Clinical Outcomes and Food Triggers Following Low Food Chemical Diet Implementation: A Retrospective Audit of Dietetic Practice

ABSTRACT

Introduction

Food hypersensitivity describes a range of nonimmune food related reactions of varying aetiology causing gastrointestinal and extraintestinal symptoms. This study aimed to evaluate if the low‐chemical diet improves gastrointestinal and/or extraintestinal symptoms, and whether specific food challenges induce symptoms.

Methods

A retrospective clinical audit was conducted on files from 2011 to 2022 from a gastrointestinal specialist dietetic practice. Fifty eligible patient files were identified, all of whom had been recommended to follow a low‐chemical diet. One research dietitian extracted data on diet implementation, symptom change during the Restrictive Phase, and symptom provocation during the Rechallenge Phase. Descriptive statistics were used.

Results

The cohort was predominantly female (80%), mean age 47 years (range 7–85). At baseline the most common gastrointestinal symptom was diarrhoea (22/50, 44%), and extraintestinal symptom was nasal congestion (14/50, 28%). Improvement in at least one symptom following the Restrictive Phase occurred in 88% (44/50). The Restrictive Phase was followed for 2–78 weeks, and unintentional weight loss was documented in 24% (2–10 kg). The Rechallenge Phase duration ranged from 5 to 191 weeks, with 96% (48/50) reporting symptom provocation following at least one challenge. Salicylate challenge most commonly induced diarrhoea (16%), bloating (16%), and itch (14%), while amine challenge induced abdominal pain (10%) and nausea (8%).

Conclusion

Patients reported an improvement in gastrointestinal and extraintestinal symptoms, but commonly experienced prolonged dietary restriction. Rechallenge with salicylates and amines provoked symptoms; but this may be confounded by other diet and non‐diet factors. High‐quality trials with isolated food chemical components are needed.

Summary

• Despite limited data, a low food chemical diet is used in clinical practice, particularly in the Australian setting, to manage a range of gastrointestinal and extraintestinal symptoms.

• The results from this single‐centre audit suggest the low food chemical diet can reduce a range of symptoms, but that patients commonly experience prolonged dietary restriction.

• Rechallenge of the food chemical subgroups can identify food triggers, with salicylates and amines most commonly identified as key triggers.

• This study highlights rationale and need for high‐quality trials investigating the role of food chemicals in food intolerances.

1. Introduction

Food hypersensitivity is thought to affect approximately 15%–20% of the global population and describes a wide range of nonimmune adverse food‐related reactions of varying aetiology [1]. Food hypersensitivities are proposed to be mediated by metabolic (i.e., enzyme deficiencies, such as lactose malabsorption), pharmacological (i.e., sensitivity to natural or artificial chemicals in foods), or undefined/idiopathic mechanisms [2]. Symptoms of food hypersensitivity may be evident immediately or delayed postexposure [3]. Gastrointestinal symptoms of food hypersensitivity such as diarrhoea, bloating, vomiting, nausea, abdominal cramping and pain are common, and extraintestinal symptoms affecting the nervous system (e.g. headache, migraine, fatigue), skin (e.g. urticaria, rash, eczema, swelling, mouth ulcers), and respiratory system (e.g. nasal congestion, mucous, asthma) can also occur [4, 5]. There are no known biological markers for diagnosis to confirm food hypersensitivity [3, 6]. Since there is heterogeneity in clinical presentation, severity, underlying aetiology, and related dietary triggers, the diagnosis and management of food hypersensitivity is challenging [3].

Food hypersensitivity is prevalent across a range of clinical conditions, such as irritable bowel syndrome (IBS), chronic urticaria, and aspirin‐exacerbated respiratory disease (AERD) [4]. It is also thought to occur in response to a variety of foods and food components, including lactose, fructose, wheat, fermentable carbohydrates (FODMAPs), caffeine, and food chemical components, both naturally occurring (i.e., salicylates, glutamates, and vaso‐active amines), and added (i.e., monosodium glutamate (MSG), propionates) [3, 5]. Salicylate hypersensitivity may involve features of pseudo allergy and hypersensitivity, whereby ingestion of salicylates inhibits the enzyme cyclo‐oxygenase (COX), reducing the synthesis of anti‐inflammatory prostaglandins and increasing pro‐inflammatory mediators, such as eosinophils and mast cells [6]. Histamine hypersensitivity ostensibly occurs via an imbalance in the amount of histamine ingested and a reduced ability of the body to degrade histamine [7], while hypersensitivity to MSG has been postulated to be related to neurotoxic and neuroexcitatory properties of MSG in animal studies [8]. Further high‐quality research is needed to better understand the precise pathophysiological mechanisms of symptom induction in response to dietary triggers.

