The primary response of the cardiovascular system to an increase in the ambient heat or heat from exertion is an increase in the blood flow to the skin (i.e., cutaneous vasodilation) to dissipate the excess heat. The modern paradigm of heat stroke suggests that the maintenance of a constant blood pressure implies/requires a reduction in blood flow to internal organs (i.e., splanchnic vasoconstriction) (1, 32, 36–38). However, splanchnic hypo-perfusion is not unique to heat stroke and common to critical illnesses (i.e., severe injury or infection) (39, 40), and may thus be a response to severe stress in general. In any case, the resulting hypoxia has important consequences on the gut and brain during heat stroke (as shown below) and promotes liver damage. In addition, the strain on the cardiovascular system often results in syncope and orthostatic intolerance in heat stroke (36).

Akin to heat stroke, several new hypotheses of ME/CFS suggest that vasoconstriction and hypoxia are central to its pathology—respectively focused on the consequence of ß2 adrenergic and M3 acetylcholine receptor autoantibodies (41, 42), a potential reduction of ACE2 expression (43), and an abnormal immune response with a concomitant impact on endothelial function (44). In addition, postural orthostatic tachycardia syndrome (POTS) is a common comorbidity of ME/CFS (45), which is a complex disorder of the vascular system also associated with gastrointestinal dysfunctions (46, 47). Impaired blood pressure variability and arrythmia have been observed in the patients with ME/CFS (48, 49).

In summary, vasoconstriction and hypoxia would appear to be common to both heat stroke in at least a subset of patients with ME/CFS—despite the difference in onset events of these two conditions. Research from critical illnesses (beyond heat stroke) suggests that splanchnic vasoconstriction is a general response to stressors. Vasoconstriction and hypoxia have far-reaching implications for organs and tissues.

Animal models of heat stroke have shown that ischemia resulting from reduced blood flow to the gut causes mucosal damage and a weakening of the tight junctions in the gut—likely via the action of oxidative and nitrosative stress (O&NS) (1, 4, 31–33, 35–38, 50, 51)—as well ATP depletion and local acidosis (50) induced by hypoxia. The result is a leaky gut characterized by a reduction of intestinal immunity and increased permeability of the intestines (1). This condition promotes gram-negative bacteria (i.e., lipopolysaccharides, LPS) that are normally contained in the gut to enter blood circulation (1, 4, 31–33, 35–38, 50, 52). Studies have shown that in the case of heat stroke, the liver is unable to effectively clear endotoxin (31), notably because of poor circulation in the venous system that returns blood from the digestive tract and spleen to the liver (37, 50). The resulting endotoxemia is assumed to trigger a systemic inflammatory response syndrome (SIRS) in heat stroke (as shown below) (4, 31–33, 35, 36, 53). Furthermore, findings from critical illness suggest that additional forms of intestinal injury play a role in driving critical illness, including the erosion of the mucus barrier, a shift in the composition and virulence of intestinal microbes, and the inability of the host epithelium to regulate its proliferative and apoptotic response (39, 54). These elements are thought to contribute to a vicious cycle of inflammation and intestinal injury. Moreover, the reduction in gut motility, the formation of toxic gut-derived lymph, and a decrease in the secretion of gastrointestinal hormones could contribute to multi-organ dysfunction in critical illness (55, 56).

Critically, normalization of the core temperature during heat stroke through cooling does not necessarily imply a reversion to normal gut permeability or the end of endotoxemia (1). Some researchers have thus suggested and tried to repair gut function to treat heat stroke (38). This includes the administration of nutritional supplements, such as glutamine and bovine colostrum with some promising results (33, 50, 57, 58). Additionally, the use of prebiotics and probiotics is being explored as an avenue for treatment (38, 50). Others have had success in limiting intestinal injury with the use of 4-phenylbutyrate to interrupt the endoplasmic reticulum stress-mediated apoptosis pathway of intestinal cells (59). Similarly, others have studied the use of xanthine oxidase inhibitor (allopurinol) to protect the integrity of tight cell-to-cell junctions in the gut of rat models (51). The inhibition of endotoxemia by pre-treatment with LPS-specific antibodies and corticosteroids to counteract LPS was shown to protect animals from lethal heat stress (31, 60). Readers are referred to the reviews for details on the results of human and animal studies (35, 38, 50, 61).

