednarska, O.; Walter, S.A.; Casado-Bedmar, M.; Ström, M.; Salvo-Romero, E.; Vicario, M.; Mayer, E.A.; Keita, Å.V. Vasoactive intestinal polypeptide and mast cells regulate increased passage of colonic bacteria in patients with irritable bowel syndrome. Gastroenterology 2017, 153, 948–960.e3. [Google Scholar] [CrossRef]
  29. Buhner, S.; Li, Q.; Vignali, S.; Barbara, G.; De Giorgio, R.; Stanghellini, V.; Cremon, C.; Zeller, F.; Langer, R.; Daniel, H.; et al. Activation of human enteric neurons by supernatants of colonic biopsy specimens from patients with irritable bowel syndrome. Gastroenterology 2009, 137, 1425–1434. [Google Scholar] [CrossRef]
  30. Barbara, G.; Wang, B.; Stanghellini, V.; de Giorgio, R.; Cremon, C.; Di Nardo, G.; Trevisani, M.; Campi, B.; Geppetti, P.; Tonini, M.; et al. Mast cell-dependent excitation of visceral-nociceptive sensory neurons in irritable bowel syndrome. Gastroenterology 2007, 132, 26–37. [Google Scholar] [CrossRef]
  31. Cremon, C.; Carini, G.; Wang, B.; Vasina, V.; Cogliandro, R.F.; De Giorgio, R.; Stanghellini, V.; Grundy, D.; Tonini, M.; De Ponti, F.; et al. Intestinal serotonin release, sensory neuron activation, and abdominal pain in irritable bowel syndrome. Am. J. Gastroenterol. 2011, 106, 1290–1298. [Google Scholar] [CrossRef] [PubMed]
  32. Klooker, T.K.; Braak, B.; Koopman, K.E.; Welting, O.; Wouters, M.M.; van der Heide, S.; Schemann, M.; Bischoff, S.C.; van den Wijngaard, R.M.; Boeckxstaens, G.E. The mast cell stabilizer ketotifen decreases visceral hypersensitivity and improves intestinal symptoms in patients with irritable bowel syndrome. Gut 2010, 59, 1213–1221. [Google Scholar] [CrossRef] [PubMed]
  33. Vivinus-Nébot, M.; Dainese, R.; Anty, R.; Saint-Paul, M.C.; Nano, J.L.; Gonthier, N.; Marjoux, S.; Frin-Mathy, G.; Bernard, G.; Hébuterne, X.; et al. Combination of allergic factors can worsen diarrheic irritable bowel syndrome: Role of barrier defects and mast cells. Am. J. Gastroenterol. 2012, 107, 75–81. [Google Scholar] [CrossRef] [PubMed]
  34. Yeom, J.S.; Choi, M.B.; Seo, J.H.; Park, J.S.; Lim, J.Y.; Park, C.H.; Woo, H.O.; Youn, H.S.; Ko, G.H.; Baik, S.C.; et al. Relationship between headache and mucosal mast cells in pediatric Helicobaori-negative functional dyspepsia. Cephalalgia 2013, 33, 323–329. [Google Scholar] [CrossRef]
  35. Henderson, W.A.; Shankar, R.; Taylor, T.J.; Del Valle-Pinero, A.Y.; Kleiner, D.E.; Kim, K.H.; Youssef, N.N. Inverse relationship of interleukin-6 and mast cells in children with inflammatory and non-inflammatory abdominal pain phenotypes. World J. Gastrointest. Pathophysiol. 2012, 3, 102–108. [Google Scholar] [CrossRef]
  36. Di Nardo, G.; Barbara, G.; Cucchiara, S.; Cremon, C.; Shulman, R.J.; Isoldi, S.; Zecchi, L.; Drago, L.; Olivia, S.; Saulle, R.; et al. Neuroimmune interactions at different intestinal sites are related to abdominal pain symptoms in children with IBS. Neurogastroenterol. Motil. 2014, 26, 196–204. [Google Scholar] [CrossRef]
  37. Mahjoub, F.E.; Farahmand, F.; Pourpak, Z.; Asefi, H.; Amini, Z. Mast cell gastritis: Children complaining of chronic abdominal pain with histologically normal gastric mucosa biopsies except for increases in mast cells, proposing a new entity. Diagn. Pathol. 2009, 4, 34. [Google Scholar] [CrossRef]
