Abstract
Introduction
Lactose intolerance is frequently suspected in disorders of gut-brain interaction, yet symptoms often do not align with objective malabsorption. While lactose-related symptoms have been investigated in irritable bowel syndrome (IBS), data on functional dyspepsia (FD), particularly patients with overlapping IBS, remain limited. This study examined the relative contribution of lactose sensitivity and lactose malabsorption to symptom burden, and evaluated whether FD-IBS overlap is associated with greater symptom severity than FD alone.
Methods
In this cross-sectional study, adults underwent standardized lactose hydrogen breath and symptom testing. Diagnoses followed Rome IV criteria. Lactose malabsorption was defined as ≥20 ppm hydrogen increase; lactose sensitivity as ≥20 mm rise on the adult Carbohydrate Perception Questionnaire. Group differences were tested non-parametrically; adjusted effects used a general linear model with age and gender.
Results
Among 587 patients, lactose sensitivity was more prevalent than lactose malabsorption (54.9% versus 41.2%; p < 0.001) and occurred more frequently in patients with FD-IBS overlap than in those with FD alone (69.8% versus 52.7%; p < 0.001). Patients with overlap exhibited the highest symptom burden (p < 0.001). In multivariate analysis, lactose sensitivity and younger age were independently associated with FD-IBS overlap, whereas lactose malabsorption and gender were not.
Conclusion
Lactose sensitivity, not malabsorption, was closely associated with symptom burden in patients with FD. FD-IBS overlap was linked to amplified burden, underscoring the importance of validated symptom assessment alongside breath testing for diagnostic precision.
Keywords: Lactose sensitivity, Functional dyspepsia, Irritable bowel syndrome, Hydrogen breath test, Adult Carbohydrate Perception Questionnaire
Introduction
Functional dyspepsia (FD) and irritable bowel syndrome (IBS) are defined by the Rome IV criteria as distinct disorders of gut-brain interaction (DGBI), each characterized by specific symptom patterns. FD manifests predominantly with upper gastrointestinal symptoms (epigastric pain, epigastric burning, early satiety, nausea and postprandial fullness) whereas IBS is defined by recurrent abdominal pain associated with altered bowel habits [1]. Despite these formal distinctions, symptom overlap between IBS and FD is highly prevalent [2, 3]. Population-based and clinical studies indicate that up to 46% of patients with FD concurrently meet criteria for IBS, and a substantial proportion of IBS patients report FD-like symptoms.
Overlap patients exhibit a more severe gastrointestinal symptom burden, greater psychosocial comorbidity, and significantly reduced quality of life compared with those with either condition alone, suggesting that FD-IBS overlap may represent a distinct and clinically relevant phenotype within the spectrum of DGBI [4]. Growing evidence indicates that these overlap presentations are not incidental but reflect shared and interacting pathophysiological pathways, reinforcing the importance of distinguishing FD-specific mechanisms from those associated with mixed phenotypes [5, 6].
Shared pathophysiological mechanisms, including visceral hypersensitivity, disordered motility, impaired gastroduodenal accommodation, and altered brain-gut signalling, likely contribute to the complex symptom presentation in the overlap group. Evidence from tertiary care further underscores the magnitude of the problem: systematic assessment can identify considerably higher rates of FD-IBS overlap than routine clinical documentation, with correspondingly elevated symptom severity [7]. This heterogeneity highlights the need to understand FD and FD-IBS overlap as related but potentially distinct subgroups within DGBI research.
Lactose intolerance is among the most frequently suspected symptom triggers in patients with DGBI [8]. The symptom profile of lactose intolerance, particularly abdominal pain, bloating, distension, and diarrhoea overlaps substantially with that of IBS, and most studies on lactose malabsorption have therefore focused on IBS populations [8]. However, emerging data indicate that a substantial proportion of patients referred for lactose breath testing carry a diagnosis of FD rather than IBS [9, 10]. Despite this high representation of FD in clinical testing populations, lactose-related symptom responses have been examined almost exclusively in IBS-driven research frameworks, leaving FD comparatively under-characterized. Although lactose malabsorption is not more prevalent in FD than in other DGBI, symptoms following lactose ingestion appear to be reported disproportionately often in FD, suggesting that symptom generation in response to lactose may differ between DGBI subgroups [10, 11]. Furthermore, existing literature rarely differentiates between FD and FD-IBS overlap, even though overlap phenotypes are known to present with heightened symptom perception and may therefore respond differently to dietary stimuli, including lactose [12].