Echoing the endotoxemia model of heat stroke, ME/CFS researchers have hypothesized that the translocation of gut microbes or toxins from the gastrointestinal tract and the resulting inflammation is central to ME/CFS (62–66). Studies have found gut hyper-permeability (63) and gut inflammation (67) in ME/CFS as well as increased levels of the antibodies to LPS (IgM and IgA) in serum of patients with ME/CFS (the prevalence of patients with CFS with abnormally increased IgM and IgA levels: 40% and 66.7%) (68). Moreover, researchers have induced fatigue in mice through the administration of LPS (69). Finally, studies have shown that the normalization of leaky gut in ME/CFS by administration of natural anti-inflammatory and antioxidative substances is accompanied by a clinical improvement (70). Readers are referred to the reviews for a detailed discussion on the implication of gut permeability on the immune system and mitochondrial function in ME/CFS (7, 71).

It is worth noting that leaky gut is distinct from irritable bowel syndrome (IBS), although the former is believed to contribute to the latter (72). Leaky gut is related to changes in the permeability of the tight junctions in the gut barrier, which can be observed in the absence of symptoms (73). In research, changes in the gut barrier have been measured in urine using sugar probes of different molecular sizes, and in the circulation, using intestinal fatty acid binding protein (iFAB), and claudine-3 (74, 75). iFAB is an intracellular protein in the intestine wall and supports the transportation of fatty acid across the gut barrier. Claudine-3 is located between the tight junctions and functions as a “glue” to preserve the integrity of the gut barrier. Leaky gut is associated with diseases beyond the gut, such as diabetes (76) and autoimmune diseases (77, 78). Conversely, IBS is related to gut dysbiosis and is primarily associated with gastrointestinal discomfort (79). Whereas IBS is widely recognized as a clinical entity by the medical profession, leaky gut is largely considered the domain of alternative medicine (80).

In summary, gut hyper-permeability and endotoxemia would appear to be common to both heat stroke and at least a subset of patients with ME/CFS patients—despite the difference in onset events of these two conditions. These mechanisms have far-reaching implications on various physiological systems, including inflammation (as shown below). The results of human and animal experiments to repair gut function and mitigate endotoxemia in heat stroke might inform and provide new therapeutic avenues for ME/CFS.

Bouchama and Knochel suggest that the inflammatory response during the initial “acute-phase of heat stress” is mediated primarily by interleukin-6 (IL-6) and other pro-inflammatory cytokines, which serve to protect against tissue injury and to promote repair. Indeed, IL-6 and other cytokines induced by exposure to heat stress appear to mediate fever, leukocytosis, increased synthesis of acute-phase proteins, muscle catabolism, stimulation of the hypothalamic–pituitary–adrenal axis, and the activation of leukocytes and endothelial cells (1). However, an exaggeration of the acute-phase response can precipitate a maladaptive progression from heat stress to heat stroke. Specifically, leaky gut (as described above) hastens local inflammation toward the “exaggerated” systemic inflammatory response that underpins heat stroke (1). The field of exercise immunology has demonstrated that LPS leaking from the gut activates toll-like receptor (TLR) 4 on immune and intestinal epithelial cell membranes. This activation results in the production of pro-inflammatory cytokines, e.g., IL-6, IL-1β, and tumor necrosis factor (TNF)-α (31, 33, 35, 50). Moreover, the animal models of heat stroke have shown that, when LPS is present, NLRP3 (NOD-, LRR-, and pyrin domain-containing protein 3) inflammasomes are activated and drive neuroinflammation (81). A vicious cycle centered around intestinal injury ensues in heat stroke involving the release of nitric oxide, the leakage of gut-related endotoxins, and increased production of inflammatory cytokines (e.g., TNF-α, IL-1β, and IFN-γ) (35). Anti-inflammatory cytokines (IL-10, IL-1 receptor antagonist (IL-1ra), and TNF receptors p55 and p75) are also elevated, but to a lesser degree (2). The mode of action of cytokines in a heat stroke remains to be fully understood (33, 36). However, the increase in inflammatory cytokine levels is associated with inflammation-associated injury and refractory immunosuppression (1, 36) and can induce fever when transported to the brain (1, 82). Mouse models indicate that glia cells are a likely source of cytokine and chemokine production (36, 83).