Food hypersensitivity cannot be cured, but typically, symptoms may be resolved following dietary elimination (e.g., the low‐chemical diet) and reproduced with challenge to offending foods [3]. In Australia, low‐chemical diets known as “The Royal Prince Alfred Hospital (RPAH) Diet”, “The Elimination Diet”, or “FAILSAFE” diet have been commonly used in clinical practice since the 1980s [9]. The initial Restrictive Phase of the low‐chemical diet involves short‐term restriction (at least 2 weeks) of specific food chemical components and dietary additives [10]. The prescribing dietitian determines the level of restriction (simple, moderate, or strict) based on clinical symptom patterns and patient preference, and may recommend adjunctive restriction of other common dietary triggers, such as wheat, dairy, and soy [10]. The Restrictive Phase is followed by a Rechallenge Phase, which is generally commenced after a period of symptom improvement or resolution. The Rechallenge Phase involves systematic reintroduction of food chemical components in graduated quantities to assess tolerance and inform the development of an individually modified diet and longer‐term dietary liberalisation [10]. The Rechallenge Phase is predicated on the fact that food hypersensitivity reactions are likely dose‐dependent, with variance in an individual's ‘threshold’ for food chemical quantity ingested/accumulated before a symptom reaction will occur [10].

The low‐chemical diet is a lengthy intervention, with limited data to support its efficacy. Therefore, concerns exist that individuals who follow the diet, especially without appropriate monitoring and follow‐up from an expert dietitian [11, 12], are at risk of prolonged, unnecessary dietary restriction and subsequent limited food variety and nutritional inadequacy [3, 12]. Accordingly, this retrospective clinical file audit of a specialist gastrointestinal dietetic practice aimed to (a) evaluate if the low‐chemical diet improves gastrointestinal or extraintestinal symptoms, and if so, identify which symptoms were alleviated; and (b) evaluate whether challenges with specific food chemical components induce gastrointestinal or extraintestinal symptoms to determine individual food triggers.

2. Methods

The study protocol was approved by the La Trobe University Human Ethics Committee on the 4th of May 2021 (HEC21107) and complied with STROBE reporting guidelines. A retrospective chart review of a convenience sample of patients referred to a dietetic clinic in Australia between January 2011 and December 2022 was completed. The dietetic clinic was a private health service with dietitians who specialize in gastrointestinal disorders and food intolerance. Patients were considered eligible for inclusion if they had documented use of the low‐chemical diet, including the initial Restrictive Phase and/or Rechallenge Phase. To obtain a wide breadth of data regarding the use of the low‐chemical diet no exclusion criteria were used.

All patients included were recommended to follow a low‐chemical diet by an individual allergist who has worked solely in this field for over 40 years, and implementation of the Restrictive Phase was guided by the allergy clinic's practice manager. Referrals were then made to the dietetic clinic for assistance in conducting the Rechallenge Phase of the diet. Initial appointments with the dietitian were scheduled to be 60 min in length, with subsequent review appointments of 30 min. A standard procedure was used to challenge individual food chemicals, with adjustments made per individual as deemed necessary (Supporting Information S2: Table 1). Electronic medical records were initially screened for eligibility by the practice manager of the dietetic clinic, who deidentified the files and extracted relevant data, including patient sex, age, number of appointments, general practitioner (GP), referrer, and clinical notes, using Microsoft Word. Data extraction criteria were developed by two research dietitians, and, for consistency, subsequent data extraction and analyses and ratings relating to how the low‐chemical diet was trialled and efficacy of the approach were undertaken independently by one research dietitian using Microsoft Excel.

The main outcome measures were whether the Restrictive Phase was implemented (yes/no), the duration of the Restrictive Phase (number of weeks), who recommended and who guided the Restrictive Phase (e.g., allergist vs. dietitian vs. GP), dietitian rated adherence to the Restrictive Phase (not at all, some of the time, most of the time (i.e., a documented occasion of moderate/high food chemical food(s) intake, all of the time (i.e., no documented occasions of moderate/high food chemical food(s) intake), or unclear), whether the Restrictive Phase achieved any symptom improvement (yes/no), which specific gastrointestinal or extraintestinal symptoms improved, and by how much (not at all, some improvement, significant improvement, or unclear). Additional outcomes related to the Rechallenge Phase included whether the Rechallenge Phase was implemented (yes/no), the total duration of the Rechallenge Phase (number of weeks), the number of challenges completed, the number of challenges repeated due to response at initial challenge (i.e., to confirm response in a second trial of the same food), and/or the number of challenges planned but incomplete (e.g. patient was lost to follow up), who recommended and guided the Rechallenge Phase, whether any challenges provoked symptoms (yes/no), specific gastrointestinal or extraintestinal symptoms related to each food chemical challenge, and whether the elimination diet provided a clear indication of specific food triggers (yes/no/unclear). Where available, specific gastrointestinal or extraintestinal symptoms related to each food chemical challenge were recorded. For patients where a specific response was not documented this was inferred from the presenting history/reason for referral and documented as ‘other’ extraintestinal or gastrointestinal symptom. For patients where it could not be inferred this data was omitted.