The long-neglected distinction between lactose malabsorption and lactose intolerance, as evidenced by the past clinical standard of performing hydrogen breath tests without symptom assessment, has gained renewed relevance with the introduction of validated, test-specific symptom assessment tools [13–15]. These allow for a more nuanced characterization of the relationship between malabsorption, symptom perception, and underlying DGBI phenotypes [16]. However, despite numerous studies on lactose intolerance, important gaps remain: FD is underrepresented in the literature, overlap phenotypes are largely unexamined, and the relative contributions of malabsorption versus hypersensitivity across these subgroups remain unclear [10, 11]. Given the high frequency of FD among patients undergoing lactose breath testing and the paucity of data examining lactose-related symptom responses specifically in FD and FD-IBS overlap, further investigation is warranted.
In this study, we therefore examined the distribution of lactose sensitivity with and without malabsorption, and lactose malabsorption with and without sensitivity, in patients with pure FD compared with those with FD-IBS overlap. This comparative approach helps clarify whether lactose-related symptom reporting differs between FD and FD-IBS overlap and to what extent these differences reflect sensitivity rather than malabsorption.
Methods
Study Design and Participants
This was a cross-sectional study based on prospectively and consecutively collected clinical data. All assessments, including the breath test, the aCPQ, and a questionnaire recalling symptom burden over the preceding 6 months, were obtained at a single visit. Adult patients referred for lactose hydrogen (H2) breath testing at the Departments of Gastroenterology and Hepatology, at the Medical University of Vienna and the Medical University of Graz, were consecutively enrolled between January 2017 and December 2023. Before referral, organic causes of the patients’ symptoms and small intestinal bacterial overgrowth (using a glucose-H2 breath test) had been ruled out. This study was approved by the Ethics Committees of the Medical University of Vienna (protocol code 1128/2023).
The study cohort comprised 587 patients with DGBI who met the inclusion criteria of having completed a breath test and having provided valid symptom documentation. No formal sample size calculation was performed because the study was planned as an exploratory, observational cohort and aimed to include all consecutive eligible patients presenting for lactose breath testing during the study period. For analyses involving a 6-month recall questionnaire, complete data were available for a subset of 388 patients. The 6-month recall questionnaire was introduced during the study period and was therefore not available for all patients; patients with incomplete responses were excluded. Patient selection and exclusions are shown in Supplementary Figure S1 (for all online suppl. material, see https://doi.org/10.1159/dig/acmag011).
Patients were classified according to the Rome IV criteria as having FD, FD-IBS overlap, or other DGBI, including patients with IBS. The FD-IBS overlap group fulfilled criteria for both FD and IBS simultaneously, in line with previous definitions of overlap disorders [2, 7]. Exclusion criteria were incomplete hydrogen measurements, missing symptom documentation, or insufficient diagnostic information. The primary comparison was between patients with FD and those with FD-IBS overlap. Other DGBI subtypes were described descriptively and used as the DGBI-control group but excluded from inferential analyses.
Hydrogen Breath Testing
Lactose breath tests were conducted in accordance with the institutional standard operating procedures and the European guidelines [13]. Patients were instructed to fast for at least 12 h overnight and to avoid high-fibre foods, alcohol, and strenuous physical activity the day before testing, and to refrain from smoking on the day of the test.
At baseline, a breath sample was obtained prior to the ingestion of a standardized lactose solution (50 g of lactose dissolved in 200 mL of water). Further samples were collected at 30, 60, 120, and 180 min. The hydrogen concentrations were expressed in parts per million (ppm), representing volume-to-volume ratios (µL H2 per litre of breath) and analysed using electrochemical hydrogen detectors (GMI- H2-Analyzer; Stimotron medical devices, Hamburg, Germany, or GastroCH4eck Gastrolyzer, https://www.bedfont.com). Lactose malabsorption (M) was defined as a rise in breath H2 ≥20 ppm above baseline within 180 min.
