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or eliminate increased gastric acidity related to gastroesophageal pathologies
Accepted Manuscript Title: New food approaches to reduce and/or eliminate increased gastric acidity related to gastroesophageal pathologies Author: Ciro Langella, Daniele Naviglio, Marina Marino, Armando Calogero, Monica Gallo PII: DOI: Reference:
S0899-9007(18)30084-4 https://doi.org/10.1016/j.nut.2018.03.002 NUT 10147
To appear in:
Nutrition
Received date: Revised date: Accepted date:
3-11-2017 21-12-2017 6-3-2018
Please cite this article as: Ciro Langella, Daniele Naviglio, Marina Marino, Armando Calogero, Monica Gallo, New food approaches to reduce and/or eliminate increased gastric acidity related to gastroesophageal pathologies, Nutrition (2018), https://doi.org/10.1016/j.nut.2018.03.002. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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New food approaches to reduce and/or eliminate increased gastric acidity related to gastroesophageal pathologies Running Title: New food approaches for gastroesophageal pathologies
Ciro Langellaa, Daniele Navigliob, Marina Marinoc, Armando Calogerod and Monica Galloa*
a
Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, via Pansini, 5; 80131 Naples, Italy b Department of Chemical Sciences, University of Naples Federico II, Via Cintia 4; 80126 Naples, Italy c Department of Economic and Statistical Sciences, University of Naples Federico II, Via Cintia, 26; 80126 Naples, Italy d Department of Advanced Biomedical Sciences, University of Naples Federico II, via Pansini, 5; 80131 Naples, Italy *Corresponding author: Tel.: +39 81 7463117; Fax: +39 81 7463117; E-mail address: [email protected] (M. Gallo) Graphical Abstract
Highlights
Limited information is available on the effects of diets on acid-related gastropathies. Reduced glycidic content with the addition of acidic pH foods in gastroesophageal pathologies. 1 Page 1 of 18
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A negative correlation exists between acidic foods and secretion of gastric acid. Acid foods may be indicators of the presence of injuries to organs affected by inflammation. A proper diet with appropriate additions can improve the symptoms of gastroesophageal diseases.
ABSTRACT Objectives: Gastroesophageal reflux disease (GERD) or Gastro-Oesophageal Reflux Disease (GORD), is a disease of interest in gastroenterology that is caused by pathological complications of gastroesophageal reflux (GER). This study aims to assess the ability of reduced-carbohydrate diets and foods enriched with acid pH (lemon and tomato) to quickly and exponentially reduce the symptoms related to conditions such as gastritis and gastroesophageal reflux that are unrelated to Helicobacter pylori. Methods: Following the administration of an anamnestic test, 130 subjects were selected (73 women, 57 men), aged 21 to 67, with a gastritis diagnosis for 92 subjects and reflux gastritis for 38 subjects. Study participants followed 3 dietary treatments in succession. Each treatment lasted two weeks, and treatments were separated by two weeks of washout. The subjects followed a diet that included the exponential reduction of glycides (simple and complex). In addition, the treatment provided for the daily intake of the juice of two lemons and approximately 100 g of fresh orange tomato without seeds eaten either raw or cooked and peeled. Results: During the treatment and at the end of two weeks of treatment, the subjects reported significant improvements, including an almost total disappearance of symptoms related to the disease in question. Conclusions: This study shows that a carbohydrate-free diet and/or highly hypoglycidal diet enriched with acid pH foods seems to lead to a decrease in the pH of the gastric contents, thus inhibiting further production of hydrochloric acid with a reduction or disappearance of heartburn symptoms typical of gastroesophageal diseases.
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Keywords: Gastroesophageal reflux, Diet, Carbohydrate reduction, Lemon, Tomato, Anamnestic test. Abbreviations GERD GORD GER NERD ERD BMI T T0 GIP CCK PZ
Gastroesophageal Reflux Disease Gastro-Oesophageal Reflux Disease Gastroesophageal Reflux Non Erosive Reflux Disease Moderate Erosive Esophagitis Body Mass Index Treatment (Nutrition therapy) Initial state or time 0 Gastric Inhibitory Peptide Cholecystokinin Pancreozimine
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Introduction Gastroesophageal reflux disease (GERD) or Gastro-Oesophageal Reflux Disease (GORD), is a disease of interest in gastroenterology that is caused by pathological complications of gastroesophageal reflux (GER). It may have several clinical presentations: disphagia, cough, rhinitis, burning in the jugular region, chest pain that mimics a heart attack, otitis. Нe definition of GERD is: “a condition that develops when the reflux of stomach contents causes troublesome symptoms and/or complications” [1-3]. Нe most common symptoms are heartburn, regurgitation, and, sometimes, dysphagia. Extra-esophageal manifestations are bronchospasm, laryngitis and chonic cough. Other symptoms of GERD include chest pain, globus sensation, odynophagia, nausea, glossitis, burning mouth, otitis, postnasal drip, sinusitis, dysphonia and headache. For the diagnosis it is preferable to make at least a gastroscopy and also an upper abdominal ultrasound. Distinguishing cardiac from non-cardiac chest pain is required before considering GERD as a cause of chest pain. Although the symptom of dysphagia can be associated with uncomplicated GERD, its presence warrants investigation for a potential complication including an underlying motility disorder, stricture, ring, or malignancy [4]. The balance of evidence suggests that symptom frequency does not change as we age, however, the intensity of symptoms may decrease after the age of 50 [5]. There is a definite relationship between GERD and obesity. Several meta-analysis suggest an association between body mass index (BMI), waist circumference, weight gain and the presence of symptoms and complications of GERD including erosive GERD (ERD) and Barrett’s esophagus [6,7]. In a study by Labenz et al. (2004) was used logistic regression analysis to identify several independent risk factors for ERD. The odds for higher degrees of ERD increased as BMI rose [8]. Furthermore, it is of greatest concern that there has been a well-documented association between BMI and carcinoma of the esophagus and gastric cardia [9]. There is an overall increase in diagnoses due to the greater ease of inspection of the early digestive tract, but above all, increases in GERD are a consequence of modernity: poor lifestyle and dietary habits, stress conditions that derive from social organizations, working conditions, and generally from the frenetic rhythm of life. The data reported in the literature varies depending on geographic locations, observation points, and the statistical methods used. There is also some intrinsic uncertainty in the data: first, there is no universally accepted definition of gastroesophageal reflux disease, resulting in possible variations in the meaning and weight attributed to the parameters used, which can lead to different interpretations of the different case presentations; second, the spectrum of clinical manifestations experienced by people who do in fact meet the clinical profile of having GERD is very wide; third, no definite and fully reliable criteria are available to achieve the assurance of a diagnosis of GERD in the absence of oesophagitis. This condition, if taken as a single parameter, accompanied by occasional symptomatology or controlled by the spontaneous intake of antacids, leads to the exclusion of a proportion of patients. This is a condition that occurs in reflux disease without inflammation and erosions of the oesophagus called NERD (Non Erosive Reflux Disease), in which the negative endoscopic diagnosis becomes a factor of exclusion from the statistical surveys. GERD, considered esophagitis, is found in 50-75% of symptomatic adult subjects in industrialized countries and up to 40% of patients undergoing asymptomatic digestive endoscopy, an increase of three- or four-fold in the last twenty years [10-12]. For example, the overall growth trend in Italy can be estimated at an ascending factor equivalent to at least three times in the last 10 years [13].