  38. Schurman, J.V.; Singh, M.; Singh, V.; Neilan, N.; Friesen, C.A. Symptoms and subtypes in pediatric functional dyspepsia: Relation to mucosal inflammation and psychological functioning. J. Pediatr. Gastroenterol. Nutr. 2010, 51, 298–303. [Google Scholar] [CrossRef]
  39. Singh, V.; Singh, M.; Schurman, J.V.; Friesen, C.A. Histopathological changes in the gastroduodenal mucosa of children with functional dyspepsia. Pathol. Res. Pract. 2018, 214, 1173–1178. [Google Scholar] [CrossRef]
  40. Schäppi, M.G.; Borrelli, O.; Knafelz, D.; Williams, S.; Smith, V.V.; Milla, P.J. Mast cell-nerve interactions in children with functional dyspepsia. J. Pediatr. Gastroenterol. Nutr. 2008, 47, 472–480. [Google Scholar] [CrossRef]
  41. Saad, A.G. Normal quantity and distribution of mast cells and eosinophils in the pediatric colon. Pediatr. Dev. Pathol. 2011, 14, 294–300. [Google Scholar] [CrossRef]
  42. Friesen, C.A.; Lin, Z.; Singh, M.; Singh, V.; Schurman, J.V.; Burchell, N.; Cocjin, J.T.; McCallum, R.W. Antral inflammatory cells, gastric emptying, and electrogastrography in pediatric functional dyspepsia. Dig. Dis. Sci. 2008, 53, 2634–2640. [Google Scholar] [CrossRef]
  43. Chernetsova, E.; Sullivan, K.; de Nanassy, J.; Barkey, J.; Mack, D.; Nasr, A.; El Demellawy, D. Histologic analysis of eosinophils and mast cells of the gastrointestinal tract in healthy Canadian children. Hum. Pathol. 2016, 54, 55–63. [Google Scholar] [CrossRef]
  44. Friesen, C.; Singh, M.; Singh, V.; Schurman, J.V. A cross-sectional study of nausea in functional abdominal pain: Relation to mucosal mast cells and psychological functioning. BMC Gastroenterol. 2020, 20, 144. [Google Scholar] [CrossRef]
  45. Goral, V.; Kucukoner, M.; Buyukbayram, H. Mast cells count and serum cytokine levels in patients with irritable bowel syndrome. Hepatogastroenterology 2010, 57, 751–754. [Google Scholar]
  46. De Silva, A.P.; Nandasiri, S.D.; Hewavisenthi, J.; Manamperi, A.; Ariyasinghe, M.P.; Dassanayake, A.S.; Jewell, D.P.; de Silva, H.J. Subclinical mucosal inflammationin diarrhea-predominant irritable bowel syndrome (IBS) in a tropical setting. Scand. J. Gastroenterol. 2012, 47, 619–624. [Google Scholar] [CrossRef]
  47. Binesh, F.; Akhondei, M.; Pourmirafzali, H.; Rajabzadeh, Y. Determination of relative frequency of eosinophils and mast cells in gastric and duodenal mucosal biopsies in adults with non-ulcer dyspepsia. J. Coll. Physicians Surg. Pak. 2013, 23, 326–329. [Google Scholar]
  48. Tunc, B.; Filik, L.; Altintaş, E.; Turhan, N.; Ulker, A.; Dağli, U. Mucosal mast cells in irritable bowel syndrome and inflammatory bowel disease. Acta Medica (Hradec Kralove) 2005, 48, 163–164. [Google Scholar] [CrossRef]
  49. Chadwick, V.S.; Chen, W.; Shu, D.; Paulus, B.; Bethwaite, P.; Tie, A.; Wilson, I. Activation of the mucosal immune system in irritable bowel syndrome. Gastroenterology 2002, 122, 1778–1783. [Google Scholar] [CrossRef]
  50. Wang, S.H.; Dong, L.; Luo, J.Y.; Gong, J.; Li, L.; Lu, X.L.; Han, S.P. Decreased expression of serotonin in the jejunum and increased numbers of mast cells in the terminal ileum in patients with irritable bowel syndrome. World J. Gastroenterol. 2007, 13, 6041–6047. [Google Scholar] [CrossRef]
  51. Yang, J.; Fox, M.; Cong, Y.; Chu, H.; Zheng, X.; Long, Y.; Fried, M.; Dai, N. Lactose intolerance in irritable bowel syndrome patients with diarrhoea: The roles of anxiety, activation of the innate mucosal immune system and visceral sensitivity. Aliments Pharmacol. Ther. 2014, 39, 302–311. [Google Scholar] [CrossRef]