Quantitative data were presented as mean or median and range for continuous data and counts and proportions for categorical data. Proportions were calculated as a proportion of both total sample size and individuals who reported relevant baseline symptoms, and totalled more than 100%, reflective of patients having multiple symptoms, reacting to more than one food chemical component and/or undergoing more than one challenge with a single food chemical component. A sample of 50 eligible patient files were identified. No formal power calculation was performed as this was a retrospective audit aimed at describing real‐world clinical practice rather than testing specific hypotheses. The sample size was determined based on feasibility and available resources for detailed chart review. All data analyses were calculated using Microsoft Excel and heatmaps were generated using GraphPad Prism version 10.0.0 for Macintosh.

3. Results

A total of 53 patient files from 2011 to 2022 were accessed. Fifty files were audited, and 3 files were excluded from analysis as they were initially referred for suspected food chemical hypersensitivity but did not involve use of a low‐chemical diet. The majority of patients were female (80%) and ranged in age from 7 to 85 years (median 49 years). The most common presenting complaint at initial assessment was IBS, reported by 20% of patients. The most common gastrointestinal symptoms at baseline were diarrhoea (44%), constipation (32%), bloating (30%), and abdominal pain (26%). Extraintestinal symptoms of nasal congestion (28%), fatigue/lethargy (22%), and itch (20%) were also commonly reported at baseline. Baseline symptom duration were documented in 54% of patient files and ranged from 6 months to “most of their life” that is, > 50 years. Patients attended a median of 5 (range 3–15) food chemical‐specific dietitian appointments. Patient file notes were documented in by a total of four dietitians (Table 1), all of whom had received in‐house training in food chemical sensitivity.

Table 1.

Patient characteristics (n = 50).

Demographics
Sex – female, n (%)			40 (80%)
Age at first appointment (years), mean (range)			47 (7‐85)
Presenting complaints, n (%)
Irritable bowel syndrome			10 (20%)
Fructose and/or lactose malabsorptiona			6 (12%)
Fibromyalgia			3 (6%)
Inflammatory bowel disease (Crohn's)			2 (4%)
Thyroidectomy			2 (4%)
Diverticulitis/diverticulosis			2 (4%)
Endometriosis			2 (4%)
Gluten intolerance			2 (4%)
Nut allergy/anaphylaxis			2 (4%)
Chronic sinus inflammation			2 (4%)
Other			19b
Number of attended food chemical specific dietitian appointments, median (range)			5 (3–15)

Baseline symptoms reported at initial dietitian consultation
Gastrointestinal, n (%)		Extraintestinal, n (%)
Diarrhoea	22 (44%)	Nasal congestion	14 (28%)
Constipation	16 (32%)	Fatigue/lethargy	11 (22%)
Bloating	15 (30%)	Itch	10 (20%)
Abdominal pain	13 (26%)	Urticaria/hives	9 (18%)
Nausea	8 (16%)	Rash	9 (18%)
Gas/wind	5 (10%)	Sinus/nasal pain/inflammation	8 (16%)
Loose stool	4 (8%)	Cough	7 (14%)
Abdominal cramping	4 (8%)	Post‐nasal drip	7 (14%)
Increased bowel urgency	4 (8%)	Mouth ulcers	6 (12%)
Burping	3 (6%)	Difficulty sleeping/sleep disturbances	6 (12%)
Vomiting	3 (6%)	Headache	5 (10%)
Reflux	2 (4%)	General swelling	5 (10%)
Indigestion	2 (4%)	Migraine	4 (8%)
Other	9c	Mood changes/irritable mood	4 (8%)
		Tongue/throat swelling	4 (8%)
		Mucous (sinus/nasal)	3 (6%)
		Brain fog	3 (6%)
		Facial swelling	3 (6%)
		Dry skin	2 (4%)
		Dry eyes	2 (4%)
		Tinnitus	2 (4%)
		Muscle/body aches	2 (4%)
		Eczema	2 (4%)
		Other	28d

^a Reported malabsorption via breath testing.