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This trend is confirmed by rates of oesophageal ulcerations over 5%, and rates of cases with complications of interstitial lung disease and oesophageal stenosis between 8 and 20% [14]. The present study aims to assess the potency of highly hypoglycidal diets that are enriched with acid pH (lemon, tomato) foods to exponentially and quickly reduce the symptoms related to pathologies such as gastritis and gastroesophageal reflux not associated with Helicobacter pylori. Materials and methods Subject selection Initially, 250 potentially suitable non-smoking subjects were recruited for the study; all initial recruits reported gastrointestinal tract disorders, particularly of the stomach and oesophagus unrelated to Helicobacter pylori infection, with a clinical diagnosis of gastritis and gastritis with reflux, based on the gastroscopic examination performed within the last year. The subjects performed a daily intake of simple and complex carbohydrates of approximately 60-70% and followed the diet and lifestyle recommendations in accordance with the Guidelines for Subjects with Acid-Related Gastropathy: do not smoke, do not eat within two hours of resting, rest and sleep with a raised backrest, limit time in supine positions, chew slowly and completely, do not eat large meals, and finally, do not consume carbonated beverages, coffee (unless decaffeinated), alcoholic beverages, mints, acidic foods, cocoa and chocolate, spices, very cold or very hot foods, and do not chew gum [15]. Subsequently, according to the presented diagnostic responses, 130 subjects were included. Moreover, these 130 subjects had a common parameter, in fact they had performed gastroscopic examination within the last year, even if some had performed other valid diagnostic tests less invasive to obtain useful information for the purpose, such as pHmetry, cytokines, cell markers. In addition, body weight and BMI of the subjects were detected before and after each treatment (Table not shown). The participants included 73 women and 57 men aged 21 to 67, of whom 92 were diagnosed with gastritis (including 56 women and 36 men) and 38 were diagnosed with gastritis with reflux (17 women and 21 men). The study was conducted according to the guidelines laid down in the Declaration of Helsinki. A validated questionnaire was used to monitor the participants’ food plans. Participants were interviewed, and their responses were evaluated to monitor compliance with the study’s protocol. Finally, for evaluated the gastritis was examined the survey results on Likert scale questionnaires. Study design The participants followed 3 dietary treatments in succession (Treatment 2, 3 and 4) for two weeks each, and each treatment was interrupted by two weeks of washout, where participants followed a typical Mediterranean diet (Treatment 1) (Figure 1). To evaluate the effects of the dietary treatment, the symptoms of the participants were statistically analysed by administering a test before and after each dietetic treatment. Specifically, a test was administered before Treatment 1 (Test at time 0, T0) and then a series of tests was given after each dietary treatment as a means of comparison to define the results. < Insert Figure 1 > 4 Page 4 of 18
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Statistical analysis Non-parametric tests were performed on paired data, in particular the Test of the Sign and the Wilcoxon Test of the Marked Ranks on the sample in question of 130 subjects with diagnosed gastro-esophageal disorders. Results and Discussion Subject characteristics Some recent studies have identified the possible relationship between sugar consumption and gastric hyperacidity and the ability of a low-carbohydrate diet to increase the pH of the gastric lumen [16-20]. Unlike past and current suppositions [15, 21-23], there could be a negative correlation, both direct and indirect, between acidic foods and the secretion of gastric acid. Acid foods may be signallers indicating the presence of injuries to the organs affected by the flogosis: acid contacting the lesion causes increased perception of "burning" by direct irritant action on the gastric mucosa. On the other hand, they would represent an important protective and preventive factor [24-27]. A possible explanation for this may be that acidic foods, due to their acid nature, would favour a relatively low gastric acid pH, thus inhibiting the further production of hydrochloric acid. While keeping the pH of the gastric environment low, the gastrin (produced by the elevation of pH) is inhibited, or rather unsalted, by stimulating the parietal cells of the oxytocin glands to produce and secrete hydrochloric acid [28-30]. In contrast, the intake of basic foods and drugs containing basic molecules such as carbonated ions seems to generate a condition of "perceived well-being" in the short term only at the symptomatic level, leading to a "rebound" effect and instead inducing a gastric hypersecretion in response to the pH reduction of the gastric contents [27, 31, 32]. In addition, antacids such as sodium bicarbonate should be avoided, among other things, because they produce a gastric CO2 environment [31-35] that further stimulates acid secretion [3639]. In the present study, the statistical analysis of the anamnestic test data (Test 1) administered to all subjects showed the following symptoms: gastric heartburn, which increased due to the intake of certain foods, swelling of the upper abdominal area, eructations, mucus of GE origin, gastric heartburn and swelling of the high-abdominal area that were common to all subjects. At the end of each treatment period, a test (Test 2) was given. A typical Mediterranean diet for all participants (Treatment 1) was administered to the 130 subjects for two weeks and which was repeated as a washout period following each subsequent stage. After 2 weeks, to this diet were added some foods with an acidic pH for another 2 weeks (Treatment 2). After this treatment, subjects were prescribed a diet with a very low glycid content (Treatment 3) for another 2 weeks. Finally, following the final washout treatment, the participants followed the same low-glycidcontaining regime with the addition of the acidic foods prescribed in Treatment 2 (Treatment 4) (Tables 1-4). < Insert Tables 1-4 >
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Throughout the experimental period, subjects were asked to strictly comply with some of the general behaviours provided by specialists and healthcare institutions contained in the guidelines (12). At the end of the first washout period (Treatment 1, T1 (I)), no major changes were reported, i.e., the symptomatic disorders reported prior to treatment remained unchanged. During and after Treatment 2, 93 subjects reported increased gastric and burning sensitivity, while the other 37 reported no changes. At the end of the second washout period (Treatment 1, T1 (II)), almost all subjects (123 subjects) had the same symptoms as at the beginning of the study. During and at the end of Treatment 3, 118 participants reported significant improvements, recording a nearly total disappearance of the symptoms associated with the disease, while the remaining 12 participants did not notice any changes; i.e., they remained in the same situation prior to Treatment 3 itself. During and at the end of the third washout period (Treatment 1, T1 (III)), the 12 subjects who had not responded positively to Treatment 3 showed improvements including a feeling of relief, mainly due to the consumption of pasta, bread and farinaceous derivatives (which, however, have a rather short duration of only approximately 2 hours). While almost all subjects (110 out of 130) resumed their usual diet, they reported gastric disorders, both during and at the end of the third washout period (Treatment 1, T1 (III)). With Treatment 4, the same 12 subjects who had been suffering with discomforts up to Treatment 3 again experienced disturbances; in contrast, the remaining 118 subjects confirmed significant benefits with the nearly total elimination of glycides and even with the addition of acidic foods. During and at the end of Treatments 3 and 4, nearly all subjects (118 out of 130) reported significant improvements, recording the almost total disappearance of the symptoms related to the pathology in question. Body weight control The body weight of the 130 subjects was measured before and after each of the treatments. At the end of the first washout period (Treatment 1, T1 (I)), 49 subjects reported a decrease in body weight between 1.1 and 1.8 kg (including 9 of the 12 subjects who responded negatively to Treatment 3 and 4), and the remaining participants did not have a significant weight decrease (data not shown). At the end of Treatment 2, the weight of all subjects remained almost unchanged from the beginning of Treatment 2 as well as at the end of the second washout period (Treatment 1, T1 (II)). At the end of Treatment 3, 102 participants (including 12 subjects who did not note an improvement in symptoms) reported a decrease in body weight between 1.7 and 3.9 kg compared with the beginning of the same treatment. At the end of the third washout period (Treatment 1, T1 (III)), 113 subjects reported weight gains between 0.8 and 2.2 kg (including the 102 subjects following Treatment 3). The results of this latter case confirm that what is known is that low-carbohydrate diets, although they are effective for weight loss, do not offer lasting results because reintroducing carbohydrates leads to an increase in weight. Finally, at the end of Treatment 4, the weight variation affected only the same 113 subjects, who returned to about the same body weight determined at the end of Treatment 3.