Assessment of Symptoms and Sensitivity
Symptom responses during the test were assessed using the validated adult Carbohydrate Perception Questionnaire (aCPQ), which quantifies acute changes in symptom intensity and location during the carbohydrate challenge [14]. Participants completed the aCPQ immediately before lactose ingestion and at each sampling point (30, 60, 120, and 180 min). The aCPQ uses visual analogue scales (VAS) to assess gastrointestinal symptoms (abdominal pain, bloating, flatulence, nausea, and diarrhoea) and is specifically designed for use during carbohydrate challenge tests [14].
Lactose sensitivity (S) was defined as an increase of ≥ 20 mm on the VAS for one or more symptoms following lactose ingestion, irrespective of H2 excretion results. This cut-off was selected in accordance with evidence demonstrating that a change of approximately 20 mm on a 100 mm visual analogue scale represents the minimal clinically important difference perceived by patients, distinguishing clinically meaningful from trivial symptom variations [17]. Accordingly, an increase of ≥ 20 mm was considered clinically relevant to ensure that only perceptible symptom changes were classified as lactose sensitivity. The same 20 mm threshold has been applied in previous studies using the aCPQ [9, 11].
A subset of patients completed a 6-month recall questionnaire incorporating the same five symptoms as the aCPQ. These symptoms were assessed using separate VAS scales. The maximum possible score for this assessment of carbohydrate-related symptom burden is 500 (five times 100). This was done to evaluate symptom burden over the previous 6 months.
Statistical Analysis
All statistical analyses were conducted using IBM SPSS Statistics version 29 (IBM Corp., Armonk, NY, USA). Continuous data were summarized as mean ± standard deviation (SD) if normally distributed and as median with interquartile range (IQR) otherwise. Categorical data were presented as counts and percentages. Normality was assessed using the Shapiro-Wilk test and equality of variances with Levene’s test.
Between-group comparisons for continuous or ordinal variables were performed using the Mann-Whitney U test for two-group comparisons and the Kruskal-Wallis test for three-group comparisons, followed by Bonferroni-adjusted post hoc tests when appropriate. Categorical variables were compared using Pearson’s chi-square test. Paired binary outcomes, specifically the comparison of lactose sensitivity and lactose malabsorption within the same individuals, were analysed using McNemar’s test.
Effect sizes were reported as r for Mann-Whitney U tests, Cramér’s V for categorical variables, and ε2 for Kruskal-Wallis models. To examine the independent association of age, gender, lactose malabsorption, and lactose sensitivity with the FD-IBS overlap phenotype, a multivariable binary logistic regression model was fitted, using FD as the reference group. Model performance was assessed using the Hosmer-Lemeshow test, Nagelkerke R2, and odds ratios (ORs) with 95% confidence intervals (CIs). A two-sided p value <0.05 was considered statistically significant for all analyses. Reporting of this observational study followed the STROBE guidelines; the completed checklist is provided in online supplementary Table S1.
Results
Patient Characteristics and Distribution of Lactose Malabsorption and Sensitivity (FD vs. FD-IBS Overlap)
Of the 587 patients undergoing lactose hydrogen breath testing, 222 (37.8%) were classified as FD, 162 (27.6%) as FD-IBS overlap (FD-IBS), and 203 (34.6%) as other DGBI (DGBI-control group). Age and gender distributions did not differ significantly between these groups (Table 1).
Table 1.