  52. Chang, L.; Adeyemo, M.; Karagiannides, I.; Videlock, E.J.; Bowe, C.; Shih, W.; Presson, A.P.; Yuan, P.Q.; Cortina, G.; Gong, H.; et al. Serum and colonic mucosal immune markers in irritable bowel syndrome. Am. J. Gastroenterol. 2012, 107, 262–272. [Google Scholar] [CrossRef]
  53. Sohn, W.; Lee, O.Y.; Lee, S.P.; Lee, K.N.; Jun, D.W.; Lee, H.L.; Yoon, B.C.; Choi, H.S.; Sim, J.; Jang, K.S. Mast cell number, substance P and vasoactive intestinal peptide in irritable bowel syndrome with diarrhea. Scand. J. Gastroenterol. 2014, 49, 43–51. [Google Scholar] [CrossRef]
  54. Ahn, J.Y.; Lee, K.H.; Choi, C.H.; Kim, J.W.; Lee, H.W.; Kim, J.W.; Kim, M.K.; Kwon, G.Y.; Han, S.; Kim, S.E.; et al. Colonic mucosal immune activity in irritable bowel syndrome: Comparison with healthy controls and patients with ulcerative colitis. Dig. Dis. Sci. 2014, 59, 1001–1011. [Google Scholar] [CrossRef]
  55. Dunlop, S.P.; Jenkins, D.; Spiller, R.C. Distinctive clinical, psychological, and histological features of postinfective irritable bowel syndrome. Am. J. Gastroenterol. 2003, 98, 1578–1583. [Google Scholar] [CrossRef]
  56. El-Salhy, M.; Gundersen, D.; Hatlebakk, J.G.; Hausken, T. Low-grade inflammation in the rectum of patients with sporadic irritable bowel syndrome. Mol. Med. Rep. 2013, 7, 1081–1085. [Google Scholar] [CrossRef]
  57. Cremon, C.; Gargano, L.; Morselli-Labate, A.M.; Santini, D.; Cogliandro, R.F.; De Giorgio, R.; Stanghellini, V.; Corinaldesi, R.; Barbara, G. Mucosal immune activation in irritable bowel syndrome: Gender-dependence and association with digestive symptoms. Am. J. Gastroenterol. 2009, 104, 392–400. [Google Scholar] [CrossRef]
  58. Dunlop, S.P.; Jenkins, D.; Neal, K.R.; Spiller, R.C. Relative importance of enterochromaffin cell hyperplasia, anxiety, and depression in postinfectious IBS. Gastroenterology 2003, 125, 1651–1659. [Google Scholar] [CrossRef]
  59. Bian, Z.X.; Li, Z.; Huang, Z.X.; Zhang, M.; Chen, H.L.; Xu, H.X.; Sung, J.J.Y. Unbalanced expression of protease-activated receptors-1 and -2 in the colon of diarrhea-predominant irritable bowel syndrome patients. J. Gastroenterol. 2009, 44, 666–674. [Google Scholar] [CrossRef]
  60. Sundin, J.; Nordlander, S.; Eutamene, H.; Alquier-Bacquie, V.; Cartier, C.; Theodorou, V.; Le Nevé, B.; Törnblom, H.; Simrén, M.; Öhman, L. Colonic mast cell numbers, symptom profile, and mucosal expression of elements of the epithelial barrier in irritable bowel syndrome. Neurogastroenterol. Motil. 2019, 31, e13701. [Google Scholar] [CrossRef]
  61. O’Sullivan, M.; Clayton, N.; Breslin, N.P.; Harman, I.; Bountra, C.; McLaren, A.; O’Morain, C.A. Increased mast cells in the irritable bowel syndrome. Neurogastroenterol. Motil. 2000, 12, 449–457. [Google Scholar] [CrossRef] [PubMed]
  62. Park, J.H.; Rhee, P.L.; Kim, H.S.; Lee, J.H.; Kim, Y.H.; Kim, J.J.; Rhee, J.C. Mucosal mast cell counts correlate with visceral hypersensitivity in patients with diarrhea predominant irritable bowel syndrome. J. Gastroenterol. Hepatol. 2006, 21 Pt 1, 71–78. [Google Scholar] [CrossRef] [PubMed]
  63. Lee, K.J.; Kim, Y.B.; Kim, J.H.; Kwon, H.C.; Kim, D.K.; Cho, S.W. The alteration of enterochromaffin cell, mast cell, and lamina propria T lymphocyte numbers in irritable bowel syndrome and its relationship with psychological factors. J. Gastroenterol. Hepatol. 2008, 23, 1689–1694. [Google Scholar] [CrossRef] [PubMed]