Critically, normalization of the core temperature does not necessarily inhibit the systemic inflammatory response in heat stroke (1). Researchers have thus suggested and tried the modulation of the inflammatory response as a form of heat stroke treatment and prophylaxis, including with the administration of IL-1 receptor antagonists (81, 84), corticosteroids (60, 85), activated protein C (86), and the inhibition of nuclear factor-kB activity (1). Others have used oleoylethanolamide to inhibit LPS-induced TLR-4 stimulation of the immune response (50, 87). Blood purification therapy (53) and bone marrow-derived mononuclear cell therapy (88) to reduce pro-inflammatory cytokines have been suggested or tested in clinical trials. Other clinical trials have tested the efficacy of antioxidants and anti-inflammatories, such as quercetin (89). One study found that parenteral administration of ascorbate attenuated heat stroke-induced systemic inflammation in mice (90). Readers are referred to the reviews for details on the results of human and animal heat stroke studies (35, 50).

Akin to heat stroke, researchers have found that chronic inflammation also underlies ME/CFS (91–95), including inflammation of the brain—hence the name myalgic encephalomyelitis (96, 97). Moreover, similarly to heat stroke, O&NS has been documented in ME/CFS (98) and the cytokine profile of patients with ME/CFS differs from healthy controls (99, 100). Researchers have also linked NLRP3 inflammasomes with inflammation in ME/CFS (101). Some researchers have theorized that the complex pathways between these elements (O&NS, cytokines, and inflammation) underpin the metabolic dysfunction characteristic of the disease (102), including by hindering mitochondrial (103) and hypothalamic function (104, 105). Significantly, researchers suggest “the possibility of a vicious cycle of immune-dysregulation and gut dysbiosis accompanied by poor physiological gut function” perpetuating a disease state in ME/CFS (7)—as is the case for heat stroke. Readers are referred to the numerous studies and reviews for a detailed discussion on the relationship between redox imbalance, cytokines, and inflammatory pathways in ME/CFS (7, 101, 106, 107).

In summary, inflammation associated with cytokines and O&NS is central to both heat stroke and ME/CFS—despite the difference in onset events of these two conditions. Moreover, a vicious inflammatory cycle involving altered gut-blood barrier function (leaky gut) may be a central element of both heat stroke and some patients with ME/CFS. The results of human and animal experiments to modulate the inflammatory response in heat stroke might inform and provide new therapeutic avenues for ME/CFS.

Delirium, convulsions, and coma are common symptoms in the clinical presentation of heat stroke. The mechanisms of central nervous system injury in heat stroke are not well understood but are likely due to the combination of ischemia, hypoxia, thermolysis (Tc > 42°C), and hemorrhage (108–110). The animal models of heat stroke identified ischemia resulting from decreased cerebral flow and increased intracranial pressure as causing extensive cerebral neuronal injury (36). Moreover, a decrease in brain blood supply and an increase in intracranial pressure are followed by a compromised blood-brain barrier and an increase in circulatory pyrogens (37). In other words, analogous to the consequences of hypo-perfusion in the gut, reduced blood flow to the brain can lead to hypoxia, inflammation, and hyper-permeability within the brain, facilitating protein and pathogen leakage from the systemic circulation into the brain (32, 36, 37, 111). The severity of this mechanism in heat stroke can lead to brain injury.