Baseline characteristics of patients by diagnostic group
| Characteristic | Total (n = 587) | FD (n = 222) | FD-IBS (n = 162) | DGBI-control (n = 203) | p value |
|---|---|---|---|---|---|
| Age (years), mean±SD (range) | 44.5±16.1 (16.4–84.5) | 45.7±15.8 (18.2–81.4) | 41.9±15.5 (17.1–80.5) | 45.1±16.7 (16.4–84.5) | 0.061 |
| Female gender, n (%) | 371 (63.2) | 132 (59.5) | 114 (70.4) | 125 (61.6) | 0.076 |
| Male gender, n (%) | 216 (36.8) | 90 (40.5) | 48 (29.6) | 78 (38.4) | |
| Malabsorption, n (%) | 242 (41.2) | 81 (36.5) | 75 (46.3) | 86 (42.4) | 0.143 |
| No malabsorption, n (%) | 345 (58.8) | 141 (63.5) | 87 (53.7) | 117 (57.6) | |
| Sensitivity, n (%) | 322 (54.9) | 117 (52.7) | 113 (69.8) | 92 (45.3) | <0.001 |
| No sensitivity, n (%) | 265 (45.1) | 105 (47.3) | 49 (30.2) | 111 (54.7) | |
| Combined subgroups, n (%) | | <0.001 | |||
| S-M+ | 59 (10.1) | 16 (7.2) | 10 (6.2) | 33 (16.3) | |
| S+M+ | 183 (31.2) | 65 (29.3) | 65 (40.1) | 53 (26.1) | |
| S-M- | 206 (35.1) | 89 (40.1) | 39 (24.1) | 78 (38.4) | |
| S+M- | 139 (23.7) | 52 (23.4) | 48 (29.6) | 39 (19.2) | |
Data are presented as mean ± SD or n (%).
DGBI, disorders of gut-brain interaction; FD, functional dyspepsia; FD-IBS, functional dyspepsia-irritable bowel syndrome overlap; M, malabsorption; n, number of patients; S, sensitivity; SD, standard deviation; +, positive; -, negative.
p values refer to the comparison between FD, FD-IBS overlap, and DGBI-control groups using Pearson’s chi-square test for categorical variables and Kruskal-Wallis test for continuous variables.
Lactose malabsorption was present in 242 of 587 (41.2%) patients; its prevalence was not significantly different, with comparable rates across FD (36.5%), FD-IBS overlap (46.3%), and DGBI-controls (42.4%). In a logistic regression adjusted for age and gender, older age was associated with malabsorption (OR 1.01, 95% CI 1.00–1.02, p = 0.035), while gender was not.
Lactose sensitivity affected 322 (54.9%) patients and differed significantly between groups (p < 0.001), being most common in FD-IBS overlap (69.8%), followed by FD (52.7%) and DGBI-controls (45.3%). Using McNemar’s test to compare paired binary outcomes within the same individuals, lactose sensitivity was significantly more prevalent than lactose malabsorption (54.9% vs. 41.2%, p < 0.001). Figure 1 illustrates the distribution of sensitivity-positive and sensitivity-negative patients in FD and FD-IBS overlap. In an adjusted model, female gender was associated with higher sensitivity (OR 1.48, 95% CI 1.05–2.07, p = 0.024), whereas age showed no significant effect (p = 0.055).
Fig. 1.
Distribution of lactose sensitivity and lactose malabsorption in patients with FD and FD-IBS overlap. Stacked bars represent the percentage of patients within each diagnostic group, stratified by combined lactose malabsorption and lactose sensitivity status (S-M+, S+M+, S-M-, S+M-). FD, functional dyspepsia; FD-IBS, functional dyspepsia-irritable bowel syndrome overlap; M+, lactose malabsorption present; M-, no lactose malabsorption; S+, lactose sensitivity present; S-, no lactose sensitivity.
Combining results of sensitivity testing (S+/S-) and malabsorption testing (M+/M-) yielded four subgroups: S-M+ (10.1%), S+M+ (31.2%), S-M- (35.1%), and S+M- (23.7%). The distribution differed significantly across diagnostic groups (p < 0.001) and remained significant when restricted to the comparison between FD and FD-IBS overlap (p < 0.007). Overlap patients showed a higher proportion of sensitivity-positive subgroups (S+M+ and S+M-), whereas FD patients more often belonged to the S-M- category (Table 1).