  64. Kim, H.S.; Lim, J.H.; Park, H.; Lee, S.I. Increased immunoendocrine cells in intestinal mucosa of postinfectious irritable bowel syndrome patients 3 years after acute Shigella infection- an observation in a small case control study. Yonsei Med. J. 2010, 51, 45–51. [Google Scholar] [CrossRef]
  65. Giancola, F.; Volta, U.; Repossi, R.; Latorre, R.; Beeckmans, D.; Carbone, F.; Van den Houte, K.; Bianco, F.; Bonora, E.; Gori, A.; et al. Mast cell-nerve interactions correlate with bloating and abdominal pain severity in patients with non-celiac gluten/wheat sensitivity. Neurogastroenterol. Motil. 2020, 32, e13814. [Google Scholar] [CrossRef]
  66. Hall, W.; Buckley, M.; Crotty, P.; O’Morain, C.A. Gastric mucosal mast cells are increased in Helicobacter pylori-negative functional dyspepsia. Clin. Gastroenterol. Hepatol. 2003, 1, 363–369. [Google Scholar] [CrossRef]
  67. Vanheel, H.; Vicario, M.; Vanuytsel, T.; Van Oudenhove, L.; Martinez, C.; Keita, Å.V.; Pardon, N.; Santos, J.; Söderholm, J.D.; Tack, J.; et al. Impaired duodenal mucosal integrity and low-grade inflammation in functional dyspepsia. Gut 2014, 63, 262–271. [Google Scholar] [CrossRef]
  68. Tanaka, F.; Tominaga, K.; Fujikawa, Y.; Nagami, Y.; Kamata, N.; Yamagami, H.; Tanigawa, T.; Shiba, M.; Watanabe, T.; Fujiwara, Y.; et al. Concentration of glial cell line-derived neurotrophic factor positively correlates with symptoms in functional dyspepsia. Dig. Dis. Sci. 2016, 61, 3478–3485. [Google Scholar] [CrossRef]
  69. Vicario, M.; González-Castro, A.M.; Martínez, C.; Lobo, B.; Pigrau, M.; Guilarte, M.; de Torres, I.; Mosquera, J.L.; Fortea, M.; Sevillano-Aguilera, C.; et al. Increased humoral immunity in the jejunum of diarrhoea-predominant irritable bowel syndrome associated with clinical manifestations. Gut 2015, 64, 1379–1388. [Google Scholar] [CrossRef]
  70. Braak, B.; Klooker, T.K.; Wouters, M.M.; Welting, O.; van der Loos, C.M.; Stanisor, O.I.; van Diest, S.; van den Wijngaard, R.M.; Boeckxstaens, G.E. Mucosal immune cell numbers and visceral hypersensitivity in patients with irritable bowel syndrome: Is there any relationship. Am. J. Gastroenterol. 2012, 107, 715–726. [Google Scholar]
  71. Boyer, J.; Saint-Paul, M.C.; Dadone, B.; Patouraux, S.; Vivinus, M.H.; Ouvrier, D.; Michiels, J.F.; Piche, T.; Tulic, M.K. Inflammatory cell distribution in colon mucosa as a new tool for diagnosis of irritable bowel syndrome: A promising pilot study. Neurogastroenterol. Motil. 2018, 30, e13223. [Google Scholar] [CrossRef]
  72. Piche, T.; Saint-Paul, M.C.; Dainese, R.; Marine-Barjoan, E.; Iannelli, A.; Montoya, M.L.; Peyron, J.F.; Czerucka, D.; Cherikh, F.; Filippi, J.; et al. Mast cells and cellularity of the colonic mucosa correlated with fatigue and depression in irritable bowel syndrome. Gut 2008, 57, 468–473. [Google Scholar] [CrossRef]
  73. Doyle, L.A.; Sepehr, G.J.; Hamilton, M.J.; Akin, C.; Castells, M.C.; Hornick, J.L. A clinicopathologic study of 24 cases of systemic mastocytosis involving the gastrointestinal tract and assessment of mucosal mast cell density in irritable bowel syndrome and asymptomatic patients. Am. J. Surg. Pathol. 2014, 38, 832–843. [Google Scholar] [CrossRef]
