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. 2026 Mar 6;12:23. doi: 10.1186/s40798-026-00998-y

Differential Intestinal Epithelial Injury Following Passive and Exertional Hyperthermia

Sharifah Badriyah Alhadad 1,2,3, Louisa Si Xian Lim 1,2, Jason Kai Wei Lee 1,2,3, Ivan Cherh Chiet Low 1,2,✉
PMCID: PMC12965931  PMID: 41790336

Abstract

Background

Passive and exertional hyperthermia can compromise gastrointestinal (GI) integrity, contributing to systemic complications and heat stroke. Intestinal epithelial injury, a potential early event in this cascade, is likely multi-factorial and context-dependent, influenced by thermal, metabolic and mechanical stress. We compared the effects of passive hyperthermia (PaH) and exertional hyperthermia (RUN) at matched peak body core temperature (Tc) on intestinal epithelial injury and endotoxin translocation to delineate the relative contributions of these mechanisms. A prolonged brisk walking (WALK) condition was included as an exploratory condition relevant to occupational heat exposures.

Methods

In this randomised, counterbalanced, repeated-measures study conducted per CONSORT guidelines, 15 male endurance athletes (age: 26 ± 3 years, VO2peak: 64 ± 6 ml/kg/min) completed PaH, WALK and RUN. PaH involved warm water immersion (42.0 ± 0.3 °C) to nipple level. WALK comprised 60 min at 6 km/h, 7% incline, followed by 30 min at 6 km/h, 1% incline to prolong exercise and facilitate continued heat storage if Tc<39.5 °C after 60 min. RUN involved treadmill running at 69 ± 2% VO2peak. PaH and RUN continued until Tc reached 39.5 °C, volitional exhaustion or 60 min. Tc, heart rate (HR), perceptual responses, and concentrations of intestinal fatty acid binding protein (IFABP) and lipopolysaccharides (LPS) were assessed. Stepwise multiple linear regression was used to identify predictors of post-condition IFABP.

Results

Peak Tc was similar between PaH (39.3 ± 0.3 °C) and RUN (39.4 ± 0.2 °C, P = 0.944), and lower in WALK (38.2 ± 0.4 °C, both P < 0.001). Cumulative heat load assessed by area under the curve Tc≥38 °C was similar between WALK (36.4 ± 11.3 °C/min) and RUN (34.3 ± 7.5 °C/min, P > 0.999) but lower in PaH (25.7 ± 5.6 °C/min, P < 0.05 vs. WALK, P < 0.01 vs. RUN). IFABP increased in RUN (745 ± 432 pg/ml vs. 1855 ± 1465 pg/ml, P < 0.001) and WALK (767 ± 476 pg/ml vs. 1144 ± 995 pg/ml, P < 0.05), but not in PaH (848 ± 569 pg/ml vs. 870 ± 562 pg/ml, P = 0.916). Post-condition IFABP was higher in RUN than PaH (P < 0.01) and WALK (P < 0.05), and similar between PaH and WALK (P > 0.999). LPS decreased in all conditions (all P < 0.05). Body fat percentage, body mass loss and body mass index explained 15% of the variance in post-condition IFABP.

Conclusions

Intestinal epithelial injury occurred following exertional, but not passive hyperthermia, at matched peak Tc. This highlights that combinations of thermal, metabolic and mechanical stress drive GI injury rather than Tc elevation alone. Prolonged low-intensity exercise relevant to occupational exposures may incur sufficient cumulative heat load to induce subclinical intestinal injury. Interventions should consider managing exertional load alongside thermal strain to protect gastrointestinal health.

Keywords: Heat stress, Core temperature, Gastrointestinal injury, Intestinal fatty acid binding protein, Exertional heat stroke

Key Points

At matched peak body core temperature, intestinal epithelial injury was observed following exertional hyperthermia but not passive hyperthermia.

IFABP was weakly associated with body fat percentage, mean and peak heart rate and percentage body mass loss, with regression models explaining a small proportion of variance, suggesting that elevated body core temperature alone does not fully account for gastrointestinal injury during heat exposure.

Marked inter-individual variability in IFABP responses across conditions supports the need for individualised risk models that can account for combinations of thermal, metabolic and mechanical stress experienced during different forms of heat exposure.

Introduction

Heat stroke represents the most severe manifestation of heat-related illness and is potentially fatal. Heat stroke is typically characterised by body core temperatures (Tc) exceeding 40 °C and central nervous system dysfunction, which can rapidly progress to multi-organ failure and death if not promptly managed [1]. Heat stroke is commonly categorised into two forms – exertional heat stroke (EHS), which typically affects healthy, active individuals during intense physical activity, often in hot environments, and classical heat stroke, which typically affects vulnerable populations during passive exposure to high environmental temperatures [2].