Symptom Distribution
Symptom-specific sensitivities differed between FD and FD-IBS overlap (Table 2). Pain occurred significantly more often in overlap patients (p < 0.002). The occurrence of nausea, bloating, flatulence, and diarrhoea did not differ between groups (all p > 0.05).
Table 2.
Frequency of symptom-specific sensitivity responses (≥20 mm VAS increase within 180 min) during the lactose hydrogen breath test in patients with FD and FD-IBS overlap
| Symptom | FD (n = 222), n (%) | FD-IBS (n = 162), n (%) | p value |
|---|---|---|---|
| Pain | 55 (24.8%) | 64 (39.5%) | 0.002 |
| Nausea | 48 (21.6%) | 48 (29.6%) | 0.073 |
| Bloating | 65 (29.3%) | 53 (32.7%) | 0.471 |
| Flatulence | 70 (31.5%) | 58 (35.8%) | 0.381 |
| Diarrhoea | 46 (20.7%) | 37 (22.8%) | 0.618 |
Data are presented as n (%).
VAS, visual analogue scale.
p values are based on Pearson’s chi-square tests comparing FD and FD-IBS groups.
Cumulative symptom responsiveness was greater in FD-IBS overlap than in FD (p < 0.009). Although the median number of positive symptoms was identical in both groups (median = 1), patients with FD-IBS overlap showed a broader distribution of symptom counts, with a higher proportion reporting multiple concurrent symptom sensitivities. The mean number of positive symptom sensitivities was 1.60 (SD 1.53) in the FD-IBS overlap group compared with 1.28 (SD 1.55) in the FD group.
Six-Month Symptom Burden (6-Month Recall Questionnaire)
Carbohydrate-related symptom burden over the preceding 6 months differed significantly across diagnostic groups (p < 0.001). Median total symptom scores were highest in FD-IBS overlap (254.5 [IQR 211–305]), followed by FD (189.5 [IQR 149–251]), and lowest in DGBI-controls (161.5 [IQR 100–221]; Table 3 and Figure 2).
Table 3.
Carbohydrate-related symptom burden, 6-month recall
| Group | N | Median (IQR) | Comparison | p value | Effect size (r) |
|---|---|---|---|---|---|
| FD-IBS | 112 | 254.5 (211–305) | vs. FD | <0.001 | 0.24 |
| vs. DGBI-controls | <0.001 | 0.48 | |||
| FD | 150 | 189.5 (149–251) | vs. FD-IBS | <0.001 | 0.24 |
| vs. DGBI-controls | 0.002 | 0.27 | |||
| DGBI-controls | 126 | 161.5 (100–221) | vs. FD-IBS | <0.001 | 0.48 |
| vs. FD | 0.002 | 0.27 |
Data are presented as median (IQR). Effect sizes (r) refer to pairwise Mann-Whitney comparisons.
IQR, interquartile range.
Fig. 2.
Carbohydrate-related symptom burden across diagnostic subgroups. Boxplots illustrate the distribution of carbohydrate-related symptom burden assessed by 6-month symptom recall across diagnostic subgroups. Boxes represent the interquartile range (IQR) with the median indicated by the horizontal line; whiskers denote the 5th-95th percentiles; circles indicate outliers beyond the 5th-95th percentile range. Brackets indicate statistically significant differences (Bonferroni-adjusted post hoc comparisons): FD vs. FD-IBS overlap (p < 0.001), FD-IBS overlap vs. Other DGBI (p < 0.001), FD vs. other DGBI (p = 0.002). FD, functional dyspepsia; FD-IBS overlap, functional dyspepsia-irritable bowel syndrome overlap; DGBI, disorders of gut-brain interaction.
Chronic symptom burden, assessed by 6-month symptom recall scores, did not differ significantly between the four subgroups defined by combined lactose sensitivity and malabsorption status (Kruskal-Wallis H = 4.659, df = 3, p = 0.199; ε2 = 0.012). Median 6-month recall scores were 216 (IQR 154–288) in S+M+, 202 (IQR 109–277) in S-M+, 193 (IQR 136–252) in S-M-, and 188 (IQR 145–247) in S+M-.