  74. Coëffier, M.; Gloro, R.; Boukhettala, N.; Aziz, M.; Lecleire, S.; Vandaele, N.; Antonietti, M.; Savoye, G.; Bôle-Feysot, C.; Déchelotte, P.; et al. Increased proteasome-mediated degradation of occluding in irritable bowel syndrome. Am. J. Gastroenterol. 2010, 105, 1181–1188. [Google Scholar] [CrossRef]
  75. Walker, M.M.; Talley, N.J.; Prabhakar, M.; Pennaneac’h, C.J.; Aro, P.; Ronkainen, J.; Storskrubb, T.; Harmsen, W.S.; Zinsmeister, A.R.; Agreus, L. Duodenal mastocytosis, eosinophilia and intraepithelial lymphocytosis as possible disease markers in irritable bowel syndrome and functional dyspepsia. Aliment. Pharmacol. Ther. 2009, 29, 765–773. [Google Scholar] [CrossRef]
  76. Taki, M.; Oshima, T.; Li, M.; Sei, H.; Tozawa, K.; Tomita, T.; Fukui, H.; Watari, J.; Miwa, H. Duodenal low-grade inflammation and expression of tight junction proteins in functional dyspepsia. Neurogastroenterol. Motil. 2019, 31, e13576. [Google Scholar] [CrossRef]
  77. Lee, M.J.; Jung, H.K.; Lee, K.E.; Mun, Y.C.; Park, S. Degranulated eosinophils contain more fine nerve fibers in the duodenal mucosa of patients with functional dyspepsia. J. Neurogastroenterol. Motil. 2019, 25, 212–221. [Google Scholar] [CrossRef]
  78. Wauters, L.; Ceulemanns, M.; Frings, D.; Lambaerts, M.; Accarie, A.; Toth, J.; Mols, R.; Augustijns, P.; De Hertogh, G.; Van Oudenhove, L.; et al. Proton pump inhibitors reduce duodenal eosinophilia, mast cells, and permeability in patients with functional dyspepsia. Gastroenterology 2021, 160, 1521–1531.e9. [Google Scholar] [CrossRef]
  79. Vanheel, H.; Vicario, M.; Boesmans, W.; Vanuytsel, T.; Salvo-Romero, E.; Tack, J.; Farré, R. Activation of eosinophils and mast cells in functional dyspepsia: An ultrastructural evaluation. Sci. Rep. 2018, 8, 5383. [Google Scholar] [CrossRef]
  80. Khatri, M.J.; Desai, R.S.; Mamatha, G.S.; Kulkarni, M.; Khatri, J. Immunohistochemical expression of mast cells using c-Kit in various grades of oral submucous fibrosis. ISRN Pathol. 2013, 2013, 1–5. [Google Scholar] [CrossRef]
  81. Atiakshin, D.; Samoilova, V.; Buchwalow, I.; Boecker, W.; Tiemann, M. Characterization of mast cell populations using different methods for their identification. Histochem. Cell Biol. 2017, 147, 683–694. [Google Scholar] [CrossRef]
  82. Qi, J.C.; Li, L.; Li, Y.; Moore, K.; Madigan, M.C.; Katsoulotos, G.; Krilis, S.A. An antibody raised against in vitro-derived human mast cells identifies mature mast cells and a population of cells that are Fc epsilon RI(+), tryptase (−), and chymase (−) in a variety of human tissues. J. Histochem. Cytochem. 2003, 51, 643–653. [Google Scholar] [CrossRef]
  83. Ribatti, D. The staining of mast cells: A historical overview. Int. Arch. Allergy Immunol. 2018, 176, 55–60. [Google Scholar] [CrossRef]
  84. Tikoo, S.; Barki, N.; Jain, R.; Zulkhernain, N.S.; Buhner, S.; Schemann, M.; Weninger, W. Imaging of mast cells. Immunol. Rev. 2018, 282, 58–72. [Google Scholar] [CrossRef]
  85. Schemann, M.; Michel, K.; Ceregrzyn, M.; Zeller, F.; Seidl, S.; Bischoff, S.C. Human mast cell mediator cocktail excites neurons in human and guinea-pig enteric nervous system. Neurogastroenterol. Motil. 2005, 17, 281–289. [Google Scholar] [CrossRef]
  86. Wang, J.; Wang, Y.; Zhou, H.; Gu, W.; Wang, X.; Yang, J. Clinical efficacy and safety of ketotifen in treating irritable bowel syndrome with diarrhea. Eur. J. Gastroenterol. Hepatol. 2020, 32, 706–712. [Google Scholar] [CrossRef]