A growing body of literature suggests the role of gastrointestinal (GI) dysfunction in the pathophysiology of heat stroke. Specifically, compromised intestinal epithelial integrity has been implicated as a key contributor to the systemic complications of heat stroke, such as endotoxemia, systemic inflammation and multi-organ failure [3–5]. The intestinal epithelium serves as a barrier between the gut lumen and systemic circulation, regulating nutrient absorption while preventing the translocation of pathogens and endotoxins such as lipopolysaccharides (LPS). During heat stress, this barrier can become compromised through both thermal and haemodynamic insults, facilitating the leakage of endotoxins into the systemic circulation, triggering a systemic inflammatory response resembling sepsis [3, 5].

The development of GI dysfunction, such as intestinal epithelial injury, which represents an early event in the cascade of heat-related systemic complications, is likely multi-factorial and context-dependent. In exertional settings, GI dysfunction likely results from multiple mechanisms involving thermal [6, 7], metabolic [5, 8] and mechanical stress [9]. Most of this research has been associated with moderate to high-intensity exercise, reflecting athletic and military settings where EHS is typically observed. Furthermore, GI dysfunction is not exclusive to exertional contexts. Individuals with classical heat stroke, who develop hyperthermia through passive environmental heat exposure, may also develop GI dysfunction [10, 11]. This suggests that hyperthermia per se, independent of physical exertion, may be sufficient to disrupt GI integrity and function, contributing to systemic pathology.

Thus, it appears that the mechanisms contributing to GI dysfunction likely differ between passive and exertional hyperthermia. A greater understanding of these relative contributions across the varying contexts is important to properly inform mitigation strategies to effectively protect the gut against insults. However, few studies have directly compared the effects of passive and exertional hyperthermia on GI dysfunction, such as intestinal epithelial injury at matched peak Tc. One previous study reported greater GI permeability following exertional rather than passive heat stress using the lactulose: rhamnose ratio as an index of GI permeability [12]. However, the small sample size (n = 6) and reliance on indirect urinary markers limit mechanistic interpretation. Therefore, we compared the effects of passive and exertional hyperthermia on circulating biomarkers of intestinal epithelial injury, and subsequent endotoxin translocation when matched for peak Tc. As a secondary aim, we also examined the effects of exertional hyperthermia induced by prolonged low-intensity physical activity in the heat. This served as an exploratory condition to provide insight into the GI responses during prolonged, submaximal activities in hot environments such as those commonly observed in occupational settings, where workers work at lower intensities for prolonged durations and experience potentially lower combined thermal, metabolic and mechanical strain, but may still be at risk of GI dysfunction and EHS. Although strict isolation of stressors is difficult in vivo, we aimed to compare GI responses across these varied conditions in a more ecologically relevant manner to provide insight into the thermal, metabolic and mechanical stressors contributing to the primary drivers of heat-induced intestinal epithelial injury and inform strategies to protect at-risk populations.

Materials and Methods

Participants

Participants were recruited through the university’s mass email system and social media platforms, including WhatsApp and Telegram groups, as well as Facebook and Instagram. The inclusion and exclusion criteria were as follows:

  1. Male volunteers aged between 21 and 35 years of age.

  2. Able to complete a 10 km run in less than 60 min.

  3. No history of prior gastrointestinal surgery, trauma to the mucosal membrane, or pelvic or abdominal surgery.

  4. No history of inflammatory and motility bowel disorders, intestinal obstruction and swallowing disorders.

  5. No history of respiratory diseases, heat injuries or heart diseases.

  6. No scheduled Magnetic Resonance Imagery (MRI) within 7 days from consumption of the telemetric capsule.

Only male participants were recruited in this study to enhance applicability of our findings to predominantly male military populations. Following recruitment efforts, fifteen males (age: 26 ± 3 years, height: 1.72 ± 0.05 m, body mass: 63.8 ± 5.0 kg, body fat: 12 ± 3%, VO2peak: 64 ± 6 ml/kg/min) participated in this study. Although recruitment was not limited by nationality, all participants in this study were native to the tropical country of Singapore (mean daily dry bulb temperature, Tdb: 27.4 °C, relative humidity, RH: 83% [13]). Participants were classified as endurance athletes based on the sports they undertook (i.e., track (> 5000 m) events, biathlon, road cycling, triathlon and marathon events) [14]. Ethical approval was obtained from the National University Institutional Review Board (Reference No.: NUS-IRB-LH-20-017) in accordance with the Declaration of Helsinki. All participants were verbally briefed on the experimental procedures and potential risks and certified as fit by an independent physician. They provided written informed consent before participating.

Experimental Design

This study was a randomised, counterbalanced, repeated-measures, laboratory-based study conducted at the National University of Singapore, in accordance with CONSORT guidelines. The study comprised of a total of four visits. The first visit consisted of anthropometric measurements and an assessment of maximal aerobic capacity (VO2peak). Body mass was measured to the nearest 0.01 kg using an electronic precision scale (Mettler-Toledo GmBH, Giessen, Germany) and height measured to the nearest 0.01 m using a stadiometer (NAGATA VW-110 H, Yong Kang, Tainan). Skinfold measurements were taken at four sites (biceps, triceps, subscapular and iliac crest) using skinfold callipers [15] (HSK-BI-2, Harpenden, Baty International, UK) and used to calculate body density [16] and estimate body fat percentage [17]. VO2peak was determined using a two-part incremental exercise protocol [18] to volitional exhaustion on a motorised treadmill (mercury®, h/p/cosmos, Germany).