Bonferroni-adjusted comparisons showed significantly higher scores in FD-IBS overlap versus FD (p < 0.001) and versus other DGBIs (p < 0.001). FD patients also reported higher burden than other DGBIs (p = 0.002). The overall effect of diagnostic group on chronic symptom burden was large (ε2 = 0.17). A general linear model adjusted for age and gender confirmed a robust group effect (F(2,383) = 34.73, p < 0.001, partial η2 = 0.153), with the same gradient (FD-IBS > FD > other DGBI).
Predictors of FD-IBS Overlap
A multivariable logistic regression including age, gender, lactose sensitivity, and malabsorption identified lactose sensitivity as the strongest predictor of FD-IBS overlap (OR 1.77, 95% CI 1.11–2.84, p = 0.017). Younger age was weakly associated with overlap (OR 0.99, 95% CI 0.97–0.999, p = 0.041). Gender (p = 0.070) and malabsorption (p = 0.345) were not significant predictors of overlap. The model explained 6.8% of the variance and showed acceptable fit (Hosmer-Lemeshow p = 0.27), correctly classifying 59.6% of cases (Table 4).
Table 4.
Multivariable binary logistic regression identifying independent predictors of FD-IBS overlap vs. FD
| Predictor | OR | 95% CI (lower-upper) | p value |
|---|---|---|---|
| Age (years) | 0.99 | 0.97–0.99 | 0.041 |
| Female gender | 1.51 | 0.97–2.35 | 0.070 |
| Malabsorption | 1.25 | 0.79–1.98 | 0.345 |
| Sensitivity | 1.77 | 1.11–2.84 | 0.017 |
Data are presented as odds ratios (ORs) with 95% confidence intervals (CIs). FD served as the reference group (n = 384). Associations were calculated using multivariable logistic regression. OR > 1 indicates a positive association with FD-IBS overlap.
Discussion
In this cohort, lactose sensitivity, but not lactose malabsorption, was associated with acute symptom induction. While malabsorption was common, it showed no meaningful relationship with symptom severity, whereas sensitivity was clearly linked to greater acute symptom induction during the lactose challenge, including higher pain scores. These findings align with current concepts in DGBI, which emphasize visceral hypersensitivity and altered gut-brain signalling as primary drivers of food-related symptoms rather than impaired digestion [14]. The study focused exclusively on patients with FD, with or without IBS-overlap, a group often neglected in studies of lactose malabsorption and intolerance. Patients with FD-IBS overlap exhibited the highest symptom burden in both retrospective assessments and during the lactose challenge. Lactose sensitivity remained an independent predictor of overlap status, whereas malabsorption did not contribute. Overall, the results highlight the limited diagnostic value of malabsorption testing when interpreted without parallel symptom assessment.
Although approximately 40% of patients were found to have lactose malabsorption, over half of all patients reported lactose-induced symptoms, which were not necessarily indicative of malabsorption. This mismatch mirrors previous observations and supports the notion that “lactose intolerance” is largely a sensitivity-driven phenomenon [18–20]. The present findings should be interpreted within the context of a non-blinded clinical lactose challenge using a standardized 50 g lactose load. Consequently, symptom responses may reflect a combination of lactose-related physiological effects, expectancy-related responses, and broader mechanisms of symptom amplification that characterize disorders of gut-brain interaction rather than lactose-specific hypersensitivity alone. The prevalence of lactose sensitivity in our cohort is broadly comparable to other study cohorts [9]. While some investigations identified malabsorption as a weak predictor of intolerance, definitions of symptoms and diagnostic thresholds vary considerably [9–11]. In our analysis in FD patients with and without IBS overlap, only sensitivity, not malabsorption, was associated with clinically relevant symptom induction.