  87. Grazioli, I.; Melzi, G.; Balsamo, V.; Castellucci, G.; Castro, M.; Catassi, C.; Rätsch, J.M.; Scotta, S. Food intolerance and irritable bowel of childhood: Clinical efficacy or oral sodium cromoglycate and elimination diet. Minerva Pediatr. 1993, 45, 253–258. [Google Scholar]
  88. Lunardi, C.; Bambara, L.M.; Biasi, D.; Cortina, P.; Peroli, P.; Nicolis, F.; Favari, F.; Pacor, M.L. Double-blind cross-over trial of oral sodium cromoglycate in patients with irritable bowel syndrome due to food intolerance. Clin. Exp. Allergy 1991, 21, 569–572. [Google Scholar] [CrossRef]
  89. Stefanini, G.F.; Saggioro, A.; Alvisi, V.; Angelini, G.; Capurso, L.; di Lorenzo, G.; Dobrilla, G.; Dodero, M.; Galimberti, M.; Gasbarrini, G.; et al. Oral cromolyn sodium in comparison with elimination diet in the irritable bowel syndrome, diarrheic type. Multicenter study of 428 patients. Scand. J. Gastroenterol. 1995, 30, 535–541. [Google Scholar] [CrossRef]
  90. Dellon, E.S.; Peterson, K.A.; Murray, J.A.; Falk, G.W.; Gonsalves, N.; Chehade, M.; Genta, R.M.; Leung, J.; Khoury, P.; Klion, A.D.; et al. Anti-siglec-8 antibody for eosinophilic gastritis and duodenitis. N. Engl. J. Med. 2020, 383, 1624–1634. [Google Scholar] [CrossRef]
  91. Friesen, C.A.; Kearns, G.L.; Andre, L.; Neustrom, M.; Roberts, C.C.; Abdel-Rahman, S.M. Clinical efficacy and pharmacokinetics of montelukast in dyspeptic children with duodenal eosinophilia. J. Pediatr. Gastroenterol. Nutr. 2004, 38, 343–351. [Google Scholar] [CrossRef] [PubMed]
Figure 1. Levels of study design decisions regarding assessment of mast cells in functional abdominal pain disorders.
Figure 1. Levels of study design decisions regarding assessment of mast cells in functional abdominal pain disorders.
Gastrointestdisord 03 00016 g001
Table 1. Summary of pediatric studies assessing mast cell density in functional abdominal pain disorders.
Table 1. Summary of pediatric studies assessing mast cell density in functional abdominal pain disorders.
AuthorCountryAge GroupPopulation (N)Mucosal SitesMast Cell ID MethodNumber of
Microscopic Fields
Assessed
Field SelectionCell Activation
Assessed
Yeom et al. [34]Korea6–12FD (56)Gastric antrum and body; duodenumAnti-tryptase5Most involved areaNo
Henderson et al. [35]USA5–17AP-FGID (26)Upper and lowerToluidine Blue10RandomNo
Di Nardo et al. [36]Italy4–18IBS (21)TI, Ascending and Descending ColonAnti-tryptaseNot statedRandomNo
Mahjoub et al. [37]Iran1–14Endoscopy patients (86)AntrumGiemsa10Not statedNo
Schurman et al. [38]USA8–17FD (59)Antrum and duodenumAnti-tryptase5Most involved areaNo
Singh et al. [39]USA8–17FD (114)Antrum and duodenumAnti-tryptase5Most involved areaNo
Schäppi et al. [40]UK2–12FD (16)GastricAnti-tryptase10Not statedYes
Saad et al. [41]USA3.3–17.9Endoscopy patients: 92% for abdominal pain (41)Cecum, ascending, transverse, descending and rectosigmoid colonAnti-tryptase5Most involved areaNo
Friesen et al. [42]USA8–17FD (30)AntrumAnti-tryptase5–10Not statedYes
Chernetsova et al. [43]Canada1–17Endoscopy patients designated as healthy (38)Gastric body and antrum, duodenum, TI, cecum, ascending, transverse, descending, and sigmoid colon, and rectumHematoxylin-Phloxine-Saffron and GiemsaNot statedMost involved areaNo
Friesen et al. [44]USA8–17AP-FGID (208)Antrum and duodenumAnti-tryptase5Most involved areaNo
Table 2. Summary of adult studies assessing mast cell density where mast cell activation was not assessed in functional abdominal pain disorders.