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Data analysis The analysis of the test data showed that subjects’ responses after the 3 treatments were significantly different from the initial status (T0), indicating a significant improvement in the symptomatology evaluated through gastric heartburn, swelling of the upper abdominal area, eructation and mucus of GE origin. In fact, hypothesis tests conducted for all these symptoms allowed us to reject the null hypothesis that the distributions are the same (Table 5). < Insert Table 5 > Specifically, evaluating Treatment 2 (typical Mediterranean diet with the addition of acidic foods) compared to time zero (T0), there was significant improvement only for two symptoms: swelling and eructation. On the other hand, with Treatment 3 (low glycaemic diet) and Treatment 4 (very low content of glycids with acidic additions), all disorders significantly improved compared to the initial status of the subjects (Table 5). Next, the answers to questions related to these symptoms were analysed at the end of each treatment with respect to the responses given during the washout period preceding the treatment in question (T1 (I), T1 (II) and T1 (III)). Again, the tests were significant, suggesting that the distributions of the sample before and after the treatment were significantly different (Table 6). < Insert Table 6 > Analysing the subjects’ responses at the end of Treatment 2 with respect to the first washout period (T1 (I)), it was shown that swelling and haemorrhage improved, while the other two symptoms persisted. Only with Treatment 3 and Treatment 4, evaluated, respectively, with washout periods (Treatment 1, T1 (II) and T1 (III)), were all symptoms improved significantly. In fact, the tests carried out led to the rejection of the null hypothesis of equality between distributions for all disorders. In addition to non-parametric tests, a survival analysis was conducted to determine the survival time of the symptoms analysed following each treatment. With this type of analysis, the probability of the single symptom occurring after a certain observation time from time zero was evaluated. Below is a table and relative graphs (not shown) with the survival rates of the respective symptoms (Table 7). < Insert Table 7 > As seen after Treatment 2, all symptoms had a survival rate of more than 90%, while this rate dropped after Treatment 3, except for the eructation rate, which instead rose by 4 percentage points. All symptoms were significantly reduced after Treatment 4, resulting in a survival rate of less than 50%, meaning that with Treatment 4, all the disorders reported at time zero (T0) were disappearing only with Treatment 4, that is, with a very low glycide content diet with the addition of acidic foods. In the present study, the biochemical processes of digestion in the concerned organs, or the influence of the nervous system on the digestive processes, were not analyzed. Therefore, we can 7 Page 7 of 18
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only hypothesize the mechanism according to which carbohydrates, and other nutrients, such as fats, are directly or indirectly responsible for the increase of gastric acidity. In fact, it is probable that carbohydrate consumption is crucial for the stimulation of gastric cells and for the production of gastric juices, by means of cephalic-vagal stimulation. On the other hand, having administered to volunteers, diets consisting mainly of protides and lipids, it is reasonable to assume that, especially by means of the latter, the reduced gastric production of hydrochloric acid is also due to the inhibitory action of hormones, such as Gastric Inhibitory Peptide (GIP) and cholecystokinin. At a later time, the GIP, stimulated by the presence of fats, has the function of inhibiting the secretion of oxyntic cells of the stomach, and the cholecystokinin (CCK) or pancreozimine (PZ), secreted by the duodenum (and in lesser quantity from the jejunum), after a meal rich above all in fats, determines, among other things, by vagal stimulation, the sense of satiety [40]. However, the limitation of this study is the possibility of demonstrating the ability of such diet treatments to reduce also the "condition" of the same pathologies, not having carried out clinical examinations on subjects recruited before during and after the dietary treatment. Therefore, this will be the goal of one of the next studies. Furthermore, further studies will be useful to evaluate both the possibility of using dietary approaches to very low carbohydrate content as short-term treatments with therapeutic aim to reduce and/or eliminate symptoms and disorders related to these pathologies, but above all the ability of such strategies to determine the remission of the same pathologies. Conclusions The results obtained in this study affirm that diets with very low content of glycids and enriched with acidic foods with reduced glycide content can significantly reduce the symptoms associated with gastroesophageal disease. In addition, fats and proteins, the main constituents of the dietary approach used, did not adversely affect those that were the targets to be observed, that is, they did not increase or cause the typical symptoms reported by people with gastropathies such as gastroesophageal burns and reflux. In conclusion, this study shows that a diet free of carbohydrates and enriched with acidic foods with reduced glycide content significantly reduces gastric heartburn related to the ailments under examination, and therefore probably gastric acidity, thus increasing the pH of the gastric lumen. However, this conclusion comes from preliminary data, so further studies should be conducted in the future to confirm the results obtained and the timing of the dietary approach. Most likely, the merit of the success of the dietary approach used in this study could be attributed to the almost absence of glycids in the diet. This factor would explain why, to date, the ability of acidic pH foods to reduce gastric acidity was not fully effective in diets with regular or high consumption of carbohydrates and/or acidic foods with medium or high glycidic content. However, this is not to say that diets lacking in carbohydrates sustained for long periods can be considered correct for a healthy lifestyle, nor do they substitute for a balanced diet such as the Mediterranean type, with its balance in favour of carbohydrates and fibre. However, surely this work can lay new foundations for effective treatments against many acid-related gastropathies. Acknowledgements The authors acknowledge the volunteers who participated in this study. 8 Page 8 of 18
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Compliance with ethical standards The authors have no funding, financial relationships, or conflicts of interest to disclose.
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Figure 1. The treatments followed by the subjects. Each treatment lasts two weeks separated by two weeks of washout
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Table 1. First food plan followed by the participants (T1): a typical Mediterranean diet for 2 weeks (washout period) Treatment 1 (T1) Breakfast h 7.45
3 white bread slices + 1 cup partly skimmed milk + 1 banana 400 ml of non-gassed water
Snack h 11.00
125 g white light yogurt + 100 g apple without peel 400 ml of non-gassed water
Lunch h 13.15 - 14.00
Mon: 100 g of pasta + 200 g of broccoli + 100 g of chicken breast + 100 g of aubergines Tue: 50 g of pasta + 80 g of cannellini beans + 150 g peppers peeled Wed: 100 g rice + 200 g zucchini + 1 tuna can of natural 50 g drained weight Thu: 100 g of pasta + 200 g of spinach + 80 g of lean ricotta of vaccine milk Fri: 50 g of pasta + 80 g of lentils + 150 g of broccoli Sat: 100 g of pasta + 200 g of cabbage + 100 g of anchovies Sun: 100 g of rice + 50 g of shrimp + 50 g raccoon + 150 g of squid 400 ml of non-gassed water
Snack from 17.00 to 17.30
250 g apple without peel + 30 g almonds 400 ml of non-gassed water
Dinner h 20.00 - 21.00
Mon: 100 g of white bread + 300 g of cooked scarlings + 150 g of cod Tue: 50 g of white bread + 180 g of sepia + 150 g potatoes + 150 g of zucchini Wed: 100 g of white bread + 200 g of spinach + 100 g of vaccine dairy Thu: 100 g of white bread + 200 g of green chillies + 150 g of bream Fri: 50 g of white bread + 2 eggs + 70 g peas + 250 g of zucchini Sat: 1 daisy pizza Sun: 50 g of white bread + 150 g of salmon + 150 g potatoes + 100 g of lettuce 250 ml of non-gassed water
450 451 452 453
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Table 2. Second food plan followed by the participants (T2): a typical Mediterranean diet with the addition of some foods with an acidic pH for 2 weeks Treatment 2 (T2) Breakfast h 7.45 Snack h 11.00
3 white cracked slices + 1 cup partly skimmed milk + 1 banana 400 ml of non-gassed water 125 g white light yogurt + 100 g apple without peel 400 ml of non-gassed water + 1 lemon juice
Lunch h 13.15 - 14.00
Mon: 100 g of pasta + 200 g of broccoli + 100 g of chicken breast + 100 g of aubergines Tue: 50 g of pasta + 80 g of cannellini beans + 150 g peppers peeled Wed: 100 g rice + 200 g zucchini + 1 can of natural tuna, drained (50 g) Thu: 100 g of pasta + 200 g of spinach + 80 g of lean ricotta of vaccine milk Fri: 50 g of pasta + 80 g of lentils + 150 g of broccoli Sat: 100 g of pasta + 200 g of cabbage + 100 g of anchovies Sun: 100 g of rice + 50 g of shrimp + 50 g raccoon + 150 g of squid 400 ml of non-gassed water
Snack from 17.00 to 17.30