^b Including inflammatory colitis (n = 1), hives (n = 1), nasal staph infection (n = 1), asthma (n = 1), idiopathic urticaria (n = 1), hiatus hernia (n = 1), cessicle adenoma with ascending colon resection (n = 1), idiopathic anaphylaxis (n = 1), garlic anaphylaxis (n = 1), cholecystectomy (n = 1), disc bulge (n = 1), small bowel resection (n = 1), C. diff infection (n = 1), Kawasaki disease (n = 1), bariatric sleeve gastrectomy (n = 1), gastro‐oesophageal reflux disease (n = 1), nerve damage (n = 1), allergic rhinitis (n = 1), coeliac disease (n = 1) note n = 3 ‘unclear’ for coeliac disease as received a negative serology test while on a gluten free diet.

^c Including reflux (n = 2), indigestion (n = 2), mucous in stool (n = 1), ‘sensitive gut’ (n = 2), sticky stool (n = 1), borborygmi (n = 1).

^d Including rosacea (n = 2), shaking (n = 2), hot flushes (n = 2), irregular heartbeat/palpitations (n = 2), skin redness (n = 2), dizziness (n = 2), tingling (n = 1), nocturnal tongue chewing (n = 1), night sweats (n = 1), sleep talking (n = 1), hyperactivity (n = 1), angioedema (n = 1), blisters on tongue (n = 1), panic attack/anxiety (n = 1), fluid retention (n = 1), shortness of breath (n = 1), puffy eyes (n = 1), jaw clenching (n = 1), joint swelling (n = 1), unbalanced gait (n = 1), irritated throat (n = 1), unspecified skin symptoms (n = 1).

All patients completed the Restrictive Phase of the low‐chemical diet, with the duration ranging from 2 to 78 weeks (median 6.5 weeks (n = 38); Table 2). Most patients (66%) adhered to the Restrictive Phase ‘all of the time’, while 26% adhered ‘most of the time’ (Table 2). Fifty‐two percent of patients were also following another diet, most commonly a low or reduced FODMAP diet (28%); patients also reported following a low‐FODMAP diet in combination with gluten (6%), or gluten and dairy (6%) restriction (Table 2).

Table 2.

Low‐chemical diet restrictive phase (n = 50).

Was the Restrictive Phase of the diet used?	n (%)
Yes	50 (100%)
Duration of Restrictive Phase
Number of weeks, range	2‐78
How strictly was the Restrictive Phase followed?
Not at all	0 (0%)
Some of the time	0 (0%)
Most of the timea	13 (26%)
All of the time	33 (66%)
Unclearb	4 (8%)
Did the restrictive diet improve at least one symptom?
Yes	44 (88%)
No	0 (0%)
Unclearc	6 (12%)
Adjunct diets followed during low‐chemical diet
Patients following an adjunct diet	26 (52%)
Low or reduced FODMAP	14 (28%)
Low‐FODMAP + gluten free	3 (6%)
Low‐FODMAP + gluten free + dairy free	3 (6%)
Gluten free	2 (4%)
Dairy free	1 (2%)
Vegetarian	1 (2%)
Vegan	1 (2%)
5:2 fasting	1 (2%)

^a Most of the time = documented occasion where patient had consumed food(s) considered to be moderate/high in food chemicals components during the restrictive diet phase. Examples of foods consumed: wine, M&Ms, ANZAC biscuits, fresh fish, fruit and nut chocolate, salted nuts, alcohol, dairy milk, cappuccino, or fruits.

^b Unclear = no documentation on patient adherence to low‐chemical diet.

^c Unclear = no documentation on patient symptom change following Restrictive Phase.

Eighty‐eight percent (n = 44/50) of patients reported improvement in at least one symptom. Forty‐four percent of patients (n = 22/50) reported a significant improvement in their ‘overall’ (general/unspecified) symptoms. Individual symptoms that were reported to be most significantly improved included sinus/nasal pain/inflammation (8%, n = 4/50 of total sample; 50% n = 4/8 of those reporting symptom at baseline). Constipation (20%, n = 10/50 of total sample; 62%, n = 10/16 of those reporting symptom at baseline) was most often reported to be ‘not at all’ improved following the Restrictive Phase of the low‐chemical diet (Table 3). Unintentional weight loss following the Restrictive Phase of the low‐chemical diet was documented in 24% (n = 12) of patient files and ranged from 2 to 10 kg (Table 3).

Table 3.

Documented improvement in symptoms following low‐chemical diet restrictive phase.