Table 2. Summary of adult studies assessing mast cell density where mast cell activation was not assessed in functional abdominal pain disorders.
AuthorCountryAge GroupPopulation (N)Mucosal SitesMast Cells ID MethodNumber of Microscopic Fields AssessedField SelectionDensity Different from Controls
Goral et al. [45]TurkeyMean 35–36 yearsIBS (72)Cecum and rectumGiemsa10Not statedYes
De Silva et al. [46]Sri Lanka18–59 yearsIBS-D (49)Ileum, cecum, ascending, transverse, descending, and rectumGiemsa10Not statedYes
Binesh et al. [47]Iran15–76 yearsFD (25)Stomach and duodenumGiemsa≥5Not statedNo
Tunc et al. [48]Turkey27–64 yearsIBS (11)CecumToluidine blue10Not statedYes
Chadwick et al. [49]New Zealand19–79 yearsIBS (77)Ascending, transverse, descending, and rectumTryptase15Not statedYes
Wang et al. [50]ChinaMean 42–49 yearsIBS-D (20) and IBS-C (18)Duodenum, jejunum, and TITryptase6Not statedYes
Yang et al. [51]China16–75 yearsIBS-D (55)TI, ascending and sigmoidTryptaseNot statedNot statedYes
Chang et al. [52]USA18–55 yearsIBS-PI (45)SigmoidTryptase% of areaNot statedNo
Sohn et al. [53]Korea18–72 yearsIBS-D (22)RectumTryptaseNot statedMost representativeYes
Ahn et al. [54]KoreaMedian 32 yearsIBS-D (83)Ascending, transverse, descending, sigmoid, and rectumTryptase6Not statedYes
Dunlop et al. [55]UKMean 38–40 yearsIBS (75)RectumTryptase4Not statedYes
El-Sahly et al. [56]Norway18–62 yearsIBS (50)RectumTryptase10RandomNo
Cremon et al. [57]Italy22–75 yearsIBS (48)Descending colonTryptase% of areaRandomYes
Dunlop et al. [58]EnglandMean 42 yearsIBS-PI (28)RectumTryptase4Not statedNo
Bian et al. [59]China21–66 yearsD-IBS (10)Descending colonTryptase≥10RandomYes
Sundin et al. [60]SwedenMean 32 yearsIBS (43)Sigmoid colonTryptase3Not statedNo
O’Sullivan et al. [61]Ireland28–65 yearsIBS (14)Cecum, ascending, descending, and rectumTryptase3Not statedYes
Park et al. [62]Korea25–65 yearsIBS-D (18)TI, ascending, and rectumTryptase6Not statedYes
Lee et al. [63]South KoreaMean 48 yearsIBS (42)RectumTryptase5Not statedYes
Kim et al. [64]KoreaMean 30–51 yearsIBS (18)Descending, sigmoid, and rectumTryptase5Not statedYes
Giancola et al. [65]Belgium18–68 yearsFD (13)DuodenumTryptase4RandomYes
Hall et al. [66]Ireland18–79 yearsFD (62)Gastric body and antrumTryptase15Not statedYes
Vanheel et al. [67]Belgium17–52 yearsFD (15)DuodenumTryptase≥7RepresentativeYes
Tanaka et al. [68]JapanMean 45 yearsFD (9)DuodenumTryptase5Not statedNo
Vicario et al. [69]Spain18–63 yearsIBS-D (49)JejunumCD1178Not statedYes
Braak et al. [70]Amsterdam19–65 yearsIBS (66)Ascending and descending colonCD11718Not statedYes- decreased
Boyer et al. [71]FranceMean 54–67 yearsIBS (11)Cecum, transverse, descending, and rectumCD1174Not statedNot reported
Piche et al. [72]FranceMean 54 yearsIBS (50)CecumCD1175Not statedYes
Doyle et al. [73]USA18–78 yearsIBS (100)ColonAnti-kit5Area of highest densityYes
Coeffier et al. [74]FranceMean 44.6 yearsIBS (25)Descending colonCD11710Not statedYes
Walker et al. [75]SwedenMean 53 yearsFD (51) and IBS (41)DuodenumCD1175Not statedYes
Taki et al. [76]JapanMean 53 yearsFD (35)DuodenumCD117≥3RepresentativeYes
Lee et al. [77]KoreaMean 36 yearsFD (51)Duodenumc-KIT5Hot spotsNo
Wauters et al. [78]Belgium18–64 yearsFD (45)Duodenumc-kit3Not statedYes
Table 3. Summary of adult studies assessing mast cell density which also assessed mast cell activation in functional abdominal pain disorders.