Subsequently, participants completed three experimental conditions in a randomised, counterbalanced order determined using Latin square design: [] (1) passive heating via warm water immersion (PaH) [], (2) low-intensity walk (WALK) and (3) moderate-intensity run (RUN) (Fig. 1). Visits were separated by at least 6 days to allow for adequate recovery and performed at the same time of the day to minimise circadian influences. Before each visit, participants were requested to replicate their diets and sleep schedules and refrain from strenuous physical activity and alcohol. A 24 h dietary and physical activity questionnaire was completed upon arrival at the laboratory to ensure participant compliance with experimental requirements. Participants were also requested to wear similar clothing across all experimental conditions. Participants then voided their bladder and provided a mid-stream urine sample for measurement of urine specific gravity (USG) using a handheld refractometer (PAL-10 S, Atago, Japan). All participants were euhydrated (USG < 1.025 [19]) before commencing.

Fig. 1.

Fig. 1

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Schematic representation of the experimental design consisting of the passive heating (PaH), brisk walking (WALK) and running (RUN) conditions and the breakdown of measurements taken. In PaH, participants were submerged to nipple level in 42.0 ± 0.3 °C water. WALK consisted of 60 min brisk walking at 6 km/h, 7% incline, followed by 30 min at 6 km/h, 1% incline to prolong exercise and facilitate continued heat storage if Tc<39.5 °C after 60 min. RUN, involved treadmill running at 69 ± 2% VO2peak. PaH and RUN continued until Tc reached 39.5 °C, volitional exhaustion or 60 min. Tc body core temperature, HR heart rate, VO2 oxygen consumption, RPE ratings of perceived exertion, RTS ratings of thermal sensation

Pre-condition nude body mass was then measured, and a pre-condition blood sample collected. Participants then commenced a 10 min seated baseline during which they remained seated quietly and still, without talking or using electronic devices to establish stable resting values of Tc and HR before the experimental conditions. PaH was conducted in an air-conditioned laboratory (Tdb: 21.6 ± 0.5 °C, RH: 68 ± 3%). Participants were submerged up to nipple level in an inflatable tub containing warm water maintained at 42.0 ± 0.3 °C by a heating unit (Compact XP Dual Temp, iCoolsport, Australia). WALK and RUN were conducted in a climate-controlled room (Tdb: 30.0 ± 0.2 °C, RH: 71 ± 2%). In WALK, participants walked on a motorised treadmill at 49 ± 5% VO2peak for 1.5 h. This was conducted via a two-stage protocol consisting of 6 km/h, 7% incline for 60 min followed by an extended 30-min walk phase of 6 km/h, 1% incline to prolong exercise and facilitate continued heat storage if Tc was below 39.5 °C after 60 min. In RUN, participants ran on a motorised treadmill at 69 ± 2% VO2peak. Both PaH and RUN continued until a Tc of 39.5 °C, volitional exhaustion or a maximum duration of 60 min. In all conditions, participants ingested 2 g/kg of body mass of ambient water maintained at 26.0 °C every 15 min. Following the experimental interventions, participants towel dried and post-condition nude body mass was recorded, and a post-condition blood sample collected.

Measurements

Pre- and post-condition nude body mass was used to estimate percentage body mass loss. Pre- and post-condition blood samples were collected from the median cubital vein into a serum tube (BD Vacutainer®, CPTTM, Becton Dickinson, USA). Blood samples were centrifuged at 3000 RPM for 10 min at 4 °C using a refrigerated centrifuge (Sigma Laborzentrifugen GmBH 2-16KL, Germany). Enzyme-linked Immunosorbent Assay (ELISA) was used to determine IFABP concentrations (pg/ml; Hycult Biotech, Uden, Netherlands). LPS concentrations were determined using Limulus Amebocyte Lysate (LAL) Chromogenic Endpoint Assay (endotoxin units (EU)/ml; Hycult Biotech, Uden, Netherlands). The coefficient of variation for IFABP and LPS was 3.3% and 6.1%, respectively.

Tc and heart rate (HR) were continuously measured. Tc was measured by a telemetric capsule (e-Celsius®, BodyCAP, Hérouville-Saint-Clair, France) ingested eight to ten hours prior to the commencement of the experimental condition (n = 10) or rectally self-inserted upon arrival to the laboratory (n = 5). The modality of ingestion or insertion of the Tc capsule was kept consistent for participants across the respective conditions. HR was monitored by a chest-based sensor (H10 monitor, Polar Electro, Kempele, Finland). Every 15-min, oxygen uptake (VO2), subjective ratings of perceived exertion (RPE; Borg’s scale [20]) and thermal sensation (RTS [21]) were recorded. VO2 was assessed using a metabolic cart (Parvomedics, Utah, USA) with breath-by-breath gas analysis to calculate the %VO2peak at which the participants performed the various experimental conditions. Environmental conditions were monitored using an environmental meter (QUESTemp44, TSI Incorporated, Minneapolis, USA).