Central nervous system dysfunctions are present in ME/CFS, albeit in a different form. Brain fog and hypersensitivity to noise and light are common symptoms in patients with ME/CFS (8, 13). However, the mechanisms in ME/CFS are arguably even less well understood than in heat stroke. Brain imaging studies revealed significant neuroinflammation (112–114) and white matter abnormalities (115), which are confirmed by autopsies (116). As mentioned above, a new unifying hypothesis of ME/CFS suggests that vasoconstriction and hypoxia in muscle and brain underpin ME/CFS, including cognitive impairments (41, 42). Studies have shown reduced cerebral blood flow during tilt tests (117). Akin to heat stroke, some patients with ME/CFS present signs of increased intracranial pressure (118, 119), consistent with altered blood flow. Alternatively, others have hypothesized that ME/CFS is promoted by gut microbes or toxin translocation from the gastrointestinal tract into other tissues, including the brain (62). The central nervous system is generally an immune-privileged site (i.e., protected from the peripheral immune system) (120), but pathogens that reach the brain can cause devastating inflammation (121).

In summary, central nervous system dysfunctions are central to both heat stroke and ME/CFS, albeit in different forms and to different degrees. Neuroinflammation, decreased blood flow to the brain and increased intracranial pressure might be common to both heat stroke and some ME/CFS patients. The animal models of heat stroke may inform the understanding of central nervous system dysfunction in ME/CFS.

Both the endotoxemia and the heat toxicity pathways are believed to contribute to coagulopathy dysfunction and endothelial-cell injury in heat stroke. First, intestine-derived endotoxins and cytokines activate vascular endothelial cells and coagulation factors to amplify the coagulation cascade (32, 35), which triggers vascular endothelial cell injury (122, 123). Moreover, the increase in core temperature directly leads to vascular endothelium damage (2), which in turn drives coagulation (32, 36). Bouchama and Knochel (1) describe a complex interplay among the cytotoxic effect of the heat and the inflammatory and coagulation responses of the host. Together these mechanisms result in a positive feedback loop, causing occlusion of the arterioles and capillaries (i.e., microvascular thrombosis) (32, 53, 90, 122). The vascular endothelial cell injury in heat stroke has been substantiated by evidence of differential expression of exosome lncRNAs and miRNAs (122).

Critically, normalization of the core temperature does not necessarily deactivate the coagulation process (1). Researchers have thus suggested anticoagulation therapy (53) with some initial positive results (124). Others have found that dexmedetomidine protects endothelial glycocalyx and increases the survival of rats during heat stroke (125). Readers are referred to the reviews for details on the results of human and animal studies (35, 38, 50).

Akin to heat stroke, hyper-coagulation was also suggested to be a contributing factor in ME/CFS (126–128), but the findings have not been consistent across the studies (129). The lessor importance or absence of coagulation dysfunctions in ME/CFS compared with heat stroke may be explained by the fact that the “heat toxicity pathway,” one of the drivers of the “positive feedback loop” driving coagulopathy dysfunction in heat stroke, is absent in ME/CFS.

Studies have shown that endothelial function is impaired in ME/CFS, both in large vessels and in microcirculation (130, 131). As in heat stroke, these findings were substantiated by indirect evidence related to the expression of miRNAs relevant to endothelial function (132). A new hypothesis for ME/CFS suggests that endothelial senescence underpins ME/CFS by disrupting the intestinal and blood-brain barriers (62).

In summary, coagulopathy dysfunction and endothelial-cell injury may be common to both heat stroke and at least a subset of patients with ME/CFS, despite the difference in onset events of these two conditions. The results of human and animal experiments to address coagulation disorders and endothelial-cell injury in heat stroke might inform and provide new therapeutic avenues for ME/CFS.

There are only few studies that assess mitochondrial function in heat stroke. ATP depletion (36) as well mitochondrial swelling and vacuolization in the epithelial cells of the gut have been observed in the mice models of heat stroke (52). Moreover, animal studies have shown that apoptosis of vascular endothelial cells in heat stroke was the deleterious consequence of reactive oxygen species (ROS)-induced p53 translocation into mitochondria (133). Finally, it was shown in vitro that higher temperatures can directly affect the viscosity of mitochondria (134).