		Improvement, n (%)
Symptom	Number of patients with symptom at baseline, n	No improvement at all		Some improvement		Significant improvement
		Of total patient sample (n = 50)	Of patients with symptom at baseline	Of total patient sample (n = 50)	Of patients with symptom at baseline	Of total patient sample (n = 50)	Of patients with symptom at baseline
‘Overall’ (general/unspecified)a				5 (10%)	N/A	22 (44%)	N/A
Extraintestinal
Sinus/nasal pain/inflammation	8					4 (8%)	4 (50%)
General swelling	5			2 (4%)	2 (40%)	3 (6%)	3 (60%)
Dry skin	2					2 (4%)	2 (100%)
Migraine	4	1 (2%)	1 (25%)			2 (4%)	2 (50%)
Headache	5	1 (2%)	1 (20%)			2 (4%)	2 (40%)
Rash	9					2 (4%)	2 (22%)
Itch	10					2 (4%)	2 (20%)
Lethargy/fatigue	11	1 (2%)	1 (9%)			2 (4%)	2 (18%)
Tingling	1					1 (2%)	1 (100%)
Dry eyes	2					1 (2%)	1 (50%)
Brain fog	3					1 (2%)	1 (33%)
Tongue swelling	4					1 (2%)	1 (25%)
Difficulty sleeping/sleep disturbances	6					1 (2%)	1 (16%)
Cough	7			2 (4%)	2 (28%)	1 (2%)	1 (14%)
Post‐nasal drip	7			1 (2%)	1 (14%)	1 (2%)	1 (14%)
Urticaria/hives	9					1 (2%)	1 (11%)
Nasal congestion	14					1 (2%)	1 (7%)
Eczema	2			1 (2%)
Mouth ulcer	6	1 (2%)
Gastrointestinal
General gastrointestinal symptoms	ND					3 (6%)	^
Diarrhoea	22	1 (2%)	1 (4%)	1 (2%)		2 (4%)	2 (9%)
Bloating	15			1 (2%)		1 (2%)	1 (6%)
Abdominal pain	13					1 (2%)	1 (7%)
Loose stools	4	1 (2%)	1 (25%)	1 (2%)	1 (25%)
Constipation	16	10 (20%)	10 (62%)	1 (2%)	1 (6%)

Note: percentages may not total 100% in instances where change in specific symptoms post Restrictive Phase were not documented. N/A = not applicable; ND = not documented; ^ = Unable to compare n (%) to baseline as n symptom not documented at baseline.

^a ‘Overall symptoms’ refers documented ‘overall’ improvement in symptoms and is not cumulative of individual symptoms.

All patients were educated by a dietitian for the Rechallenge Phase of the low‐chemical diet, with the duration of this phase ranging widely among patients from 5 to 191 weeks (median 39.5 weeks, Table 4). The number of challenges completed by patients ranged from 3 to 20 (median 10.5), and the number of challenges that were planned but incomplete ranged from 0 to 7 (median 2) (Table 4). Ninety‐six percent of patients reported provocation of symptoms following at least one food challenge (Table 4). The number of specific food challenges repeated or planned but incomplete are presented in Supporting Information S1: Table 2.

Table 4.

Low‐chemical diet—rechallenge phase (n = 50).

Was the Rechallenge Phase of the diet used? n (%)
Yes	50 (100%)
Duration of rechallenge diet phase
Number of weeks, median (range)a	39.5 (5–191)
Challenges, median (range)
Number of completed challenges	10.5 (3–20)
Number of repeated challenges	0 (0–3)
Number of planned but incomplete challengesb	2 (0–7)
Did any challenge provoke symptom response?
Yes	48 (96%)
No	2 (4%)

^a Data not documented for n = 2 patients.

^b Challenges that were documented as planned but were not completed before their final dietitian appointment.

Regarding gastrointestinal symptom provocation during the challenges, diarrhoea and bloating were most commonly reported following challenges with salicylates (each 16%), amine (cheese) (each 8%), and dairy (6% and 10% respectively), while wheat also provoked bloating in 6% of patients. Gas was most reported following challenges with salicylates (12%), amine (banana) (8%), metabisulphites (6%), and propionate (6%). Abdominal pain was reported following challenge with amine (cheese) (10%), salicylates (8%), dairy (8%), and metabisulphites (8%), while nausea was most reported following amine (banana) (8%) challenge (Figure 1a).

Figure 1.

(A) Heatmap of the prevalence of gastrointestinal symptoms following rechallenge with dietary triggers after implementation of a low‐chemical diet (n = 50). (B) Heatmap of the prevalence of extraintestinal symptoms following rechallenge with dietary triggers after implementation of a low‐chemical diet (n = 50). Specific symptoms induced were unclear for n = 7 challenges among n = 6 patients with a mixed history of gastrointestinal and extraintestinal symptoms. This data is not included in heatmaps.