Statistical Analysis

A priori power calculation using G*Power (Heinrich-Heine-Universität Düsseldorf, Germany) was performed to determine the number of participants required (n = 15) employing an alpha level of 0.05, a beta level of 0.20 and a desired power of 0.8. Statistical analyses were performed using GraphPad Prism version 10.0.1 (GraphPad Prism Software Inc., San Diego, CA, USA). Data was assessed for approximation to a normal distribution using the Shapiro-Wilk test and sphericity using Mauchly’s test of sphericity for repeated-measures variables. Greenhouse-Geisser corrections were applied to adjust for the lack of sphericity. Differences between conditions for pre-condition USG, baseline, mean, end, peak data during the experimental conditions were analysed using one-way repeated measures ANOVA, whilst parameters collected across time were analysed using two-way (condition x time) repeated measures ANOVA. Where significant main or interaction effects were observed, post hoc Bonferroni-adjusted pairwise comparisons were made. In addition to the peak and rate indices of Tc, cumulative heat load was quantified as the area under the curve Tc ≥ 38 °C (AUC ≥ 38 °C) and expressed as °C/min. Tc ≥ 38 °C was chosen based on general limits of hyperthermia and occupational heat strain [22–24], and AUC ≥ 38 °C values were compared using one-way repeated measures ANOVA. Pearson’s correlation coefficient was used to test the strength of the association between various parameters and post-condition IFABP. Correlations were classified as very weak (< 0.20), weak (0.20–0.39), moderate (0.40–0.59), strong (0.60–0.79) or very strong (≥ 0.80) [25]. Step-wise multiple linear regression analysis was employed to determine significant independent contributors to post-condition IFABP. All input variables for the correlational analysis were included in the multiple linear regression analysis. Variables were progressively removed in a stepwise manner to minimise multicollinearity and improve model performance. Significance was set at P < 0.05, and all values are expressed as mean ± SD unless stated otherwise.

Results

Physiological and Perceptual Responses

Condition duration differed across all conditions (Pcondition < 0.001) and was longest in WALK (90 min), followed by RUN (44 ± 10 min) and PaH (31 ± 5 min). An effect of condition was observed for percentage body mass loss (Pcondition < 0.01). Post hoc comparisons revealed percentage body mass loss was higher in RUN (−1.8 ± 0.7%) than PaH (−1.2 ± 0.6%, P < 0.01), but similar between WALK (−1.4 ± 0.8%) and PaH (P > 0.999) and RUN (P = 0.090), respectively.

Baseline Tc and HR were similar between conditions (Tc: PaH: 37.0 ± 0.2 °C, WALK: 36.9 ± 0.2 °C, RUN: 37.0 ± 0.2 °C, P = 0.294; HR: PaH: 60 ± 8 bpm, WALK: 64 ± 7 bpm, RUN: 66 ± 8 bpm, P = 0.103). Mean Tc was different across all conditions (Pcondition < 0.001) and was highest in RUN (38.3 ± 0.2 °C), followed by PaH (38.1 ± 0.2 °C) and WALK (37.8 ± 0.2 °C; Fig. 2A). Peak Tc was similar between RUN (39.4 ± 0.2 °C) and PaH (39.3 ± 0.3 °C, P = 0.944) and was higher in both RUN and PaH as compared to WALK (38.2 ± 0.4 °C, both P < 0.001; Fig. 2B). Rate of rise in Tc observed a similar trend to peak Tc and was similar between RUN (0.06 ± 0.02 °C/h) and PaH (0.07 ± 0.02 °C/h, P = 0.066), but higher in both RUN and PaH as compared to WALK (0.01 ± 0.00 °C/h, both P < 0.001; Fig. 2C). Although peak Tc and rate of rise in Tc were lower in WALK than RUN, AUC ≥ 38 °C was comparable between WALK (36.4 ± 11.3 °C/min) and RUN (34.3 ± 7.5 °C/min, P > 0.999; Fig. 2D). AUC ≥ 38 °C was lower in PaH (25.7 ± 5.6 °C/min) compared to WALK (P < 0.05) and RUN (P < 0.01), respectively. Mean HR was different across all conditions (Pcondition < 0.001) and was highest in RUN (160 ± 9 bpm), followed by WALK (128 ± 14 bpm) and PaH (105 ± 11 bpm; Fig. 2E). Similarly, peak HR was different across all conditions (Pcondition < 0.001), with RUN having the highest peak HR (179 ± 10 bpm), followed by WALK (149 ± 17 bpm) and PaH (127 ± 15 bpm; Fig. 2F).

Fig. 2.

