At least 40% of all the gastroenterological outpatient visits are due to functional gastrointestinal disorders (FGIDs), among which irritable bowel syndrome (IBS) is the most common, accounting for a worldwide prevalence of about 12% [...]

Cintoni, M

Gasbarrini, A. (ORCID:0000-0002-7278-4823)

Mele, Mc (ORCID:0000-0003-0153-5819)

Rinninella, E (ORCID:0000-0002-9165-2367)

English

Rinninella E (ORCID:0000-0002-9165-2367)

Cintoni M (ORCID:0000-0002-9610-0748)

Mele MC (ORCID:0000-0003-0153-5819)

Gasbarrini A. (ORCID:0000-0002-7278-4823)

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nutrientsEditorialIrritable Bowel Syndrome (IBS) and Non-Celiac GlutenSensitivity (NCGS): Where Is the Culprit Hiding?Nutritional Tips for GastroenterologistsEmanuele Rinninella 1,2,* , Marco Cintoni 3 , Maria Cristina Mele 2,4 and Antonio Gasbarrini 2,51 UOC di Nutrizione Clinica, Dipartimento di Scienze Gastroenterologiche, Endocrino-MetabolicheNefro-Urologiche, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy2 Istituto di Patologia Speciale Medica, Università Cattolica del Sacro Cuore, 00168 Rome, Italy;mariacristina.mele@unicatt.it (M.C.M.); antonio.gasbarrini@unicatt.it (A.G.)3 Scuola di Specializzazione in Scienza dell’Alimentazione, Università di Roma Tor Vergata, Via Montpellier 1,00133 Rome, Italy; marco.cintoni@gmail.com4 UOSA di Nutrizione Avanzata in Oncologia, Dipartimento di Scienze Gastroenterologiche,Endocrino-Metaboliche e Nefro-Urologiche, Fondazione Policlinico Universitario A. Gemelli IRCCS,Largo A. Gemelli 8, 00168 Rome, Italy5 UOC di Medicina Interna e Gastroenterologia, Dipartimento di Scienze Gastroenterologiche,Endocrino-Metaboliche e Nefro-Urologiche, Fondazione Policlinico Universitario A. Gemelli IRCCS,00168 Rome, Italy* Correspondence: emanuele.rinninella@unicatt.itReceived: 8 October 2019; Accepted: 16 October 2019; Published: 17 October 2019At least 40% of all the gastroenterological outpatient visits are due to functional gastrointestinaldisorders (FGIDs), among which irritable bowel syndrome (IBS) is the most common, accounting for aworldwide prevalence of about 12% [1]. Patients affected by IBS have a significant impairment of theirquality of life and productivity, and this, in turn, has an impact on social and economic costs [2].The diagnosis of IBS lacks a specific biomarker and, to date, it relies on the so-called “Rome IVCriteria”, a symptom-based scheme requiring that patient complains of abdominal pain on average atleast 1 day/week and that pain is associated with two or more of the following characteristics: (1) it isrelated to defecation; (2) it is associated with a change in the frequency of stool; or (3) it is associated witha change in the form (appearance) of the stool. These criteria should be fulfilled for the last 3 months,with the onset at least 6 months before diagnosis [3]. Although the physiopathology of IBS is not fullyunderstood, a biopsychosocial model correlates early life’s sociocultural factors, family interactions,and psychosocial factors (i.e., abnormal emotional responses to stress and a sexual or physical abusehistory) with functional gut alterations, such as abnormal motility, visceral hypersensitivity, immunedysregulation, inflammation, and barrier dysfunction, through the bidirectional neuroanatomicsubstrate of the “brain–gut axis” [3]. In some cases, the onset of the disease can appear after an infection,like acute bacterial, protozoal, or viral gastroenteritis [2]. Furthermore, a possible role of gut microbiotain the onset and maintenance of IBS was suggested [3]. Indeed, these patients, compared to the healthycontrols, show a different gut microbiota composition, with the loss of microbial richness, an increasedFirmicutes to Bacteroidetes