Regarding extraintestinal symptom provocation during the challenges, symptoms of itch were most commonly reported following challenge with salicylates (14%), amine (chocolate) (8%), and fish (8%); headache was also reported following challenge with salicylates (12%) and fish (10%), as well as glutamate (6%), dairy (6%), and metabisulphites (6%). Fatigue/lethargy and difficulty sleeping were both most reported following salicylate challenge (9% and 7% respectively). Cough was most reported following challenge with salicylates (8%), amines (cheese) (8%), and egg (8%). Post‐nasal drip was most common following salicylate (6%), amine (chocolate) (6%), and dairy (6%) challenges, while nasal congestion was also provoked by amine (chocolate) (6%), as well as antioxidants (6%). Additional symptoms, including tingling or burning sensations, shaking, dry or sore eyes, blocked ears, restless legs, hot flushes, snoring, sneezing, mood changes, and feeling unwell were grouped as ‘other’ and were reported in response to challenge with salicylates (12%), fish (11%), amines (cheese, chocolate, banana) (9%, 6%, and 5% respectively), dairy (8%), glutamate (5%), and antioxidants (5%) (Figure 1b).

In 64% of patients the low‐chemical diet provided a clear indication of specific dietary triggers; that is, patients experienced symptom improvement during the Restrictive Phase and symptom provocation during the Rechallenge Phase of the diet, with salicylates being the most common trigger of both gastro‐ and extraintestinal symptoms. For 8% of patients, the Rechallenge Phase did not provide a clear indication of specific triggers that is, no food challenges triggered symptoms (n = 2) or environmental/other factors (e.g., patient later diagnosed with Crohn's disease) were identified as the probable culprits driving symptoms (n = 2). For the remaining 28% of patients, it was unclear whether symptoms were related to food chemical components or other dietary triggers (i.e., FODMAPs), non‐diet factors such as psychological stress, COVID‐19 pandemic, environmental factors (e.g., season, weather, hay fever, fumes, air‐conditioning), concurrent illness (e.g., common cold, shingles, Kawasaki disease, fibromyalgia, gastroenteritis), and/or menstruation.

4. Discussion

This study evaluated the real‐world use of a low‐chemical diet for managing gastrointestinal and extraintestinal symptoms in those with suspected food chemical hypersensitivity. This clinical audit identified the Restrictive Phase provided improvement in symptoms in most patients, especially in overall (general/unspecified), sinus/nasal pain/inflammation, general swelling, and gastrointestinal symptoms. Salicylate challenges most often induced gastrointestinal symptoms of bloating, gas, and diarrhoea, and extraintestinal symptoms of itch, fatigue/lethargy, difficulty sleeping, cough, and post‐nasal drip. Additionally, it identified practical challenges, including prolonged periods of dietary restriction and the risk of unintentional weight loss and constipation.

Improvement in at least one symptom was reported in 88% of patients. While no studies of the low‐chemical diet in people with food hypersensitivity are available for direct comparison, a related study found patients self‐reported that dietary salicylates trigger rhinosinusitis [13]. Likewise, a low‐salicylate diet decreases sinus/nasal symptoms in RCTs of patients with aspirin‐exacerbated respiratory disease [14, 15], and in a non‐randomised study of participants with hypersensitivity to nonsteroidal anti‐inflammatory agents (NSAIDs) [16]. Our clinical audit found 60% of patients with general swelling at baseline improved. There is no published data on swelling in a general population with reported food chemical hypersensitivity, with mixed results reported in relation to angioedema in defined clinical populations. For example, Joneja et al. [17] reported a 4‐week histamine‐restricted diet improved urticaria, angioedema, and pruritus in 61% of participants, but King et al. [18] found no improvement in angioedema after 6 weeks on a low‐histamine, additive‐free diet. Further controlled studies are needed to understand the impact of food chemicals on extraintestinal symptom induction.

In this audit, 6% of our total patient cohort reported improvements in general gastrointestinal symptoms, as well as improvements in specific gastrointestinal symptoms of diarrhoea (4%), bloating (2%), and abdominal pain (2%). Elsewhere, mixed findings have been reported in relation to the impact of specific food chemicals on gastrointestinal symptoms. While an RCT showed no differences in gastrointestinal symptoms in those on a high versus low‐salicylate diet [19], gastrointestinal symptom improvement has been reported following the removal/reduction of MSG in participants with co‐morbid IBS and fibromyalgia [20], glutamate in individuals with gulf war illness [21], and histamine in individuals with urticaria, angio‐oedema, and pruritus [17]. In our audit, reduced gastrointestinal symptoms may relate to concurrent low/reduced FODMAP diet, which was reported by 40% of participants. In clinical practice, dietitians should consider implementing a stratified approach to the Restrictive Phase of the low‐chemical diet to identify potential triggers. That is, if food chemical hypersensitivity is suspected, initial implementation of restriction of food chemical components, and if symptoms persist throughout this phase, then consider altering the approach to restriction of FODMAPs and/or other common dietary allergens. Should any dietary interventions be simultaneously used, i.e., ‘diet stacking’, then careful monitoring for nutritional inadequacies would be required [10]. Further efficacy data is needed to understand the role of food chemicals in gastrointestinal symptom provocation.