Lactose was chosen as the focus of this study primarily for practical and clinical reasons rather than as a generalizable marker of symptom responsiveness: lactose hydrogen breath testing is among the most frequently performed carbohydrate breath tests in clinical practice, and lactose intolerance is one of the most commonly suspected dietary triggers of gastrointestinal symptoms in patients with DGBI [8]. Applying the validated aCPQ during this widely used test therefore captures a diagnostically relevant symptom response with direct applicability to routine clinical evaluation. Mechanistic research provides a rationale for this dissociation: fermentable carbohydrates may promote mast cell activation, epithelial barrier disruption, and visceral hyperalgesia, which can occur independently of maldigestion. Notably, we used the validated aCPQ to quantify symptoms, enabling a standardized assessment of sensitivity during the hydrogen breath test. Further refinement of sensitivity thresholds based on therapeutic response may enhance clinical interpretability in the future [21].
FD-IBS overlap was associated with the highest symptom burden both in retrospective reports and during the lactose challenge, with greater lactose-induced abdominal pain compared with FD alone. Younger age showed a modest association with overlap in multivariable analysis. These results are consistent with earlier cohort and population-based studies demonstrating that overlap syndromes are associated with greater symptom burden, impaired quality of life, and higher healthcare use [7, 9]. Proposed mechanisms include additive visceral hypersensitivity, central amplification of pain, and psychological comorbidity. Neuroimmune interactions, including altered mast cell activity, may also contribute to the broader symptom profile in overlap disorders [22, 23]. Clinically, recognizing FD-IBS overlap as a distinct phenotype is important because these patients experience greater morbidity and may require more integrated management strategies addressing dietary triggers, pain hypersensitivity, and psychosocial factors [2, 7, 12]. Although lactose sensitivity emerged as an independent predictor of FD-IBS overlap, the multivariable model explained only a limited proportion of the variance (Nagelkerke R2 = 6.8%; 59.6% correctly classified). Consistent with the multifactorial nature of FD-IBS overlap, lactose sensitivity should therefore be regarded as one contributing marker of symptom amplification rather than a dominant determinant of overlap, and the corresponding association should be interpreted with appropriate caution.
The acute symptom response during the lactose challenge and the 6-month symptom burden should be distinguished, although both used the same five symptoms. Acute lactose sensitivity was more prevalent in FD-IBS overlap and independently predicted overlap status, yet the sensitivity/malabsorption status did not stratify long-term burden (four subgroups, p = 0.199), which was instead strongly graded by diagnostic phenotype (p < 0.001). This dissociation is plausible because the two measures probe different constructs: the acute response reflects immediate reactivity to a single supraphysiological stimulus, whereas long-term burden is shaped by habitual dietary exposure, avoidance, and the broader mechanisms of the DGBI phenotype, in which lactose sensitivity is only one contributor.
Taken together, these findings underscore the importance of systematic symptom monitoring for the clinical interpretation of lactose breath tests and illustrate that malabsorption alone provides only limited insight into patient-reported intolerance. Strengths of this study include a well-characterized, large Rome IV cohort, systematic hydrogen breath testing, and the combined use of retrospective symptom assessment and prospective structured symptom quantification during lactose challenge using the validated aCPQ. Multivariable models accounted for age and gender, increasing confidence in the observed associations. Limitations include the bicentric study design involving two hospitals in close geographic proximity, potential selection bias toward more symptomatic patients, and the retrospective nature of the 6-months recall, which is susceptible to recall bias. All participants were referred to tertiary centres specifically for lactose breath testing, typically after symptoms had persisted or initial management had failed. This referral pathway selects for patients with more severe, chronic, or diagnostically complex presentations, and both the prevalence of lactose sensitivity and the reported symptom burden are therefore likely to be higher than in FD or IBS patients managed in primary care. The absolute prevalences reported here accordingly should not be regarded as population estimates, whereas the relative comparisons between diagnostic groups are less likely to be affected.