ratio, and decreased Lactobacillus and Bifidobacterium abundances [4].Even though up to 70% of patients experience symptoms after eating certain foods, like wheat or dairyproducts [5], a specific food or nutrient has not clearly been implicated in the pathogenesis of thedisease. However, in the last ten years, a low fermentable oligo-, di-, and monosaccharide and polyol(FODMAP) diet, developed by the Monash University (Melbourne, Australia), was largely employedand was effective in reducing the symptoms of IBS patients [6]. FODMAPs are osmotically activeshort-chain carbohydrates, which are poorly absorbed and rapidly fermented by gut bacteria in thelarge intestine, thereby increasing intraluminal water volume by an osmotic effect and producing gasNutrients 2019, 11, 2499; doi:10.3390/nu11102499 www.mdpi.com/journal/nutrientsNutrients 2019, 11, 2499 2 of 5due to fermentation. To date, at least two meta-analyses have confirmed a significant reduction inabdominal pain and bloating in patients receiving a low-FODMAP diet compared with those receivinga standard diet, suggesting the key role of a low FODMAP diet in the first-line treatment of IBS [7,8].Non-Celiac Gluten Sensitivity (NCGS) is a syndrome characterized by intestinal and extra-intestinalsymptoms, related to the ingestion of gluten in subjects who are not affected by celiac disease (CD) orwheat allergy (WA) [9].The prevalence of NCGS is still difficult to ascertain, ranging from 0.6% to 10.6% in the generalpopulation, according to studies. However, a lack of specific diagnostic tests (see below) suggestsa selection bias [10]. As in IBS, abdominal pain, bloating, borborygmus, and changes in bowelhabits may occur, and a specific diagnostic biomarker has not yet been identified. Unlike IBS,in NCGS, extra-intestinal symptoms such as a headache, dermatitis, and foggy mind can also bepresent. Gastroenterologists use the Salerno Experts’ Criteria to formulate the diagnosis of NCGS [9].The Salerno diagnostic protocol uses a double-step approach defined only by symptoms. In Step 1,after excluding CD and WA through a clinical and laboratory evaluation, patients have to eat agluten-containing diet for at least six weeks; then (at the baseline visit), they report symptoms accordingto a self-administered modified version of the Gastrointestinal Symptom Rating Scale (GSRS), gradingthem according to a Numerical Rating Scale (NRS). After that (time 0), they start a gluten-free diet(GFD) for at least six weeks, recording possible variations of the symptoms among those describedabove. A decrease of at least 30% of the baseline score is considered a positive response. Step 2 is called“the Gluten Challenge” and is required to confirm the diagnosis in patients responding to the GFD.This is provided through a reintroduction of gluten in a double-blind placebo-controlled challengewith cross-over design, in which a variation of symptoms of at least 30% between gluten and placebodiscriminate a positive from a negative result [9].Some concerns may afflict the Gastroenterologists in the clinical practice between IBS and NCGS.An interesting review published by Catassi et al. [10] tried to shed light upon this problem.First, the lack of a specific diagnostic biomarker for the diagnosis of both IBS and NCGS can makethe diagnostic approach difficult. This is especially true for NCGS, whose diagnostic protocol has beendefined as “cumbersome” by the same experts of Salerno, and not apt for epidemiological studies [9].Secondly, at present, a GFD is generally perceived by common people as “healthy”, and manyindividuals start a GFD just because they feel better, self-reporting an NCGS without a medicaldiagnosis and a personalized dietary plan. This issue also complicates