250 g apple without peel + 30 g almonds 400 ml of non-gassed water + 1 lemon juice
Dinner h 20.00 - 21.00
Mon: 100 g of white bread + 300 g of cooked scarlings + 150 g of cod Tue: 50 g of white bread + 180 g of sepia + 150 g potatoes + 150 g of zucchini Wed: 100 g of white bread + 200 g of spinach + 100 g of vaccine dairy product Thu: 100 g of white bread + 200 g of green chillies + 150 g of bream Fri: 50 g of white bread + 2 eggs + 70 g peas + 250 g of zucchini Say: 1 daisy pizza sun: 50 g of white bread + 150 g of salmon + 150 g potatoes + 100 g of lettuce
250 ml of non-gassed water Distributed fairly equally between lunch and dinner daily, with the addition of 150 g of fresh orange tomatoes eaten uncooked or cooked without seeds and without peel. 456 457 458
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Table 3. Third food plan followed by the participants (T3): a typical Mediterranean diet with the addition of some foods with a very low glycid content for 2 weeks Treatment 3 (T3) Breakfast h 7.45
1 cup of partially skimmed milk + 125 g white light yogurt + 20 g of almonds 400 ml of non-gassed water
Snack h 11.00
2x125 g white light yogurt 400 ml of non-gassed water
Lunch h 13.15 - 14.00
Mon: 100 g of broccoli + 200 g of chicken breast + 100 g of aubergines Tue: 100 g of green beans + 150 g peppers peeled + 2 eggs Wed: 200 g zucchini + 2 tuna can of natural 50 g drippled weight + 150 g fennel Thu: 250 g of spinach + 150 g of lean ricotta of vaccine milk Fri: 130 g bresaola + 100 g broccoli + 100 g zucchini Sat: 100 g of mushrooms + 100 g of cabbage + 350 g of anchovies Sun: 100 g of shrimp + 50 g raccoon + 350 g of squid 400 ml of non-gassed water
Snack from 17.00 to 17.30
125 g white light yogurt + 20 g almonds 400 ml of non-gassed water
Dinner h 20.00 - 21.00
Mon: 300 g of cooked scarlet + 250 g of cod Tue: 280 g of sepia + 150 g of green chili peppers + 150 g of zucchini Wed: 100 g pumpkin + 200 g vaccine dairy product Thu: 200 g of green chili peppers + 350 g of bream Fri: 2 eggs + 250 g of zucchini + 1 tuna can of natural 50 g dripped weight Sat: 240 g of calf + 200 g of spinach Sun: 350 g salmon + 100 g asparagus + 100 g lettuce 250 ml of non-gassed water
461 462 463 464 465
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466 467 468
Table 4. Fourth food plan followed by the participants (T4): a typical Mediterranean diet with the addition of some foods with a very low glycid content and some foods with an acidic pH for 2 weeks. Treatment 4 (T4) Breakfast h 7.45
1 cup of partially skimmed milk + 125 g white light yogurt + 20 g of almonds 400 ml of non-gassed water
Snack h 11.00
2x125 g white light yogurt 400 ml of non-gassed water + 1 lemon juice
Lunch h 13.15 - 14.00
Mon: 100 g of broccoli + 200 g of chicken breast + 100 g of aubergines Tue: 100 g of green beans + 150 g peppers peeled + 2 eggs Wed: 200 g zucchini + 2 tuna can of natural 50 g drippled weight + 150 g fennel Thu: 250 g of spinach + 150 g of lean ricotta of vaccine milk Fri: 130 g bresaola + 100 g broccoli + 100 g zucchini Sat: 100 g of mushrooms + 100 g of cabbage + 350 g of anchovies Sun: 100 g of shrimp + 50 g raccoon + 350 g of squid 400 ml of non-gassed water
Snack from 17.00 to 17.30
125 g white light yogurt + 20 g almonds 400 ml of non-gassed water + 1 lemon juice
Dinner h 20.00 - 21.00
Mon: 300 g of cooked scarlet + 250 g of cod Tue: 280 g of sepia + 150 g of green chili peppers + 150 g of zucchini Wed: 100 g pumpkin + 200 g vaccine dairy product Thu: 200 g of green chili peppers + 350 g of bream Fri: 2 eggs + 250 g of zucchini + 1 tuna can of natural 50 g dripped weight Sat: 240 g of calf + 200 g of spinach Sun: 350 g salmon + 100 g asparagus + 100 g lettuce
250 ml of non-gassed water Distributed fairly equally between lunch and dinner daily, with the addition of 150 g of fresh orange tomatoes eaten uncooked or cooked without seeds and without peel. 469 470 471 472
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473 474
Table 5. The Test of the Sign and the Wilcoxon Test of the Marked Ranks on 130 subjects with gastroesophageal disorders compared to time zero (T0) T2/T0*
Gastric heartburn Swelling of the upper abdominal area Eructation Mucus of GE origin 475
T3/T0*
T4/T0*
Test of the Sign
< 0,0001 < 0,0001 < 0,0001
Wilcoxon Test of Marked Ranks
< 0,0001 < 0,0001 < 0,0001
Test of the Sign Wilcoxon Test of Marked Ranks Test of the Sign Wilcoxon Test of Marked Ranks Test of the Sign Wilcoxon Test of Marked Ranks
< 0,0001 < 0,0001 0,314 0,518 0,362 0,311
< 0,0001 < 0,0001 < 0,0001 < 0,0001 < 0,0001 < 0,0001
< 0,0001 < 0,0001 < 0,0001 < 0,0001 < 0,0001 < 0,0001
* T2,T3 and T4 = Treatments 2, 3 and 4; T0 = time 0
476 477 478 479
Table 6. The Test of the Sign and the Wilcoxon Test of the Marked Ranks on 130 subjects with gastro-oesophageal disorders compared to washout periods (T1 (I), T1 (II) and T1 (III)) T2/T1(I) T3/T1(II) T4/T1(III) * * * Test of the Sign Wilcoxon Test Ranks Swelling of the upper abdominal Test of the Sign Wilcoxon Test area Ranks Test of the Sign Eructation Wilcoxon Test Ranks Test of the Sign Mucus of GE origin Wilcoxon Test Ranks
Gastric heartburn
480
< 0,0001
< 0,0001
< 0,0001
< 0,0001 < 0,0001
< 0,0001 < 0,0001
< 0,0001 < 0,0001
< 0,0001 0,210
< 0,0001 < 0,0001
< 0,0001 < 0,0001
0,670 0,008
< 0,0001 < 0,0001
< 0,0001 < 0,0001
0,105
< 0,0001
< 0,0001
of Marked
of Marked
of Marked
of Marked
* T2,T3 and T4 = Treatments 2, 3, and 4; T1(I), T1(II) and T1(III) = first, second and third washout period
481 482
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483 484
Table 7. Symptoms and symptom persistence rates: gastric heartburn, high-abdominal area swelling, eructation and mucus of GE origin Symptoms after treatment
Gastric heartburn
T2 T3 T4
1,000 0,861 0,476
Survival rates Swelling of the upper abdominal area 0,966 0,864 0,456
Eructation
Mucus of GE origin
0,931 0,974 0,412
0,941 0,918 0,470
485 486
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S0899-9007(18)30084-4 https://doi.org/10.1016/j.nut.2018.03.002 NUT 10147
To appear in:
Nutrition
Received date: Revised date: Accepted date:
3-11-2017 21-12-2017 6-3-2018
Please cite this article as: Ciro Langella, Daniele Naviglio, Marina Marino, Armando Calogero, Monica Gallo, New food approaches to reduce and/or eliminate increased gastric acidity related to gastroesophageal pathologies, Nutrition (2018), https://doi.org/10.1016/j.nut.2018.03.002. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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New food approaches to reduce and/or eliminate increased gastric acidity related to gastroesophageal pathologies Running Title: New food approaches for gastroesophageal pathologies
Ciro Langellaa, Daniele Navigliob, Marina Marinoc, Armando Calogerod and Monica Galloa*
a
Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, via Pansini, 5; 80131 Naples, Italy b Department of Chemical Sciences, University of Naples Federico II, Via Cintia 4; 80126 Naples, Italy c Department of Economic and Statistical Sciences, University of Naples Federico II, Via Cintia, 26; 80126 Naples, Italy d Department of Advanced Biomedical Sciences, University of Naples Federico II, via Pansini, 5; 80131 Naples, Italy *Corresponding author: Tel.: +39 81 7463117; Fax: +39 81 7463117; E-mail address: [email protected] (M. Gallo) Graphical Abstract
Highlights
Limited information is available on the effects of diets on acid-related gastropathies. Reduced glycidic content with the addition of acidic pH foods in gastroesophageal pathologies. 1 Page 1 of 18
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A negative correlation exists between acidic foods and secretion of gastric acid. Acid foods may be indicators of the presence of injuries to organs affected by inflammation. A proper diet with appropriate additions can improve the symptoms of gastroesophageal diseases.
ABSTRACT Objectives: Gastroesophageal reflux disease (GERD) or Gastro-Oesophageal Reflux Disease (GORD), is a disease of interest in gastroenterology that is caused by pathological complications of gastroesophageal reflux (GER). This study aims to assess the ability of reduced-carbohydrate diets and foods enriched with acid pH (lemon and tomato) to quickly and exponentially reduce the symptoms related to conditions such as gastritis and gastroesophageal reflux that are unrelated to Helicobacter pylori. Methods: Following the administration of an anamnestic test, 130 subjects were selected (73 women, 57 men), aged 21 to 67, with a gastritis diagnosis for 92 subjects and reflux gastritis for 38 subjects. Study participants followed 3 dietary treatments in succession. Each treatment lasted two weeks, and treatments were separated by two weeks of washout. The subjects followed a diet that included the exponential reduction of glycides (simple and complex). In addition, the treatment provided for the daily intake of the juice of two lemons and approximately 100 g of fresh orange tomato without seeds eaten either raw or cooked and peeled. Results: During the treatment and at the end of two weeks of treatment, the subjects reported significant improvements, including an almost total disappearance of symptoms related to the disease in question. Conclusions: This study shows that a carbohydrate-free diet and/or highly hypoglycidal diet enriched with acid pH foods seems to lead to a decrease in the pH of the gastric contents, thus inhibiting further production of hydrochloric acid with a reduction or disappearance of heartburn symptoms typical of gastroesophageal diseases.