Food challenges induced symptoms in 96% of patients, with a relatively high degree of heterogeneity in associations between specific symptoms and food chemical components. The highest proportion of symptom induction was apparent for salicylates causing headache, itch, diarrhoea, gas, and bloating, as well as triggering fatigue/lethargy and difficulty sleeping. Respiratory symptoms, such as cough and post‐nasal drip were also reported post‐salicylate challenge. Mechanistic studies support the manifestation of salicylate hypersensitivity in respiratory symptoms [4, 6], but their role in the provocation of other extraintestinal symptoms, like itch, headache, and fatigue, is largely based on anecdotal evidence. There is a lack of high‐quality trials featuring blinded challenges with salicylates. One small study found that 2 of 10 participants with IBS following a provided diet high in salicylate had increased abdominal pain [19]. These data highlight the need for further blinded challenge studies.

Amine challenge with cheese most frequently induced abdominal pain, while challenge with banana were found to provoke nausea. Further, amine (cheese) and antioxidant challenges were most frequently reported to cause nasal congestion in our cohort. Two studies [22, 23] have examined gastrointestinal symptoms in participants with a blinded challenge of 75 mg of pure histamine via oral capsules or dissolved in peppermint tea, whereby diarrhoea occurred in participants with chronic spontaneous urticaria (5%) [22], and diarrhoea (40%), flatulence (30%), and loose stools (10%) occurred in healthy females [23]. Likewise, previous studies have found a positive correlation between IBS‐symptoms and histamine hypersensitivity [24] and identified histamine as a key mediator in IBS [25, 26]. Although diamine oxidase (DAO) has been proposed as a potential biomarker for histamine intolerance, existing studies present conflicting findings regarding its diagnostic accuracy, and its routine use in clinical practice is not currently recommended [3, 27]. Consistent with previous literature, a cross‐sectional cohort study found histamine‐releasing foods and vaso‐active amine‐rich foods, including banana and cheese, to be perceived dietary triggers in 77% of IBS participants [28]. Our findings support current literature highlighting the potential role of histamine in inducing gastrointestinal symptoms, but further RCTs are needed to evaluate mechanisms of action, and more comprehensive histamine composition data in common foods is required. Ingestion of vaso‐active amine‐rich or histamine‐releasing foods is thought to mimic allergic‐like respiratory and sinus/nasal symptoms in those with histamine hypersensitivity [29]. A 75 mg oral histamine challenge caused immediate sneezing and headache in 1/10 healthy female participants [23], but provocation of sinus/nasal symptoms were not found in a population with chronic urticaria [22]. The differences in these findings may relate to a focus on skin symptoms in the urticaria population, or that the dose (75 mg) or duration (2 days) of histamine challenge were insufficient to induce symptoms. These data again highlight the need for future studies to understand the role of histamine and amines for symptom induction across a range of conditions.

Patient adherence to elimination diets generally decreases with the restrictiveness of the diet, which can increase burden of food preparation and decrease opportunities for social dining [30], and is further complicated by low medical literacy, socioeconomic status (due to higher cost of speciality food), and food‐related anxiety [31]. Despite this, we found high self‐reported patient adherence to the Restrictive Phase. High adherence may reflect that the cohort was motivated, able to seek specialist support, and had high rates of positive treatment outcomes. Future studies and clinical practice should consider use of food records for improved compliance monitoring, given potential inaccuracies of self‐reported adherence [32].