the diagnostic protocol of NCGS,since patients have to eat a gluten-containing diet in Step 1 [10].Thirdly, other wheat components may trigger an immune or inflammatory response, apart fromgluten. For example, amylase trypsin inhibitors (ATIs), pest resistance molecules contained in theendosperm of wheat and related cereals, have been identified as strong activators of innate immuneresponses in human and murine macrophages, monocytes, and dendritic cells, eliciting the release ofproinflammatory cytokines via the activation of toll-like receptor 4 (TLR4) [11]. In the same way, wheatgerm agglutinins (WGA) have been shown to promote the release of pro-inflammatory cytokines, thusimpairing the integrity of the intestinal epithelial layer [12]. Wheat contains also fructans—belongingto the category of FODMAPs—whose content varies according to the final product [13]. A recentdouble-blind placebo-controlled crossover study in patients with self-reported NCGS showed thatfructans (rather than gluten) are more likely to induce symptoms, with no effect on the glutenchallenge [14]. Another randomized clinical study reported that a double-blind gluten challengeinduced symptom recurrence only in one-third of patients fulfilling the clinical diagnostic criteria forNCGS. Interestingly, in this trial, almost half of the patients, after the challenge, reported a recurrenceof symptoms with gluten-free flour [15].Nutrients 2019, 11, 2499 3 of 5The differential diagnosis between IBS and NCGS is, furthermore, challenging since patientssuspected to have IBS may undergo a low FODMAP diet, which excludes wheat due to its high contentof fructans. In this way, gluten is avoided by default, without allowing for a possible diagnosis of NCGS.Indeed, patients tend to have rapid relief from gastrointestinal symptoms by avoiding FODMAPs, andphysicians may often underestimate the role of gluten as the causative agent of disease. This commonevidence has been already confirmed in a placebo-controlled, cross-over rechallenge study, in whichthe authors aimed to investigate the specific effect of gluten reintroduction after a low FODMAPdiet in patients with self-reported NCGS. After a 2-week period of a low FODMAP diet, the authorsfound no significant gastrointestinal effects after gluten reintroduction through a high-gluten meal(16 g gluten/day) compared to a low-gluten meal (2 g gluten/day; 14 g whey protein/day) or a controlmeal (16 g whey protein/day) [16].The huge impact of a low FODMAP diet on NCGS may cause confusion on at least two levels.(1) The appropriateness of diagnosis: Indeed, a population study (over 1000 patients) in the UKdemonstrated that individuals with NCGS have a 20% prevalence of fulfilling the IBS diagnosticcriteria [17]; (2) dietary management: Is it still recommended to prescribe a GFD to NCGS patients?Should the patients suspected to suffer from NCGS eat a low FODMAP diet?On the other hand, a low FODMAP diet is not recommended as a long-term treatment even forIBS patients, given its significant impact on gut microbiota and because this impact has not yet beenfully evaluated for its long-term clinical consequences [18].Such evidence raises a question about the identification of gluten as the only culprit of thesymptoms of NCGS. For these reasons, the term Non-Celiac Wheat Sensitivity (NCWS) appears, to date,more appropriate than NCGS to describe this syndrome [19].In the above-cited review, Catassi et al. [10] proposed a practical guide for the Gastroenterologists,including the clinical assessment of IBS symptoms (Rome IV Criteria), the exclusion of alarm (red flag)features, and diagnostic tests to exclude other organic diseases. After that, first and second-line dietaryrecommendations are proposed, the latter