Fig. 2

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A Mean body core temperature (Tc), B peak Tc, C rate of rise in Tc, D area under the curve (AUC) ≥ 38 °C, E mean heart rate (HR), F peak HR, G mean ratings of perceived exertion (RPE), H peak RPE, I mean ratings of thermal sensation (RTS) and (J) peak RTS. Absolute data are presented as mean and SD (error bars), while individual data are presented as symbols. *(P < 0.05), **(P < 0.01) and ***(P < 0.001) denote significant differences between conditions. Significance is presented as a single line across all bars if all three conditions were statistically significant from each other, or as joined lines between specific bars if two conditions were statistically significant from the other. PaH passive heating condition, WALK brisk walking condition, RUN running condition

An effect of condition was observed for mean RPE (Pcondition < 0.05), however, post hoc comparisons revealed no differences between conditions (PaH: 11.4 ± 1.6, WALK: 11.4 ± 1.6, RUN: 12.6 ± 0.9, all P > 0.05; Fig. 2G). Peak RPE was similar between RUN (16.6 ± 1.8) and PaH (16.5 ± 2.7, P > 0.999) and was higher in both RUN (P < 0.05) and PaH (P < 0.01) as compared to WALK (13.7 ± 2.4; Fig. 2H). Mean RTS was higher in RUN (5.5 ± 0.5) compared to WALK (4.9 ± 0.5, P < 0.05), but similar between RUN and PaH (5.2 ± 0.5, P = 0.200) and PaH and WALK (P = 0.631; Fig. 2I). Comparatively, peak RTS differed across all conditions (Pcondition < 0.001) and was highest in PaH (6.8 ± 0.8), followed by RUN (6.4 ± 0.7) and WALK (5.6 ± 0.6; Fig. 2J).

Intestinal Injury and Microbial Translocation

Pre-condition IFABP was similar between conditions (PaH: 848 ± 569 pg/ml, WALK: 767 ± 476 pg/ml, RUN: 745 ± 432 pg/ml, P = 0.833). An interaction effect was observed for IFABP over time (Pint < 0.01). Post hoc analysis revealed that IFABP increased from pre- to post-condition in RUN (745 ± 432 pg/ml vs. 1855 ± 1465 pg/ml, P < 0.001) and WALK (767 ± 476 pg/ml vs. 1144 ± 995 pg/ml, P < 0.05), but not in PaH (848 ± 569 pg/ml vs. 870 ± 562 pg/ml, P = 0.916). Post-condition IFABP was also higher in RUN than in PaH (P < 0.01) and WALK (P < 0.05) and similar between PaH and WALK (P > 0.999, Fig. 3A). ΔIFABP was higher in RUN (1110 ± 1251 pg/ml) than in PaH (23 ± 230 pg/ml, P < 0.05) and WALK (378 ± 647 pg/ml, P < 0.05), and similar between PaH and WALK (P = 0.148; Fig. 3B).

Fig. 3.

Fig. 3

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A Pre-and post-condition intestinal fatty acid binding protein (IFABP), B change in IFABP (ΔIFABP), C Pre- and post-condition lipopolysaccharide (LPS) and D change in LPS (ΔLPS). Absolute data are presented as mean and SD (error bars), while individual data are presented as symbols. *(P < 0.05) and **(P < 0.01) denote significant differences between conditions. PaH passive heating condition, WALK brisk walking condition, RUN running condition

Pre-condition LPS was similar between conditions (PaH: 1.7 ± 2.1 EU/ml, WALK: 1.6 ± 1.8 EU/ml, RUN: 1.5 ± 1.1 EU/ml, P = 0.928). No interaction effect was observed for LPS over time (Pint = 0.714), although main effects of time were observed (Ptime < 0.01). LPS decreased from pre- to post-condition in PaH (1.7 ± 2.1 EU/ml vs. 0.9 ± 0.5 EU/ml), WALK (1.6 ± 1.8 EU/ml vs. 0.7 ± 0.5 EU/ml) and RUN (1.5 ± 1.1 EU/ml vs. 1.0 ± 0.7 EU/ml, all P < 0.05, Fig. 3C). ΔLPS was similar across conditions (PaH: −0.8 ± 2.1 EU/ml, WALK: −0.9 ± 1.5 EU/ml, RUN: −0.5 ± 0.8 EU/ml, P = 0.643, Fig. 3D).

Correlation and Multiple Linear Regression Analyses

Correlational analysis revealed body fat percentage (r = 0.299), mean HR (r = 0.355) and peak HR (r = 0.295) had weak positive correlations, while percentage body mass loss (r = −0.301) had weak negative correlations with post-condition IFABP concentrations (all P < 0.05; Fig. 4A).

Fig. 4.