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Keywords: Gastroesophageal reflux, Diet, Carbohydrate reduction, Lemon, Tomato, Anamnestic test. Abbreviations GERD GORD GER NERD ERD BMI T T0 GIP CCK PZ
Gastroesophageal Reflux Disease Gastro-Oesophageal Reflux Disease Gastroesophageal Reflux Non Erosive Reflux Disease Moderate Erosive Esophagitis Body Mass Index Treatment (Nutrition therapy) Initial state or time 0 Gastric Inhibitory Peptide Cholecystokinin Pancreozimine
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Introduction Gastroesophageal reflux disease (GERD) or Gastro-Oesophageal Reflux Disease (GORD), is a disease of interest in gastroenterology that is caused by pathological complications of gastroesophageal reflux (GER). It may have several clinical presentations: disphagia, cough, rhinitis, burning in the jugular region, chest pain that mimics a heart attack, otitis. Нe definition of GERD is: “a condition that develops when the reflux of stomach contents causes troublesome symptoms and/or complications” [1-3]. Нe most common symptoms are heartburn, regurgitation, and, sometimes, dysphagia. Extra-esophageal manifestations are bronchospasm, laryngitis and chonic cough. Other symptoms of GERD include chest pain, globus sensation, odynophagia, nausea, glossitis, burning mouth, otitis, postnasal drip, sinusitis, dysphonia and headache. For the diagnosis it is preferable to make at least a gastroscopy and also an upper abdominal ultrasound. Distinguishing cardiac from non-cardiac chest pain is required before considering GERD as a cause of chest pain. Although the symptom of dysphagia can be associated with uncomplicated GERD, its presence warrants investigation for a potential complication including an underlying motility disorder, stricture, ring, or malignancy [4]. The balance of evidence suggests that symptom frequency does not change as we age, however, the intensity of symptoms may decrease after the age of 50 [5]. There is a definite relationship between GERD and obesity. Several meta-analysis suggest an association between body mass index (BMI), waist circumference, weight gain and the presence of symptoms and complications of GERD including erosive GERD (ERD) and Barrett’s esophagus [6,7]. In a study by Labenz et al. (2004) was used logistic regression analysis to identify several independent risk factors for ERD. The odds for higher degrees of ERD increased as BMI rose [8]. Furthermore, it is of greatest concern that there has been a well-documented association between BMI and carcinoma of the esophagus and gastric cardia [9]. There is an overall increase in diagnoses due to the greater ease of inspection of the early digestive tract, but above all, increases in GERD are a consequence of modernity: poor lifestyle and dietary habits, stress conditions that derive from social organizations, working conditions, and generally from the frenetic rhythm of life. The data reported in the literature varies depending on geographic locations, observation points, and the statistical methods used. There is also some intrinsic uncertainty in the data: first, there is no universally accepted definition of gastroesophageal reflux disease, resulting in possible variations in the meaning and weight attributed to the parameters used, which can lead to different interpretations of the different case presentations; second, the spectrum of clinical manifestations experienced by people who do in fact meet the clinical profile of having GERD is very wide; third, no definite and fully reliable criteria are available to achieve the assurance of a diagnosis of GERD in the absence of oesophagitis. This condition, if taken as a single parameter, accompanied by occasional symptomatology or controlled by the spontaneous intake of antacids, leads to the exclusion of a proportion of patients. This is a condition that occurs in reflux disease without inflammation and erosions of the oesophagus called NERD (Non Erosive Reflux Disease), in which the negative endoscopic diagnosis becomes a factor of exclusion from the statistical surveys. GERD, considered esophagitis, is found in 50-75% of symptomatic adult subjects in industrialized countries and up to 40% of patients undergoing asymptomatic digestive endoscopy, an increase of three- or four-fold in the last twenty years [10-12]. For example, the overall growth trend in Italy can be estimated at an ascending factor equivalent to at least three times in the last 10 years [13].
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This trend is confirmed by rates of oesophageal ulcerations over 5%, and rates of cases with complications of interstitial lung disease and oesophageal stenosis between 8 and 20% [14]. The present study aims to assess the potency of highly hypoglycidal diets that are enriched with acid pH (lemon, tomato) foods to exponentially and quickly reduce the symptoms related to pathologies such as gastritis and gastroesophageal reflux not associated with Helicobacter pylori. Materials and methods Subject selection Initially, 250 potentially suitable non-smoking subjects were recruited for the study; all initial recruits reported gastrointestinal tract disorders, particularly of the stomach and oesophagus unrelated to Helicobacter pylori infection, with a clinical diagnosis of gastritis and gastritis with reflux, based on the gastroscopic examination performed within the last year. The subjects performed a daily intake of simple and complex carbohydrates of approximately 60-70% and followed the diet and lifestyle recommendations in accordance with the Guidelines for Subjects with Acid-Related Gastropathy: do not smoke, do not eat within two hours of resting, rest and sleep with a raised backrest, limit time in supine positions, chew slowly and completely, do not eat large meals, and finally, do not consume carbonated beverages, coffee (unless decaffeinated), alcoholic beverages, mints, acidic foods, cocoa and chocolate, spices, very cold or very hot foods, and do not chew gum [15]. Subsequently, according to the presented diagnostic responses, 130 subjects were included. Moreover, these 130 subjects had a common parameter, in fact they had performed gastroscopic examination within the last year, even if some had performed other valid diagnostic tests less invasive to obtain useful information for the purpose, such as pHmetry, cytokines, cell markers. In addition, body weight and BMI of the subjects were detected before and after each treatment (Table not shown). The participants included 73 women and 57 men aged 21 to 67, of whom 92 were diagnosed with gastritis (including 56 women and 36 men) and 38 were diagnosed with gastritis with reflux (17 women and 21 men). The study was conducted according to the guidelines laid down in the Declaration of Helsinki. A validated questionnaire was used to monitor the participants’ food plans. Participants were interviewed, and their responses were evaluated to monitor compliance with the study’s protocol. Finally, for evaluated the gastritis was examined the survey results on Likert scale questionnaires. Study design The participants followed 3 dietary treatments in succession (Treatment 2, 3 and 4) for two weeks each, and each treatment was interrupted by two weeks of washout, where participants followed a typical Mediterranean diet (Treatment 1) (Figure 1). To evaluate the effects of the dietary treatment, the symptoms of the participants were statistically analysed by administering a test before and after each dietetic treatment. Specifically, a test was administered before Treatment 1 (Test at time 0, T0) and then a series of tests was given after each dietary treatment as a means of comparison to define the results. < Insert Figure 1 > 4 Page 4 of 18
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Statistical analysis Non-parametric tests were performed on paired data, in particular the Test of the Sign and the Wilcoxon Test of the Marked Ranks on the sample in question of 130 subjects with diagnosed gastro-esophageal disorders. Results and Discussion Subject characteristics Some recent studies have identified the possible relationship between sugar consumption and gastric hyperacidity and the ability of a low-carbohydrate diet to increase the pH of the gastric lumen [16-20]. Unlike past and current suppositions [15, 21-23], there could be a negative correlation, both direct and indirect, between acidic foods and the secretion of gastric acid. Acid foods may be signallers indicating the presence of injuries to the organs affected by the flogosis: acid contacting the lesion causes increased perception of "burning" by direct irritant action on the gastric mucosa. On the other hand, they would represent an important protective and preventive factor [24-27]. A possible explanation for this may be that acidic foods, due to their acid nature, would favour a relatively low gastric acid pH, thus inhibiting the further production of hydrochloric acid. While keeping the pH of the gastric environment low, the gastrin (produced by the elevation of pH) is inhibited, or rather unsalted, by stimulating the parietal cells of the oxytocin glands to produce and secrete hydrochloric acid [28-30]. In contrast, the intake of basic foods and drugs containing basic molecules such as carbonated ions seems to generate a condition of "perceived well-being" in the short term only at the symptomatic level, leading to a "rebound" effect and instead inducing a gastric hypersecretion in response to the pH reduction of the gastric contents [27, 31, 32]. In addition, antacids such as sodium bicarbonate should be avoided, among other things, because they produce a gastric CO2 environment [31-35] that further stimulates acid secretion [3639]. In the present study, the statistical analysis of the anamnestic test data (Test 1) administered to all subjects showed the following symptoms: gastric heartburn, which increased due to the intake of certain foods, swelling of the upper abdominal area, eructations, mucus of GE origin, gastric heartburn and swelling of the high-abdominal area that were common to all subjects. At the end of each treatment period, a test (Test 2) was given. A typical Mediterranean diet for all participants (Treatment 1) was administered to the 130 subjects for two weeks and which was repeated as a washout period following each subsequent stage. After 2 weeks, to this diet were added some foods with an acidic pH for another 2 weeks (Treatment 2). After this treatment, subjects were prescribed a diet with a very low glycid content (Treatment 3) for another 2 weeks. Finally, following the final washout treatment, the participants followed the same low-glycidcontaining regime with the addition of the acidic foods prescribed in Treatment 2 (Treatment 4) (Tables 1-4). < Insert Tables 1-4 >