This clinical audit provides several important practical considerations for the application of the low‐chemical diet. Notably, patients may remain on Restrictive Phase far beyond the recommended 2 weeks [10], followed by a typically lengthy Rechallenge Phase (median of 39.5 weeks, and up to 78 weeks). This prolonged timeframe of dietary restriction is particularly concerning given the risk of macro and micro‐nutrient deficiencies among those following restrictive elimination diets [12, 33]. Unintentional weight loss that was reported among 24% of participants following the Restrictive Phase is also cause for concern. While calorie and macronutrient intake were not documented, this unintentional loss of weight indicates suboptimal caloric intake among these patients, reflecting not only nutritional challenges but also the potential psychological and practical difficulties of maintaining such a restricted diet. Considering this, close monitoring of body weight and nutritional status in patients following low‐chemical diets is advisable. In those with suspected suboptimal dietary intake, dietitians may consider reducing the strictness of dietary restriction prescribed (i.e., adopting a simple‐moderate approach), as well as providing dietary education on increasing energy and protein intake and food fortification. Dietary supplementation with a suitable low‐chemical multivitamin should also be considered. In our audit, once the main food chemical challenges were completed (i.e., salicylates, amine, and glutamate), patients were allowed to reintroduce foods that were well tolerated while completing their remaining food challenges. While this allowed patients to more quickly increase their variety of foods, particularly those of high nutritional value, this approach should be taken cautiously to limit the potential confounding effect of these foods on reported symptoms during the Rechallenge Phase. Another adverse outcome identified was worsening constipation. This may be due to restricted intake of high‐chemical, fibre‐rich foods, such as fruits, vegetables, and grains [10]. Patients should be advised to monitor their bowel activity and provided education on suitable higher fibre, low chemical alternatives, such as quinoa, brown rice, legumes, and rolled oats, or fibre supplements (e.g., psyllium husk) [10]. It is common for individuals whose symptoms improve with dietary restriction to continue to avoid foods that are perceived to induce their symptoms [2]. It is possible that the patients who had planned but incomplete food challenges at their final dietitian consultation did not attempt to challenge these foods and continued to restrict them unnecessarily. It is important that patients are educated on the importance of challenging foods to build up a tolerance to individualised quantities of offending food components with the aim of dietary liberalisation while managing their symptoms.

The findings from this single‐centre audit, while valuable, should be interpreted within context. The key strengths of this audit are the real‐world nature of the data and the use of a standardised dietary protocol. However, the findings are limited by patients' clinical and symptom heterogeneity, and lack of objective measures and blinded challenge of food chemical components. It is possible that perceived hypersensitivity to specific food triggers may contribute towards symptom anticipation and food aversions [2]. However, for practical reasons of cost, time‐efficiency, and difficulty obtaining suitable placebos, open food challenges are not typically performed in clinical practice [2]. The patient population was predominantly female (80%) and managed through a specialized dietetic practice, and the intensive follow‐up (median 5 appointments) may not be feasible in all healthcare environments, particularly in public health settings or rural areas. While advancements in telehealth may alleviate certain barriers, financial constraints are likely to remain a persistent challenge within private healthcare settings. The ability to maintain such a restricted diet may be influenced by socioeconomic factors not captured in this audit, such as food security, cooking skills, and family support structures. The sample size was determined pragmatically rather than through power calculations, larger studies would be valuable to confirm these findings. Due to the absence of comprehensive food chemical composition data and the variability in dietary intake data among patients, it was not possible to quantify the intake of specific food chemical subgroups within this cohort.

In conclusion, this clinical audit provides important knowledge of implementing and using the low‐chemical diet in real‐world clinical practice, with the majority of patients reporting symptom improvement. This study suggests the low‐chemical diet does offer potential as a management strategy for gastrointestinal and extraintestinal symptoms, but the risk of unintentional weight loss, constipation and prolonged dietary restriction highlight the need for careful monitoring and individualised dietary protocols. Through a structured rechallenge protocol identification of food chemical triggers, particularly salicylates and amines, is possible. When considering implementation of the low‐chemical diet an individualised, balanced approach and careful monitoring of nutritional status are imperative. High‐quality controlled trials are needed to optimise low‐chemical diet protocols and better understand the mechanisms of food chemical hypersensitivity. Future studies should use double‐blinded placebo‐controlled challenges with isolated food chemical components objective outcome markers, validated symptom scoring systems and biomarkers where applicable, such as DAO [27]. Future studies may also develop and evaluate modified protocols of reduced intensity and duration.

Author Contributions

J.R.B., J.B., G.T., and C.T. designed the study. Z.C. undertook the file audit. Z.C. and K.L. undertook the data analysis. Z.C., G.T., C.T. drafted the manuscript. All authors contributed to reviewing the manuscript and approved the final draft of the manuscript submitted for publication. The content prepared within this manuscript has not been published elsewhere.

Ethics Statement

The study protocol was approved by La Trobe University Human Ethics Committee on the 4th of May 2021 (HEC21107).

Conflicts of Interest

J.R.B. and C.J.T. have received project funds from Yakult Australia. C.J.T. has received project funds from DSM Nutritional Products. J.B. is the Director of, and C.J.T. is an employee of, Diet Solutions, the private dietetic clinic where subjects were recruited for this study. The other authors declare no conflicts of interest.

Peer Review

The peer review history for this article is available at https://www.webofscience.com/api/gateway/wos/peer-review/10.1111/jhn.70134.

Supporting information

STROBE checklist file audit 23.

Supplementary Table 1: Low chemical diet protocol. Supplementary Table 2: Repeated and planned but incomplete challenges for low chemical diet rechallenge phase (n = 50)

Data Availability Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.