Fig. 4

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A Pearson’s correlation coefficient (r) for analyses between various parameters and post-condition IFABP. *(P < 0.05) denote significant correlations. B Explained and unexplained adjusted partial contributions to total variance for post-condition IFABP. VO2peak maximal aerobic capacity, Tc body core temperature, HR heart rate, RPE ratings of perceived exertion, RTS ratings of thermal sensation

The final model from the stepwise multiple linear regression accounted for only 15% of the variance in post-condition IFABP concentrations (Fig. 4B), with an adjusted R2 of 0.22, suggesting a weak relationship between fitted and actual post-condition IFABP concentration. The model had a high tolerance, with acceptable collinearity and model stability. Of the initial input variables, only three variables contributed to post-condition IFABP concentrations in the final model (Table 1), namely body fat percentage (6.8%), body mass loss percentage (4.1%) and body mass index (4.0%).

Table 1.

Multiple linear regression model for key contributors of post-condition IFABP concentration

Constant B 95% CI β p Tolerance Explained variance (%)
857 [−42092, 43806] 0.97
Body fat (%) 269 [116, 422] 0.62 < 0.01 0.92 6.8
Body mass loss (%) −600

[−1070,

−131]

 −0.38 < 0.05 0.90 4.1
BMI (kg/m 2) −226 [−436, −16] −0.38 < 0.05 0.99 4.0
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B: unstandardised regression coefficient, 95% CI confidence intervals of the slope coefficient or intercept, β: standardised regression coefficient. BMI Body Mass Index.

Discussion

We compared intestinal epithelial injury and endotoxin translocation following passive (PaH) and exertional hyperthermia (RUN), matched for peak Tc, and included a prolonged low-intensity walking (WALK) condition as an exploratory condition to provide ecological context relevant to occupational exposures. We also investigated potential predictors of post-intervention IFABP in order to better understand individual susceptibility to intestinal epithelial injury under varying thermal, metabolic, and mechanical stress conditions. Our findings demonstrate that exertional hyperthermia resulted in the greatest degree of intestinal epithelial injury compared with passive hyperthermia despite comparable peak Tc. Although WALK was characterised by lower peak Tc compared with RUN, cumulative heat load was comparable between WALK and RUN, and greater than PaH, indicating that prolonged, lower-intensity walking relevant to occupational exposure can induce subclinical elevations in IFABP despite modest workloads and Tc attained. These findings underscore the dominant role of combined thermal, metabolic and mechanical stress induced by exercise over thermal load alone in the pathogenesis of intestinal epithelial injury. Regression models revealed that body composition and fluid loss can account for 15% of the variance in post-condition IFABP concentrations. However, the small proportion of variance explained suggest other potential contributors that remain to be elucidated.

IFABP increased following moderate-intensity exercise in the heat (△1110 pg/ml) but not following passive hyperthermia (△23 pg/ml), despite comparable peak Tc between PaH and RUN (~ 39.3 °C). While past evidence has demonstrated that exertional hyperthermia with Tc ≥ 39.0 °C invariably disrupts intestinal epithelial integrity [26, 27], our findings suggest that elevated Tc alone is insufficient to elicit intestinal epithelial injury. Instead, a combination of thermal, metabolic and mechanical strain induced via exercise is likely required for the development of intestinal epithelial injury. During exercise, blood flow is preferentially redistributed towards active muscles and the skin to support metabolic and thermoregulatory demands, respectively [28]. This redistribution can lead to reduced perfusion of the splanchnic organs (splanchnic hypoperfusion), a condition that is further exacerbated by fluid loss through sweating during exercise [29, 30]. Prolonged or severe splanchnic hypoperfusion can result in intestinal ischemia, oxidative stress, and subsequent cellular injury [5, 8]. Although thermoregulatory demands during passive heating may also impact blood flow redistribution and contribute to splanchnic hypoperfusion, the degree of hypoperfusion observed during exercise is likely to exceed that in passive heating. This is where reductions in splanchnic hypoperfusion of up to 80% have been observed during exercise, and this likely affects intestinal ischaemia, tight junction integrity and intestinal barrier permeability to a much greater extent [30, 31]. Additionally, mechanical strain from exercise, such as elevated intra-abdominal pressure and increased GI jostling, can contribute to epithelial strain, compromising the mucosa [9]. Thus, passive hyperthermia may lack the profound redistribution of blood flow and mechanical impact associated with exercise, potentially limiting its effect on intestinal epithelial injury despite a similar thermal load. These findings augment preliminary evidence on the potential role of exertional and passive hyperthermia on GI perturbations previously reported in a small sample size of n = 6 [12].