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Throughout the experimental period, subjects were asked to strictly comply with some of the general behaviours provided by specialists and healthcare institutions contained in the guidelines (12). At the end of the first washout period (Treatment 1, T1 (I)), no major changes were reported, i.e., the symptomatic disorders reported prior to treatment remained unchanged. During and after Treatment 2, 93 subjects reported increased gastric and burning sensitivity, while the other 37 reported no changes. At the end of the second washout period (Treatment 1, T1 (II)), almost all subjects (123 subjects) had the same symptoms as at the beginning of the study. During and at the end of Treatment 3, 118 participants reported significant improvements, recording a nearly total disappearance of the symptoms associated with the disease, while the remaining 12 participants did not notice any changes; i.e., they remained in the same situation prior to Treatment 3 itself. During and at the end of the third washout period (Treatment 1, T1 (III)), the 12 subjects who had not responded positively to Treatment 3 showed improvements including a feeling of relief, mainly due to the consumption of pasta, bread and farinaceous derivatives (which, however, have a rather short duration of only approximately 2 hours). While almost all subjects (110 out of 130) resumed their usual diet, they reported gastric disorders, both during and at the end of the third washout period (Treatment 1, T1 (III)). With Treatment 4, the same 12 subjects who had been suffering with discomforts up to Treatment 3 again experienced disturbances; in contrast, the remaining 118 subjects confirmed significant benefits with the nearly total elimination of glycides and even with the addition of acidic foods. During and at the end of Treatments 3 and 4, nearly all subjects (118 out of 130) reported significant improvements, recording the almost total disappearance of the symptoms related to the pathology in question. Body weight control The body weight of the 130 subjects was measured before and after each of the treatments. At the end of the first washout period (Treatment 1, T1 (I)), 49 subjects reported a decrease in body weight between 1.1 and 1.8 kg (including 9 of the 12 subjects who responded negatively to Treatment 3 and 4), and the remaining participants did not have a significant weight decrease (data not shown). At the end of Treatment 2, the weight of all subjects remained almost unchanged from the beginning of Treatment 2 as well as at the end of the second washout period (Treatment 1, T1 (II)). At the end of Treatment 3, 102 participants (including 12 subjects who did not note an improvement in symptoms) reported a decrease in body weight between 1.7 and 3.9 kg compared with the beginning of the same treatment. At the end of the third washout period (Treatment 1, T1 (III)), 113 subjects reported weight gains between 0.8 and 2.2 kg (including the 102 subjects following Treatment 3). The results of this latter case confirm that what is known is that low-carbohydrate diets, although they are effective for weight loss, do not offer lasting results because reintroducing carbohydrates leads to an increase in weight. Finally, at the end of Treatment 4, the weight variation affected only the same 113 subjects, who returned to about the same body weight determined at the end of Treatment 3.
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Data analysis The analysis of the test data showed that subjects’ responses after the 3 treatments were significantly different from the initial status (T0), indicating a significant improvement in the symptomatology evaluated through gastric heartburn, swelling of the upper abdominal area, eructation and mucus of GE origin. In fact, hypothesis tests conducted for all these symptoms allowed us to reject the null hypothesis that the distributions are the same (Table 5). < Insert Table 5 > Specifically, evaluating Treatment 2 (typical Mediterranean diet with the addition of acidic foods) compared to time zero (T0), there was significant improvement only for two symptoms: swelling and eructation. On the other hand, with Treatment 3 (low glycaemic diet) and Treatment 4 (very low content of glycids with acidic additions), all disorders significantly improved compared to the initial status of the subjects (Table 5). Next, the answers to questions related to these symptoms were analysed at the end of each treatment with respect to the responses given during the washout period preceding the treatment in question (T1 (I), T1 (II) and T1 (III)). Again, the tests were significant, suggesting that the distributions of the sample before and after the treatment were significantly different (Table 6). < Insert Table 6 > Analysing the subjects’ responses at the end of Treatment 2 with respect to the first washout period (T1 (I)), it was shown that swelling and haemorrhage improved, while the other two symptoms persisted. Only with Treatment 3 and Treatment 4, evaluated, respectively, with washout periods (Treatment 1, T1 (II) and T1 (III)), were all symptoms improved significantly. In fact, the tests carried out led to the rejection of the null hypothesis of equality between distributions for all disorders. In addition to non-parametric tests, a survival analysis was conducted to determine the survival time of the symptoms analysed following each treatment. With this type of analysis, the probability of the single symptom occurring after a certain observation time from time zero was evaluated. Below is a table and relative graphs (not shown) with the survival rates of the respective symptoms (Table 7). < Insert Table 7 > As seen after Treatment 2, all symptoms had a survival rate of more than 90%, while this rate dropped after Treatment 3, except for the eructation rate, which instead rose by 4 percentage points. All symptoms were significantly reduced after Treatment 4, resulting in a survival rate of less than 50%, meaning that with Treatment 4, all the disorders reported at time zero (T0) were disappearing only with Treatment 4, that is, with a very low glycide content diet with the addition of acidic foods. In the present study, the biochemical processes of digestion in the concerned organs, or the influence of the nervous system on the digestive processes, were not analyzed. Therefore, we can 7 Page 7 of 18
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only hypothesize the mechanism according to which carbohydrates, and other nutrients, such as fats, are directly or indirectly responsible for the increase of gastric acidity. In fact, it is probable that carbohydrate consumption is crucial for the stimulation of gastric cells and for the production of gastric juices, by means of cephalic-vagal stimulation. On the other hand, having administered to volunteers, diets consisting mainly of protides and lipids, it is reasonable to assume that, especially by means of the latter, the reduced gastric production of hydrochloric acid is also due to the inhibitory action of hormones, such as Gastric Inhibitory Peptide (GIP) and cholecystokinin. At a later time, the GIP, stimulated by the presence of fats, has the function of inhibiting the secretion of oxyntic cells of the stomach, and the cholecystokinin (CCK) or pancreozimine (PZ), secreted by the duodenum (and in lesser quantity from the jejunum), after a meal rich above all in fats, determines, among other things, by vagal stimulation, the sense of satiety [40]. However, the limitation of this study is the possibility of demonstrating the ability of such diet treatments to reduce also the "condition" of the same pathologies, not having carried out clinical examinations on subjects recruited before during and after the dietary treatment. Therefore, this will be the goal of one of the next studies. Furthermore, further studies will be useful to evaluate both the possibility of using dietary approaches to very low carbohydrate content as short-term treatments with therapeutic aim to reduce and/or eliminate symptoms and disorders related to these pathologies, but above all the ability of such strategies to determine the remission of the same pathologies. Conclusions The results obtained in this study affirm that diets with very low content of glycids and enriched with acidic foods with reduced glycide content can significantly reduce the symptoms associated with gastroesophageal disease. In addition, fats and proteins, the main constituents of the dietary approach used, did not adversely affect those that were the targets to be observed, that is, they did not increase or cause the typical symptoms reported by people with gastropathies such as gastroesophageal burns and reflux. In conclusion, this study shows that a diet free of carbohydrates and enriched with acidic foods with reduced glycide content significantly reduces gastric heartburn related to the ailments under examination, and therefore probably gastric acidity, thus increasing the pH of the gastric lumen. However, this conclusion comes from preliminary data, so further studies should be conducted in the future to confirm the results obtained and the timing of the dietary approach. Most likely, the merit of the success of the dietary approach used in this study could be attributed to the almost absence of glycids in the diet. This factor would explain why, to date, the ability of acidic pH foods to reduce gastric acidity was not fully effective in diets with regular or high consumption of carbohydrates and/or acidic foods with medium or high glycidic content. However, this is not to say that diets lacking in carbohydrates sustained for long periods can be considered correct for a healthy lifestyle, nor do they substitute for a balanced diet such as the Mediterranean type, with its balance in favour of carbohydrates and fibre. However, surely this work can lay new foundations for effective treatments against many acid-related gastropathies. Acknowledgements The authors acknowledge the volunteers who participated in this study. 8 Page 8 of 18
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Compliance with ethical standards The authors have no funding, financial relationships, or conflicts of interest to disclose.