according to diagnostic suspicions: (1) Consider trying aGFD for 4 to 6 weeks if the patient reports wheat and gluten-related intestinal and gastrointestinalsymptoms, especially if anti-gliadin antibodies are present; (2) consider a low FODMAP diet if thepatient self-reports predominantly gastrointestinal symptoms related to high FODMAP food.Finally, one must remember that “all wheat is not the same and all gluten is not the same” [10].Recently, an Italian double-blind randomized cross-over trial [20] was released comparing the effects ofan organic durum wheat variety (the ancient organic wheat single variety Senatore Cappelli) with thoseof standard commercial wheat varieties in patients with recognized NCGS, according to the SalernoCriteria. Enrolled patients experienced lower gastrointestinal and extra-intestinal symptom scoresafter eating the Senatore Cappelli wheat variety-based product than after eating standard commercialwheat products. This evidence, if confirmed in further studies, could open new dietary alternatives toGFD in NCGS with consequential health, economic, and social benefits.In conclusion, FGIDs and NCGS may often overlap due to their common symptoms. A GFD anda low FODMAP diet are not always the only solution. Differential diagnosis requires both accuratediagnostic and therapeutic approaches, the latter mostly relying on nutritional counseling and apersonalized dietary plan. Clinical Nutritionists, Dieticians, and Gastroenterologists should worktogether to better understand and manage such complex syndromes.Funding: This research received no external funding.Conflicts of Interest: The authors declare no conflict of interest.References1. Lacy, B.E.; Patel, N.K. Rome criteria and a diagnostic approach to irritable bowel syndrome. J. Clin. Med.2017, 6, 99. [CrossRef] [PubMed]Nutrients 2019, 11, 2499 4 of 52. Ford, A.C.; Lacy, B.E.; Talley, N.J. Irritable bowel syndrome. N. Engl. J. Med. 2017, 29, 2566–2578. [CrossRef][PubMed]3. Drossman, D.A. Functional gastrointestinal disorders: History, pathophysiology, clinical features and RomeIV. Gastroenterology 2016, 150, 1262–1279. [CrossRef] [PubMed]4. Rinninella, E.; Raoul, P.; Cintoni, M.; Franceschi, F.; Miggiano, G.A.D.; Gasbarrini, A.; Mele, M.C. What isthe healthy gut microbiota composition? A changing ecosystem across age, environment, diet and diseases.Microorganisms 2019, 7, 14. [CrossRef] [PubMed]5. Hayes, P.A.; Fraher, M.H.; Quigley, E.M. Irritable bowel syndrome: The role of food in pathogenesis andmanagement. Gastroenterol. Hepatol. 2014, 10, 164–174.6. Gibson, P.R. History of the low FODMAP diet. J. Gastroenterol. Hepatol. 2017, 32 (Suppl. 1), 5–7. [CrossRef][PubMed]7. Altobelli, E.; Del Negro, V.; Angeletti, P.M.; Latella, G. Low-FODMAP diet improves irritable bowel syndromesymptoms: A meta-Analysis. Nutrients 2017, 9, 940. [CrossRef] [PubMed]8. Varjú, P.; Farkas, N.; Hegyi, P.; Garami, A.; Szabó, I.; Illés, A.; Solymár, M.; Vincze, Á.; Balaskó, M.; Pár, G.;et al. Low fermentable oligosaccharides, disaccharides, monosaccharides and polyols (FODMAP) dietimproves symptoms in adults suffering from irritable bowel syndrome (IBS) compared to standard IBS diet:A meta-analysis of clinical studies. PLoS ONE 2017, 12, e0182942. [CrossRef] [PubMed]9. Catassi, C.; Elli, L.; Bonaz, B.; Bouma, G.; Carroccio, A.; Castillejo, G.; Cellier, C.; Cristofori, F.; de Magistris, L.;Dolinsek, J.; et al. Diagnosis of non-celiac gluten sensitivity (NCGS): The Salerno experts’ criteria. Nutrients2015, 7, 4966–4977. [CrossRef] [PubMed]10. Catassi, C.; Alaedini, A.; Bojarski, C.; Bonaz, B.; Bouma, G.; Carroccio, A.; Castillejo, G.; De Magistris, L.;Dieterich, W.; Di Liberto, D.; et al. The overlapping area of non-celiac gluten sensitivity (NCGS) andwheat-sensitive irritable bowel syndrome (IBS): An update. Nutrients 2017, 9, 1268. [CrossRef] [PubMed]11. Junker, Y.; Zeissig, S.; Kim, S.J.; Barisani, D.; Wieser, H.; Leffler, D.A.; Zevallos, V.; Libermann, T.A.; Dillon, S.;Freitag, T.L.; et al. Wheat amylase trypsin inhibitors drive intestinal inflammation via activation of toll-likereceptor 4. J. Exp. Med. 2012, 209, 2395–2408. [CrossRef] [PubMed]12. Dalla Pellegrina, C.; Perbellini, O.; Scupoli, M.T.; Tomelleri, C.; Zanetti, C.; Zoccatelli, G.; Fusi, M.; Peruffo, A.;Rizzi, C.; Chignola, R. Effects of wheat germ agglutinin on human gastrointestinal epithelium: Insights froman experimental model of immune/epithelial cell interaction. Toxicol. Appl. Pharmacol. 2009, 237, 146–153.[CrossRef] [PubMed]13. Biesiekierski, J.R.; Rosella, O.; Rose, R.; Liels, K.; Barrett, J.S.; Shepherd, S.J.; Gibson, P.R.; Muir, J.G.Quantification of fructans, galacto-oligosacharides and other short-chain carbohydrates in processed grainsand cereals. J. Hum. Nutr. Diet. 2011, 24, 154–176. [CrossRef] [PubMed]14. Skodje, G.I.; Sarna, V.K.; Minelle, I.H.; Rolfsen, K.L.; Muir, J.G.; Gibson, P.R.; Veierød, M.B.; Henriksen, C.;Lundin, K.E.A. Fructan, rather than gluten, induces symptoms in patients with self-reported non-celiacgluten sensitivity. Gastroenterology 2018, 154, 529–539.e2. [CrossRef] [PubMed]15. Zanini, B.; Baschè, R.; Ferraresi, A.; Ricci, C.; Lanzarotto, F.; Marullo, M.; Villanacci, V.; Hidalgo, A.; Lanzini, A.Randomised clinical study: Gluten challenge induces symptom recurrence in only a minority of patientswho meet clinical criteria for non-coeliac gluten sensitivity. Aliment. Pharmacol. Ther. 2015, 42, 968–976.[CrossRef] [PubMed]16. Biesiekierski, J.R.; Peters, S.L.; Newnham, E.D.; Rosella, O.; Muir, J.G.; Gibson, P.R. No effects of glutenin patients with self-reported non-celiac gluten sensitivity after dietary reduction of fermentable, poorlyabsorbed, short-chain carbohydrates. Gastroenterology 2013, 145, 320–328.e1-3. [CrossRef] [PubMed]17. Aziz, I.; Lewis, N.R.; Hadjivassiliou, M.; Winfield, S.N.; Rugg, N.; Kelsall, A.; Newrick, L.; Sanders, D.S. A UKstudy assessing the population prevalence of self-reported gluten sensitivity and referral characteristics tosecondary care. Eur. J. Gastroenterol. Hepatol. 2014, 26, 33–39. [CrossRef] [PubMed]18. Rinninella, E.; Cintoni, M.; Raoul, P.; Lopetuso, L.R.; Scaldaferri, F.; Pulcini, G.; Miggiano, G.A.D.;Gasbarrini, A.; Mele, M.C. Food components and dietary habits: Keys for a healthy gut microbiotacomposition. Nutrients 2019, 11, 2393. [CrossRef] [PubMed]Nutrients 2019, 11, 2499 5 of 519. Carroccio, A.; Rini, G.; Mansueto, P. Non-celiac wheat sensitivity is a more appropriate label than non-celiacgluten sensitivity. Gastroenterology 2014, 146, 320–321. [CrossRef] [PubMed]20. Ianiro, G.; Rizzatti, G.; Napoli, M.; Matteo, M.V.; Rinninella, E.; Mora, V.; Fanali, C.; Leonetti, A.; Benedettelli, S.;Mele, M.C.; et al. A durum wheat variety-based product is effective in reducing symptoms in patients withnon-celiac gluten sensitivity: A double-blind randomized cross-over trial. Nutrients 2019, 11, 712. [CrossRef][PubMed]© 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open accessarticle distributed under the terms and conditions of the Creative Commons Attribution(CC BY) license (http://creativecommons.org/licenses/by/4.0/).

Irritable Bowel Syndrome (IBS) and Non-Celiac Gluten Sensitivity (NCGS): Where Is the Culprit Hiding? Nutritional Tips for Gastroenterologists.

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Irritable Bowel Syndrome (IBS) and Non-Celiac Gluten Sensitivity (NCGS): Where Is the Culprit Hiding? Nutritional Tips for Gastroenterologists.

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