Akin to heat stroke, the immuno-inflammatory pathways associated with O&NS are thought to be one of the possible mechanisms driving mitochondrial dysfunction in ME/CFS (103, 107). [Alternatively, mitochondrial dysfunction could be caused by viral reactivation in ME/CFS (135, 136)]. Impaired energy production (97, 137) and reduced mitochondrial activity (138–140) are central to the pathology of ME/CFS (7). Researchers have observed mitochondrial fragmentation (135) and impaired pyruvate dehydrogenase function as well as lactate degradation deficiencies in ME/CFS (141). Moreover, irregularities in the metabolites of patients with ME/CFS (141, 142) suggest that patients experience a hypometabolic or “dauer” state (143) maintained by mitochondria; an evolutionary adaptation to protect the cells and hosts from harm (c.f., “cell danger response”) (30, 144, 145). Readers are referred to the reviews for a detailed discussion on the relationship between the immune system and mitochondrial function in ME/CFS (7, 71).

In summary, mitochondrial dysfunction may be common to both heat stroke and ME/CFS, despite the difference in onset events of these two conditions. Mitochondrial dysfunction can be driven by immuno-inflammatory and O&NS pathways. The animal models of heat stroke may inform the understanding of mitochondrial dysfunction in some cases of ME/CFS.

A human transcriptome study performed by Bouchama et al. using peripheral blood mononuclear cells (PBMCs) of healthy volunteers exposed to short but extreme environmental heat treatment found “downregulation of most of the genes involved in the respiratory chain […] with a predicted decrease in ATP production and increase in oxidative stress.” The findings suggested that the “shift to glycolysis as a source of energy” and “inhibition of mitochondrial respiration” were sustained at least an hour after the end of the heat treatment. In addition, there was a “downregulation of ubiquitin conjugation and proteasome genes with a predicted decrease of protein refolding, mono- and poly-ubiquitination, and antigen presentation” as well as “decreased expression of the major histocompatibility I and II complexes genes, suggesting reduced antigen presentation” that persisted at least an hour after the end of treatment. To be clear, the volunteers did not experience heat stroke (only heat stress), but nonetheless, the study showed an adaptive response of mitochondria to heat stress - namely, altered protein synthesis, and reduced expression of genes related to immune function - to persist at least an hour after the heat stress ended. The authors could not explain why cellular stress response to heat would involve a “switch to a less efficient form of metabolism”(146).

Transcriptome studies have generally found altered gene expression in patients with ME/CFS (147–154). Researchers, for example, identified changes in the expression of genes in peripheral immune cells related to inflammation and mitochondrial function (153) as well as to oxidative stress (149) and immune function (149, 150, 154). Others have found specific microRNA expression patterns associated with specific symptom severities (155). Readers are referred to the reviews for a detailed discussion on alterations in gene expression in ME/CFS (95).

In summary, initial gene transcriptome studies would appear to suggest overlaps in alterations of gene expressions between the two conditions. Specifically, alterations in genes related to mitochondrial and immune function may be common to both heat stroke and some patients with ME/CFS. Future transcriptome studies of heat stroke may inform the understanding of ME/CFS.

Young children, the elderly, and patients with chronic diseases are most susceptible to classic heat stroke. Further intrinsic risk factors for classic heat stroke include underlying illness, cardiovascular insufficiency, concurrent infections, and an immune-compromised state (36).

However, the predisposing factors for exertional heat stroke—which affects young and apparently healthy and active individuals—are less clear. Similar to classic heat stroke, researchers have suggested that prior bouts of illness, infection or inflammation, preexisting barrier dysfunction, and a compromised immune system may increase the risk of exertional heat stroke (50, 156, 157). Specifically, prolonged stress exposure and/or suboptimal dietary intake - which suppress the immune system and alter the microbiome of the host, thus depleting its immune and epithelial barrier functions - are thought to be the determining factors in the susceptibility to exertional heat stroke (31, 50). Accordingly, some researchers have suggested that stress and lifestyle factors set the stage for a single event that promotes LPS translocation (such as exertion) to overwhelm the suppressed immune system (31). In the central circulation, LPS can be bound to LPS-specific antibodies, monocytes, or high-density lipoprotein and transported to the liver for removal by the reticuloendothelial system (31, 34). Immune suppression compromises LPS removal by monocytes and LPS-specific antibodies, leading to an increase in the concentration of LPS in the circulation (34, 158) and thus susceptibility to endotoxemia.