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[17] Austin GL, Thiny MT, Westman EC, Yancy WS, Shaheen NJ. A very low-carbohydrate diet improves gastroesophageal reflux and its symptoms. Digestive Diseases and Sciences 2006;51(8):1307–1312. [18] Song JH, Chung SJ, Lee JH, Kim YH, Chang DK, Son HJ, Kim JJ, Rhee JC, Rhee PL. Relationship between gastroesophageal reflux symptoms and dietary factors in Korea. Journal of Neurogastroenterology and Motility 2011;17(1): 54–60. [19] Shon SM, Song CW, Koo JS, Choung RS, Shin JH, Kim YB, Chun HJ, Lee SW, ChoiJH, Kim CD, Ryu HS, Hyun JH. Gastroesophageal acid reflux according to different meals: flour cake vs rice cake. Kor J Neurogastroenterol Motil 2001;7(2):181–187. [20] Punjabi P, Hira A, Prasad S, Wang X, Chokhavatia, S. Review of gastroesophageal reflux disease (GERD) in the diabetic patient. Journal of Diabetes 2015);7(5):599–609. [21] Katz PO, Gerson LB, Vela MF. Guidelines for the diagnosis and management of gastroesophageal reflux disease. The American journal of gastroenterology 2013;108(3):308– 328. [22] DeVault KR, Castell DO. Updated guidelines for the diagnosis and treatment of gastroesophageal reflux disease. Am J Gastroenterol. 2005;100(1):190–200. [23] Waldum HL, Hauso Ø, Fossmark R. The regulation of gastric acid secretion–clinical perspectives. Acta physiologica 2014; 210(2):239–256. [24] Murphy SJ, Anderson LA, Ferguson HR, Johnston BT, Watson PR, McGuigan J, Comber H, Reynolds JV, Murray RJ, Cantwell MM. Dietary antioxidant and mineral intake in humans is associated with reduced risk of esophageal adenocarcinoma but not reflux esophagitis or Barrett's esophagus. The Journal of Nutrition 2010;140(10):1757–1763. [25] Wang A, Zhu C, Fu L, Wan X, Yang X, Zhang H, Miao R, He L, Sang X, Zhao H. Citrus fruit intake substantially reduces the risk of esophageal cancer: A meta-analysis of epidemiologic studies. Medicine 2015; 94(39):e1390. [26] Corvaglia L, Monari C, Martini S, Aceti A, Faldella G. Pharmacological therapy of gastroesophageal reflux in preterm infants. Gastroenterology Research and Practice 2013; 2013: 714564. [27] Orlando RC. The integrity of the esophageal mucosa. Balance between offensive and defensive mechanisms. Best Practice & Research Clinical Gastroenterology 2010; 24(6):873–882. [28] Urushidani T, Forte JG, Sachs G. (Eds.). Mechanisms and consequences of proton transport. Springer Science & Business Media 2012. [29] Sleisenger MH, Feldman M, Friedman LS, Brandt LJ. Sleisenger & Fordtran's gastrointestinal and liver disease. Saunders 2006. [30] Hammer GD, McPhee SJ. Pathophysiology of disease: An introduction to clinical medicine 7/E (pp. 145–146). McGraw Hill Professional 2014. [31] Erickson-Levendoski E, Sivasankar MP. Role for ion transport in porcine vocal fold epithelial defense to acid challenge. Otolaryngology--Head and Neck Surgery 2012;146(2):272–278. [32] Coppolino G, Lucisano S, Rivoli L, Fuiano G, Villari A, Villari I, Leonello G, Lacquaniti A, Santoro D, Buemi M. Sevalamer hydrochloride, sevelamer carbonate and lanthanum carbonate: in vitro and in vivo effects on gastric environment. Therapeutic Apheresis and Dialysis 2015;19(5):471–476. [33] Christie KN, Thomson C, Xue L, Lucocq JM, Hopwood D. Carbonic anhydrase isoenzymes I, II, III, and IV are present in human esophageal epithelium. J Histochem Cytochem. 1997;45(1):35–40. [34] Zentilin P, Dulbecco P, Savarino E, Parodi A, Iiritano E. Bilardi C, Reglioni S, Vigneri S, Savarin V. An evaluation of the antireflux properties of sodium alginate by means of combined multichannel intraluminal impedance and pH-metry. Alimentary Pharmacology and Therapeutics. 2005;21(1):29–34. [35] Christie KN, Thomson C, Morley S, Anderson J, Hopwood D. Carbonic anhydrase is present in human oesophageal epithelium and submucosal glands. Histochem J. 1995;27:587–90. 10 Page 10 of 18
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[36] Fordtran JS, Morawski SG, Santa Ana CA, Rector FC. Gas production after reaction of sodium bicarbonate and hydrochloric acid. Gastroenterology 1984;87(5):1014–1021. [37] Pillai A, Bogod D. (2015). Chestnut′s Obstetric Anesthesia: Principles and Practice. British Journal of Anaesthesia 2015;114(5):861. [38] Ajala TO, Silva BO. The effect of pharmaceutical properties on the acid neutralizing capacity of antacid oral suspensions. Journal of Pharmaceutical Investigation 2015;45(5):433–439. [39] Akiba Y, Mizumori M, Kuo M, Ham M, Guth PH, Engel E, Kaunitz JD. CO2 chemosensing in rat oesophagus. Gut 200;57(12):1654–1664. [40] Pocock G, Richards CD, Richards DA. Human physiology. Oxford University Press 2013.