Table 3. Summary of adult studies assessing mast cell density which also assessed mast cell activation in functional abdominal pain disorders.
AuthorCountryAge GroupPopulation (N)Mucosal SitesMast Cells ID MethodNumber of Microscopic Fields AssessedField SelectionDensity Different from ControlsActivation Different from Controls
Park et al. [10]KoreaMean 48 yearsIBS-D (14)Cecum and rectumToluidine blueUp to 20Not statedYesYes
Liu et al. [11]China22–40 yearsIBS-D (42)Rectosigmoid junctionToluidine blue5RandomNoYes
Xu et al. [12]China18–49 yearsIBS-D (38)Rectosigmoid junctionToluidine blue5RandomYesNo
Yuan et al. [13]ChinaMean 45–47 yearsFD (48)DuodenumToluidine blueNot statedNot statedYesYes
Yuan et al. [14]ChinaMean 45–47 yearsFD (48)DuodenumToluidine blueNot statedNot statedYesYes
Wang et al. [15]ChinaMean 46 yearsFD (141)DuodenumToluidine blue4-6 random sites, then 5RandomYesYes
Foley et al. [16]EnglandMean 42 yearsIBS-D (20)DuodenumTryptaseNot statedNot statedYesYes
Lee et al. [24]Korea24–66 yearsIBS-D (16)RectumTryptase5Not statedNoYes
Barbara et al. [17]Italy22–75 yearsIBS (44)Descending colonTryptaseArea occupiedRandomYesYes
Balestra et al. [25]Italy21–70 yearsIBS (37)Descending colonTryptase% of LP occupiedRandomYesYes
Han et al. [26]China18–59 yearsPI-IBS (23)Left colonTryptase≥8Not statedYes-area; No- numberYes
Cremon et al. [27]Italy, Spain, France, Croatia, and Bosnia and HerzegovinaMean 37–40 yearsIBS (54)Proximal descending colonTryptaseNot statedNot statedYesNot reported
Bednarska et al. [28]Sweden19–55 yearsIBS (32)30-40 cm from anal vergeTryptaseNot statedNot statedYesYes
Buhner et al. [29]Italy27–68 yearsIBS (11)Proximal descending colonTryptaseNot statedNot statedYesYes
Barbara et al. [30]Italy19–70 yearsIBS (29)Proximal descending colonTryptaseNot statedNot statedYesYes
Li et al. [20]China17–65 yearsFD (65)AntrumTryptase10Not statedYesYes
Vanheel et al. [79]Belgium23–43 yearsFD (24)DuodenumTryptase≥7RepresentativeYesNo
Du et al. [19]ChinaMean 48 yearsFD (96)DuodenumTryptase5RandomNot reportedNo
Cremon et al. [31]Italy22–56 yearsIBS (25)Descending colonTryptaseArea occupiedRandomYesYes
Klooker et al. [32]The Netherlands19–65 yearsIBS (29)Descending and rectumTryptase or CD11718Not statedYes- decreasedYes- decreased
Martinez et al. [21]Spain18–60 yearsIBS-D (45)JejunumCD117Not statedNot statedYesYes
Vivinus-Nébot et al. [33]France42–58 yearsIBS (34)CecumCD1173Not statedYesYes
Lobo et al. [18]Spain18–65 yearsIBS-D (43)JejunumCD11710Not statedNoYes
Guilarte et al. [22]Spain21–56 yearsD-IBS (20)JejunumCD1178Not statedYesYes
Martinez et al. [23]Spain18–59 yearsIBS-D (25)JejunumCD117Not statedNot statedYesYes
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