In terms of prior infection, a hypothesis derived from exercise immunology research suggests that the immune system is suppressed temporarily immediately post-intense exercise, which provides a window for dormant viruses to be reactivated to cause an infection (c.f. “open window theory”) (159). More specifically, a group of researchers has shown that the increased incidence of illness in response to excessive exercise is not due to immunosuppression per se, but rather to an altered focus of the immune function: an upregulation of humoral immunity and suppression of cell-mediated immunity (160).

Regarding gender bias, a review of 22 studies found that the overall risk for heat illnesses was 2.64 times higher in men than in women, but the authors suggest this could relate to sex-associated behavioral differences rather than physiology (161). Indeed, women are disadvantaged in terms of thermoregulation because of the smaller body surface area (BSA) to mass ratio, a higher percentage of body fat, and lower maximal oxygen consumption (VO₂max) (158). A study showed that greater heat intolerance in women relative to men is largely explained by VO₂max (162). A review of 24 studies of gender differences in the armed forces suggest that being a female was associated with a greater risk of exertional heat illnesses, but men experienced a slightly higher incidence of exertional heat stroke (163)—perhaps also because of behavioral differences.

Failure to increase the expression of heat shock proteins (HSPs) has been implicated in the pathogenesis of heat stroke (146). HSPs play a central role in the maintenance of endothelial and epithelial barrier function (164, 165). Conditions associated with a low level of expression of HSPs, for instance, aging, lack of acclimatization to heat, and certain genetic polymorphisms, may favor the progression from heat stress to heat stroke (1). Initial studies have shown that selective pharmacologic induction of the expression of HSPs (e.g., with alpha-lipoic acid) can protect cells from apoptosis and inflammatory responses induced by heat stroke (166).

Finally, Bouchama and Knochel suggest that “genetic factors may determine the susceptibility to heat stroke; candidate susceptibility genes include those that encode cytokines, coagulation proteins, and heat-shock proteins involved in the adaptation to heat stress” (1). Specifically, TLR4 polymorphisms may be a genetic factor predisposing to mortality during the systemic inflammatory response to heat stroke (36). However, the importance of genetic factors as a risk for heat stroke remains unresolved.

Akin to exertional heat stroke, the predisposing factors for ME/CFS are not clear. Certainly, existing inflammation or infection is likely a risk factor (167). Echoing the “open window theory” of exercise immunology, it has long been suggested that ME/CFS results from bacterial or viral reactivation in the context of a suppressed immune system (168, 169), particularly the reactivation of Epstein-Barr virus (EBV) and cytomegalovirus (CMV) (170, 171). Cumulative life stress is considered a predisposing factor for ME/CFS (172), which is also thought to alter gut permeability and thus immune function (173). As in heat stroke, the microbiome disturbances and dysbiosis are associated with ME/CFS pathology (147, 174–179). Gender is a risk factor for ME/CFS: the female-to-male ratio ranges from 2:1 to 6:1 (12).

Moreover, the studies have shown that ME/CFS is characterized by impaired HSPs production (180) which, combined with O&NS and low-grade inflammation, could explain muscle dysfunction and exercise intolerance (181, 182). Akin to heat stroke, it has been suggested (but not yet trialed) to incorporate the upregulation of HSP into future treatments for ME/CFS (183).

Finally, research suggests there may be a genetic element in the pathogenesis of ME/CFS, such as polymorphism in genes related to immunomodulatory response (184, 185), hormone action (184, 186), and metabolic kynurenic pathways (187). However, genetic associations are not consistent (188) and studies have had quality-control issues (188, 189).

In summary, there are important similarities in predisposing factors for heat stroke and ME/CFS. Pre-existing inflammation or infection may make individuals susceptible to the conditions. Viral reactivation may also play a role in both conditions. Both are associated with immune suppression. Parallel hypotheses suggest that cumulative stress and associated degradation of microbiome health could set the stage for increased susceptibility for both conditions. There is a female predominance in ME/CFS; physiological differences may make women intrinsically more susceptible to exertional heat illnesses than men. In addition, insufficient expression of HSPs has been identified as a factor in both conditions. Finally, genetics are thought to be a risk factor for both conditions, but studies are inconclusive.