Complete 6-month recall data were available for 388 of 587 patients. The questionnaire was introduced during the study period, so that patients tested earlier could not complete it; patients with incomplete responses were excluded from the cohort. As we consider the timing of testing to be the predominant reason for missing data, rather than patient- or symptom-related factors, a systematic responder bias appears unlikely, although it cannot be excluded, and a formal comparison of responders and nonresponders was not performed. Classification of malabsorption and sensitivity relied on predefined cut-offs, which remain debated [9]. Furthermore, the absence of a blinded placebo challenge precludes differentiation between lactose-specific physiological responses and expectation-related symptom generation. Therefore, lactose sensitivity as defined in this study should be interpreted as symptom induction during lactose exposure rather than definitive evidence of lactose-specific visceral hypersensitivity. Moreover, a 50 g lactose was chosen to maximize diagnostic sensitivity for malabsorption [13]. It is important to be aware that as a diagnostic provocation, the lactose challenge does not aim to reproduce habitual dietary exposure, under which lactose is never ingested in isolation but together with other nutrients and foods; the absolute prevalence of lactose sensitivity reported should accordingly not be extrapolated to real-world dietary intake, irrespective of the specific dose used. Additionally, only lactose was tested, limiting extrapolation to other fermentable carbohydrates. Beyond this, the use of a single isolated carbohydrate means these findings cannot be directly extrapolated to composite meals, in which fat, protein, volume, and other FODMAPs engage additional symptom-generating mechanisms; generalization to meal-related symptom generation in FD and FD-IBS overlap therefore remains to be established. Finally, only H2 was measured during breath testing, whereas combined hydrogen-methane measurement is recommended to improve diagnostic accuracy [13]. Methane-predominant, low-hydrogen producers may therefore have been misclassified as non-malabsorbers, which would underestimate lactose malabsorption and bias towards the sensitivity-positive/malabsorption-negative (S+M-) phenotype. Several considerations argue against a relevant impact: methane production alone rarely accounts for lactose malabsorption in adults [11], and in a study specifically evaluating methane measurement during carbohydrate breath testing, the addition of methane did not significantly change the detection rate of malabsorption when established cut-offs were applied, albeit in a paediatric and adolescent cohort [24]. Nonetheless, a small number of missed malabsorbers cannot be excluded.
Conclusions
In this cohort of patients with FD, lactose sensitivity was the key correlate of acute symptom induction and overlap status, whereas chronic symptom burden was more strongly determined by diagnostic phenotype, supporting the notion that hypersensitivity plays a central role in symptom generation, particularly for acute symptom perception [9, 11]. Patients with FD-IBS overlap displayed the highest symptom levels and greater abdominal pain, confirming that overlap represents a clinically relevant phenotype with increased morbidity.
The findings underscore the limited diagnostic value of hydrogen breath testing in isolation and highlight the need to integrate validated symptom assessment tools, such as the aCPQ, into clinical evaluation. Notably, symptom-based identification of intolerance with the aCPQ predicts the response to dietary carbohydrate restriction independently of malabsorption [25], supporting the clinical relevance of the symptom-based threshold applied here. Future prospective multicentre studies incorporating other carbohydrates, biomarker analysis, and neuroimaging will be essential to validate these results and refine diagnostic and therapeutic strategies in DGBI.
Statement of Ethics
This study protocol was reviewed and approved by the Ethics Committee of the Medical University of Vienna, approval number 1128/2023. Written informed consent was waived by the Ethics Committee of the Medical University of Vienna because this study used anonymized, routinely collected clinical data without any study-specific interventions. Supplementary material is available online. Supplementary Figure S1 shows the flow diagram of patient selection and exclusions. Supplementary Table S1 provides the STROBE checklist for cross-sectional studies.
Conflict of Interest Statement
The authors have no conflicts of interest to declare.
Funding Sources
This study was not supported by any sponsor or funder.
Author Contributions
Conceptualization, validation, and methodology: A.V. and J.H.; software, data curation, writing – original draft preparation, visualization, and formal analysis: A.V.; resources, investigation, and project administration: J.H.; writing – review and editing, A.V. and J.H. and H.H.; supervision, J.H. and H.H. All authors have read and agreed to the published version of the manuscript.
Funding Statement
This study was not supported by any sponsor or funder.
Data Availability Statement
Data supporting the findings of this study are available from the corresponding author upon reasonable request. The data are not publicly available due to privacy and ethical restrictions.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
Data supporting the findings of this study are available from the corresponding author upon reasonable request. The data are not publicly available due to privacy and ethical restrictions.