Prolonged walking in the heat, characterised by lower peak Tc (38.2 ± 0.4 °C) and longer exercise durations (90 min), produced a modest rise in IFABP (△378 pg/ml). Despite lower peak Tc, cumulative heat load assessed as AUC Tc ≥38 °C was similar between WALK and RUN, yet intestinal epithelial injury was greater in RUN. This demonstrates that prolonged, low-intensity exercise in the heat can still induce minor intestinal epithelial injury, likely due to prolonged splanchnic hypoperfusion despite lower metabolic and mechanical strain [8, 32, 33]. Although the △IFABP in WALK was lower than 1000 pg/ml, a proposed clinical threshold consistently linked to GI dysfunction and subsequent systemic endotoxemia and inflammation [32, 34], subclinical insults may accumulate over time. In a trained cohort such as the one in this study, repeated exposures may represent a form of physiological eustress, in which mild, non-damaging GI perturbations serve as stimuli for adaptation, potentially enhancing GI resilience to future heat exposures. This may contrast with less-trained populations, which are more common in occupational settings. In such populations, repeated heat exposures combined with occupational stressors (e.g., long working hours, circadian disruption, psychological stress and adverse lifestyle factors associated with work patterns) have been associated with chronic low-grade inflammation linked to the development of diseases such as cardiovascular disease and chronic kidney disease [35–38]. While direct evidence linking subclinical intestinal epithelial injury to chronic systemic inflammation is lacking, this represents an avenue for future investigations. Thus, whether these repeated subclinical GI disturbances during heat exposure promote protective adaptation or increase susceptibility to exertional heat-related illnesses or GI disorders remains unclear, particularly across the diverse populations that may be chronically exposed to hot environments.

A potential responder vs. non-responder paradigm to GI dysfunction following passive hyperthermia has been previously suggested [39]. 50% of participants who attained a group mean Tc of 39.1 °C following whole-body passive hyperthermia had an increase in IFABP, suggesting intestinal epithelial injury [40]. A separate study observed that 33% of participants (Tc: 39.3 ± 0.2 °C) had increased [lactulose: rhamnose] ratios following passive hyperthermia, indicative of increased GI permeability [12]. Similarly, our study observed that 38% of participants (Tc: 39.3 ± 0.2 °C) had an increase in IFABP (△222 pg/ml) following passive hyperthermia. Comparatively, an increase in IFABP was observed in all participants in RUN, and 87% of participants in WALK. Although the magnitude of △IFABP in these responders following passive hyperthermia is considerably smaller than the increase observed in RUN, the disparate IFABP responses despite similar Tc attained may also suggest individual differences that can increase susceptibility to GI dysfunction, independent of Tc.

To gain insights into potential factors which may contribute to differences in individual responses, we explored regression models to identify predictors of IFABP. This, in part, also allowed us to account for the potential effect that unequal stressors, such as condition duration, may have on intestinal epithelial injury. Three variables, namely body fat percentage (6.8%), body mass loss percentage (4.1%) and body mass index (4.0%), contributed to post-condition IFABP concentrations in the final model. These findings suggest that fluid loss and body composition may contribute to the risk of intestinal epithelial injury. Indeed, dehydration following exercise in the heat can contribute to GI dysfunction due to impaired GI barrier maintenance and systemic hypovolemia, which can exacerbate splanchnic hypoperfusion [41, 42]. Similarly, higher adiposity has also been previously linked to increased intestinal permeability and GI dysfunction [43]. However, the small proportion of variance explained may suggest that our cohort of male endurance athletes had relatively homogeneous characteristics (e.g., age, VO2peak), potentially limiting variability in the predictors included in the regression analysis, and that other unmeasured variables likely contribute more substantially to intestinal epithelial injury. Among these unmeasured factors, individual differences in GI microbiome composition [34] have emerged as a potential contributor that could impact individual susceptibility to GI dysfunction, independent of Tc elevations. For example, GI barrier integrity has been linked to microbial diversity and the relative abundance of different bacterial taxa [34]. It should be noted that previous work has reported positive correlations between Tc and IFABP during prolonged, matched exertional heat stress, where metabolic and mechanical stress are likely similarly matched. Under these conditions, Tc was shown to be a robust predictor of GI injury [44]. Our study, however, included conditions in which the relative contributions of thermal, mechanical and metabolic stress differ. Despite achieving matched peak Tc, intestinal epithelial injury was observed in RUN but not PaH, while despite comparable cumulative heat load between RUN and WALK, intestinal epithelial injury was greater in RUN. These findings suggest that Tc alone does not fully account for intestinal epithelial injury when metabolic and mechanical stressors vary, emphasising the combined effects of thermal, metabolic and mechanical factors. Thus, while prior work may suggest that a longer duration of sustained exertional hyperthermia allows Tc elevation alone to dominate other stressors, our findings identify conditions in which additional stressors play a more important role. This highlights the multifactorial determinants of intestinal epithelial injury in the heat and the importance of considering the context in which elevated Tc may incur GI damage.

LPS was assessed as a marker of endotoxin leakage in this study, which is typically released following increased intestinal permeability and injury [4, 45]. However, in the present study, LPS decreased post-condition, despite evidence of intestinal epithelial injury in the heat. Similar findings have been reported, where trained individuals demonstrated a reduction in LPS despite elevated IFABP post-exercise [46], or constant LPS concentrations with Tc of up to 40 °C following exercise [47, 48]. Thus, we believe that these findings reflect effective endotoxin clearance, rather than a lack of translocation. This is where endurance athletes (VO2peak: 64 ± 6 ml/kg/min) who frequently train in hot and humid environments may develop greater endotoxin tolerance [46]. This may culminate in greater tolerance for GI dysfunction, preventing significant endotoxin translocation and potentially higher levels of resting anti-LPS antibodies, which improve the efficiency of clearance mechanisms such as the LPS scavenging response to prevent accumulation in the systemic circulation [47, 48].