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442 443
Figure 1. The treatments followed by the subjects. Each treatment lasts two weeks separated by two weeks of washout
444 445 446 447
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448 449
Table 1. First food plan followed by the participants (T1): a typical Mediterranean diet for 2 weeks (washout period) Treatment 1 (T1) Breakfast h 7.45
3 white bread slices + 1 cup partly skimmed milk + 1 banana 400 ml of non-gassed water
Snack h 11.00
125 g white light yogurt + 100 g apple without peel 400 ml of non-gassed water
Lunch h 13.15 - 14.00
Mon: 100 g of pasta + 200 g of broccoli + 100 g of chicken breast + 100 g of aubergines Tue: 50 g of pasta + 80 g of cannellini beans + 150 g peppers peeled Wed: 100 g rice + 200 g zucchini + 1 tuna can of natural 50 g drained weight Thu: 100 g of pasta + 200 g of spinach + 80 g of lean ricotta of vaccine milk Fri: 50 g of pasta + 80 g of lentils + 150 g of broccoli Sat: 100 g of pasta + 200 g of cabbage + 100 g of anchovies Sun: 100 g of rice + 50 g of shrimp + 50 g raccoon + 150 g of squid 400 ml of non-gassed water
Snack from 17.00 to 17.30
250 g apple without peel + 30 g almonds 400 ml of non-gassed water
Dinner h 20.00 - 21.00
Mon: 100 g of white bread + 300 g of cooked scarlings + 150 g of cod Tue: 50 g of white bread + 180 g of sepia + 150 g potatoes + 150 g of zucchini Wed: 100 g of white bread + 200 g of spinach + 100 g of vaccine dairy Thu: 100 g of white bread + 200 g of green chillies + 150 g of bream Fri: 50 g of white bread + 2 eggs + 70 g peas + 250 g of zucchini Sat: 1 daisy pizza Sun: 50 g of white bread + 150 g of salmon + 150 g potatoes + 100 g of lettuce 250 ml of non-gassed water
450 451 452 453
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454 455
Table 2. Second food plan followed by the participants (T2): a typical Mediterranean diet with the addition of some foods with an acidic pH for 2 weeks Treatment 2 (T2) Breakfast h 7.45 Snack h 11.00
3 white cracked slices + 1 cup partly skimmed milk + 1 banana 400 ml of non-gassed water 125 g white light yogurt + 100 g apple without peel 400 ml of non-gassed water + 1 lemon juice
Lunch h 13.15 - 14.00
Mon: 100 g of pasta + 200 g of broccoli + 100 g of chicken breast + 100 g of aubergines Tue: 50 g of pasta + 80 g of cannellini beans + 150 g peppers peeled Wed: 100 g rice + 200 g zucchini + 1 can of natural tuna, drained (50 g) Thu: 100 g of pasta + 200 g of spinach + 80 g of lean ricotta of vaccine milk Fri: 50 g of pasta + 80 g of lentils + 150 g of broccoli Sat: 100 g of pasta + 200 g of cabbage + 100 g of anchovies Sun: 100 g of rice + 50 g of shrimp + 50 g raccoon + 150 g of squid 400 ml of non-gassed water
Snack from 17.00 to 17.30
250 g apple without peel + 30 g almonds 400 ml of non-gassed water + 1 lemon juice
Dinner h 20.00 - 21.00
Mon: 100 g of white bread + 300 g of cooked scarlings + 150 g of cod Tue: 50 g of white bread + 180 g of sepia + 150 g potatoes + 150 g of zucchini Wed: 100 g of white bread + 200 g of spinach + 100 g of vaccine dairy product Thu: 100 g of white bread + 200 g of green chillies + 150 g of bream Fri: 50 g of white bread + 2 eggs + 70 g peas + 250 g of zucchini Say: 1 daisy pizza sun: 50 g of white bread + 150 g of salmon + 150 g potatoes + 100 g of lettuce
250 ml of non-gassed water Distributed fairly equally between lunch and dinner daily, with the addition of 150 g of fresh orange tomatoes eaten uncooked or cooked without seeds and without peel. 456 457 458
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459 460
Table 3. Third food plan followed by the participants (T3): a typical Mediterranean diet with the addition of some foods with a very low glycid content for 2 weeks Treatment 3 (T3) Breakfast h 7.45
1 cup of partially skimmed milk + 125 g white light yogurt + 20 g of almonds 400 ml of non-gassed water
Snack h 11.00
2x125 g white light yogurt 400 ml of non-gassed water
Lunch h 13.15 - 14.00
Mon: 100 g of broccoli + 200 g of chicken breast + 100 g of aubergines Tue: 100 g of green beans + 150 g peppers peeled + 2 eggs Wed: 200 g zucchini + 2 tuna can of natural 50 g drippled weight + 150 g fennel Thu: 250 g of spinach + 150 g of lean ricotta of vaccine milk Fri: 130 g bresaola + 100 g broccoli + 100 g zucchini Sat: 100 g of mushrooms + 100 g of cabbage + 350 g of anchovies Sun: 100 g of shrimp + 50 g raccoon + 350 g of squid 400 ml of non-gassed water
Snack from 17.00 to 17.30
125 g white light yogurt + 20 g almonds 400 ml of non-gassed water
Dinner h 20.00 - 21.00
Mon: 300 g of cooked scarlet + 250 g of cod Tue: 280 g of sepia + 150 g of green chili peppers + 150 g of zucchini Wed: 100 g pumpkin + 200 g vaccine dairy product Thu: 200 g of green chili peppers + 350 g of bream Fri: 2 eggs + 250 g of zucchini + 1 tuna can of natural 50 g dripped weight Sat: 240 g of calf + 200 g of spinach Sun: 350 g salmon + 100 g asparagus + 100 g lettuce 250 ml of non-gassed water
461 462 463 464 465
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466 467 468
Table 4. Fourth food plan followed by the participants (T4): a typical Mediterranean diet with the addition of some foods with a very low glycid content and some foods with an acidic pH for 2 weeks. Treatment 4 (T4) Breakfast h 7.45
1 cup of partially skimmed milk + 125 g white light yogurt + 20 g of almonds 400 ml of non-gassed water
Snack h 11.00
2x125 g white light yogurt 400 ml of non-gassed water + 1 lemon juice
Lunch h 13.15 - 14.00
Mon: 100 g of broccoli + 200 g of chicken breast + 100 g of aubergines Tue: 100 g of green beans + 150 g peppers peeled + 2 eggs Wed: 200 g zucchini + 2 tuna can of natural 50 g drippled weight + 150 g fennel Thu: 250 g of spinach + 150 g of lean ricotta of vaccine milk Fri: 130 g bresaola + 100 g broccoli + 100 g zucchini Sat: 100 g of mushrooms + 100 g of cabbage + 350 g of anchovies Sun: 100 g of shrimp + 50 g raccoon + 350 g of squid 400 ml of non-gassed water
Snack from 17.00 to 17.30
125 g white light yogurt + 20 g almonds 400 ml of non-gassed water + 1 lemon juice
Dinner h 20.00 - 21.00
Mon: 300 g of cooked scarlet + 250 g of cod Tue: 280 g of sepia + 150 g of green chili peppers + 150 g of zucchini Wed: 100 g pumpkin + 200 g vaccine dairy product Thu: 200 g of green chili peppers + 350 g of bream Fri: 2 eggs + 250 g of zucchini + 1 tuna can of natural 50 g dripped weight Sat: 240 g of calf + 200 g of spinach Sun: 350 g salmon + 100 g asparagus + 100 g lettuce
250 ml of non-gassed water Distributed fairly equally between lunch and dinner daily, with the addition of 150 g of fresh orange tomatoes eaten uncooked or cooked without seeds and without peel. 469 470 471 472
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473 474
Table 5. The Test of the Sign and the Wilcoxon Test of the Marked Ranks on 130 subjects with gastroesophageal disorders compared to time zero (T0) T2/T0*
Gastric heartburn Swelling of the upper abdominal area Eructation Mucus of GE origin 475
T3/T0*
T4/T0*
Test of the Sign
< 0,0001 < 0,0001 < 0,0001
Wilcoxon Test of Marked Ranks
< 0,0001 < 0,0001 < 0,0001
Test of the Sign Wilcoxon Test of Marked Ranks Test of the Sign Wilcoxon Test of Marked Ranks Test of the Sign Wilcoxon Test of Marked Ranks
< 0,0001 < 0,0001 0,314 0,518 0,362 0,311
< 0,0001 < 0,0001 < 0,0001 < 0,0001 < 0,0001 < 0,0001
< 0,0001 < 0,0001 < 0,0001 < 0,0001 < 0,0001 < 0,0001
* T2,T3 and T4 = Treatments 2, 3 and 4; T0 = time 0
476 477 478 479
Table 6. The Test of the Sign and the Wilcoxon Test of the Marked Ranks on 130 subjects with gastro-oesophageal disorders compared to washout periods (T1 (I), T1 (II) and T1 (III)) T2/T1(I) T3/T1(II) T4/T1(III) * * * Test of the Sign Wilcoxon Test Ranks Swelling of the upper abdominal Test of the Sign Wilcoxon Test area Ranks Test of the Sign Eructation Wilcoxon Test Ranks Test of the Sign Mucus of GE origin Wilcoxon Test Ranks
Gastric heartburn
480
< 0,0001
< 0,0001
< 0,0001
< 0,0001 < 0,0001
< 0,0001 < 0,0001
< 0,0001 < 0,0001
< 0,0001 0,210
< 0,0001 < 0,0001
< 0,0001 < 0,0001
0,670 0,008
< 0,0001 < 0,0001
< 0,0001 < 0,0001
0,105
< 0,0001
< 0,0001
of Marked
of Marked
of Marked
of Marked
* T2,T3 and T4 = Treatments 2, 3, and 4; T1(I), T1(II) and T1(III) = first, second and third washout period
481 482
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483 484
Table 7. Symptoms and symptom persistence rates: gastric heartburn, high-abdominal area swelling, eructation and mucus of GE origin Symptoms after treatment
Gastric heartburn
T2 T3 T4
1,000 0,861 0,476
Survival rates Swelling of the upper abdominal area 0,966 0,864 0,456
Eructation
Mucus of GE origin
0,931 0,974 0,412
0,941 0,918 0,470
485 486
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