Several limitations of this study should be acknowledged. Firstly, this study only included male endurance athletes native to the tropical country of Singapore. This may limit the generalisability of the findings to other populations such as individuals from temperate countries, females and less aerobically fit populations that may exhibit differing thermoregulatory or GI responses. Second, we only assessed Tc and HR, alongside two biomarkers (IFABP and LPS). The inclusion of skin temperature measures and a broader panel of biomarkers, including markers of tight junction integrity (e.g. claudins), intestinal permeability (e.g. [lactulose: rhamnose] ratios) and endotoxin translocation (e.g., LPS binding protein), alongside more direct measures of splanchnic perfusion and subjective measures of GI symptoms, would allow for a more comprehensive assessment of the thermoregulatory and GI responses in the heat. Thirdly, haemoglobin and haematocrit measurements were not performed, which prevented adjustment for changes in plasma volume. Future studies should include correction for plasma volume changes to delineate the contribution that fluid shifts may have on GI responses. Finally, the WALK condition was designed as a two-stage protocol to prevent premature termination due to local fatigue, while still allowing for metabolic heat production with low mechanical stress to explore the potential impact of lower-intensity prolonged exercise in the heat, similar to that observed in occupational settings, on intestinal epithelial injury. Thus, the WALK condition was not matched for peak Tc nor for duration. This was intentional to represent the ecologically distinct modes of hyperthermia during occupational exposure. However, similar cumulative heat load between WALK and RUN provides insight into how total heat load can interact with metabolic and mechanical stressors to induce intestinal epithelial injury. Nonetheless, the WALK condition does not provide a pure mechanistic isolation of the impact of various mechanisms underlying intestinal epithelial injury in exertional hyperthermia, and its findings should be interpreted as an exploratory, ecologically relevant condition rather than a mechanistic control. Although strict isolation of the various stressors in vivo is difficult to achieve as thermal, metabolic and mechanical stressors converge, future studies should aim to include matched-duration and/or matched-peak Tc protocols across exercise intensities to more precisely determine the individual mechanistic contributions of thermal, metabolic, and mechanical strain.

Conclusion

Taken together, our findings suggest that despite matched peak Tc, exertional, but not passive hyperthermia induces intestinal epithelial injury. This underscores the combined contribution of thermal, metabolic, and mechanical strain on intestinal epithelial injury in the heat, rather than thermal strain alone. Furthermore, low-intensity prolonged exercise in the heat may induce subclinical GI injury when cumulative heat load is sufficient, which has potential implications for GI health and systemic inflammation during occupational exposure. Body composition and fluid loss were also observed to partially predict intestinal epithelial injury; however, a substantial proportion of individual susceptibility to such injury remains unexplained. This highlights the need for more comprehensive studies in the future to augment responder versus non-responder analysis and identify potential at-risk individuals, informing more tailored heat management strategies.

Acknowledgements

The authors would like to thank Mr Tan Chee Chong Shawn, Ms Joon Han Yi and Ms Lim Jing Yi for their assistance in data collection, and all participants for their time and effort.

Abbreviations

AUC

Area under the curve

EHS

Exertional heat stroke

GI

Gastrointestinal

HR

Heart rate

IFABP

intestinal fatty acid binding protein

LPS

Lipopolysaccharides

PaH

Passive heating condition

RH

Relative humidity

RPE

Ratings of perceived exertion

RTS

Ratings of thermal sensation

RUN

Moderate-intensity run condition

SD

Standard deviation

Tc

Body core temperature

Tdb

Dry bulb temperature

USG

Urine specific gravity

VO2

Oxygen uptake

VO2peak

Maximal aerobic capacity

WALK

Prolonged brisk walking condition

Author Contributions

The study was conceptualised and designed by SBA, JKWL and ICCL. Data collection and analysis was conducted by SBA and LSXL. Manuscript preparation, writing and editing were completed by all authors. All authors have read and agreed to the submission of the finalised manuscript.

Funding

This research was funded by the Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore.

Data and Code Availability

The data and codes used during the current study are available from the corresponding author upon reasonable request.

Declarations

Ethics Approval and Consent to Participate

Ethical approval was obtained from the National University Institutional Review Board (Reference No.: NUS-IRB-LH-20-017) in accordance with the Declaration of Helsinki. All participants provided their written informed consent after being verbally briefed on the experimental procedures and potential risks associated with the study.

Consent for Publication

Not applicable.

Competing Interests

Sharifah Badriyah Alhadad, Louisa Si Xian Lim, Jason Kai Wei Lee and Ivan Cherh Chiet Low declare that they have no competing interests.

Footnotes

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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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

The data and codes used during the current study are available from the corresponding author upon reasonable request.

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