key: cord-0730622-ivkw8wpq authors: Stanculescu, Dominic; Bergquist, Jonas title: Perspective: Drawing on Findings From Critical Illness to Explain Myalgic Encephalomyelitis/Chronic Fatigue Syndrome date: 2022-03-08 journal: Front Med (Lausanne) DOI: 10.3389/fmed.2022.818728 sha: cccafdf30bd43a87008cff28c068131cc965d248 doc_id: 730622 cord_uid: ivkw8wpq We propose an initial explanation for how myalgic encephalomyelitis / chronic fatigue syndrome (ME/CFS) could originate and perpetuate by drawing on findings from critical illness research. Specifically, we combine emerging findings regarding (a) hypoperfusion and endotheliopathy, and (b) intestinal injury in these illnesses with our previously published hypothesis about the role of (c) pituitary suppression, and (d) low thyroid hormone function associated with redox imbalance in ME/CFS. Moreover, we describe interlinkages between these pathophysiological mechanisms as well as “vicious cycles” involving cytokines and inflammation that may contribute to explain the chronic nature of these illnesses. This paper summarizes and expands on our previous publications about the relevance of findings from critical illness for ME/CFS. New knowledge on diagnostics, prognostics and treatment strategies could be gained through active collaboration between critical illness and ME/CFS researchers, which could lead to improved outcomes for both conditions. Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating illness that affects millions of people worldwide (an estimated 800,000 to 2.5 million in the USA) (1, 2) . Impaired function, post-exertional malaise, and unrefreshing sleep are core symptoms (1, 3, 4) . At least onequarter of ME/CFS patients are house-or bedbound at some point in their lives (1) ; the illness can be completely incapacitating (5) . The etiology of the illness is unclear (6, 7) and peri-onset events include infection-related episodes, stressful incidents, and exposure to environmental toxins (8) . Critical illness refers to the physiological response to virtually any severe injury or infection, such as head injury, burns, cardiac surgery, SARS-CoV-2 infection and heat stroke (9) . Researchers make a distinction between the acute phase of critical illness-in the first hours or days following severe trauma or infection; and the chronic or prolonged phase-in the case of patients who survive the acute phase but for unknown reasons do not start recovering and continue to require intensive care (10-13). Regardless of the initial injury or infection, these "chronic Intensive Care Unit (ICU) patients" experience profound muscular weakness, cognitive impairment, pain, vulnerability to infection, etc. (9, 11, 14) . The treatment of prolonged critical illness is incomplete and remains an active area of research. Moreover, cognitive and/or physical disability can last for months or even years after treatment in ICUs (i.e., post intensive care syndrome, PICS) for as of yet unexplained reasons (15) (16) (17) . Drawing on findings from critical illness, we here propose an initial explanation for how ME/CFS could originate and perpetuate. Specifically, we combine emerging findings regarding (a) hypoperfusion and endotheliopathy, and (b) intestinal injury in these illnesses with our previously published hypothesis about the role of (c) pituitary suppression, and (d) low thyroid hormone function associated with redox imbalance in ME/CFS. Moreover, we describe interlinkages between these pathophysiological mechanisms as well as "vicious cycles" involving cytokines and inflammation that may contribute to explain the chronic nature of these illnesses. This explanation summarizes and expands on our previous publications about the relevance of findings from critical illness for ME/CFS (18) (19) (20) and builds on the work by Nacul et al. (21) . The general lack of large high-quality ME/CFS studies (a reflection of the lack of funding in this field) poses a challenge for the assessment of overlaps between the two conditions. In the following sections we describe four central pathophysiological mechanisms in critical illness, including their relationship to inflammation. We also provide initial arguments for suggesting that similar mechanisms may underlie ME/CFS. Readers are referred to our prior publications for additional details about these mechanisms in critical illness (including heat stroke) and possible lessons for understanding ME/CFS (18) (19) (20) . It has long been suggested that inadequate oxygen circulation is central to critical illness (22). Specifically, the redistribution of blood away from the splanchnic area to critical tissues is considered an adaptive androgenic response to physiological stress (23, 24). However, the resulting ischemia / reperfusion (I/R) can contribute to tissue injury driving sepsis and multiorgan dysfunction (25, 26). The relative importance of reduced blood flow, vasoconstriction (27), capillary flow disturbances (28) and impaired cellular oxygen utilization (29, 30) in driving critical illness continues to be debated. Endothelial dysfunction appears to occur in parallel with circulation disturbances during critical illness. Probable drivers of distortions in the structure and function of endothelial lining (i.e., glycocalyx) are cytokines (31), inflammation, exposure to oxidative stress (28, 32) and/or sympatho-adrenal hyperactivation (33). Crucially, endothelial dysfunction during critical illness has been associated with altered cerebral blood flow (34, 35) and increased blood-brain barrier (BBB) permeability resulting in long-term cognitive impairment (36, 37). A leaky BBB could also contribute to increased intracranial pressure (38, 39). Finally, researchers have found that endotheliopathy and coagulation disorder bolster each other via inflammatory pathways (40). Coagulation abnormalities vary in critical illness, but coagulopathy is associated with unfavorable outcomes in prolonged critical illness (i.e., length of ICU stay and mortality) (41). We propose that similar alterations of the vascular system in response to a physical, infectious and / or emotional stressor (i.e., physiological insult) may also contribute to explain the emergence of ME/CFS. This is consistent with recent hypotheses describing vasoconstriction in muscle and brain as a principal element of ME/CFS (42-46), and findings of cerebral hypoperfusion (47-49) and intracranial hypertension (50) in ME/CFS patients. It is also consistent with studies that have shown that endothelial function is impaired in ME/CFS (51, 52), both in large vessels and in the microcirculation (53, 54)-associated with redox imbalance (51). Finally, it is consistent with a new hypothesis for ME/CFS which suggests that endothelial senescence underpins ME/CFS by disrupting the intestinal barriers and BBBs (55), as well as with suggestions that leakage from dysfunctional blood vessels could explain many of the symptoms in ME/CFS (56). Critical illness researchers have found profound intestinal alterations within hours following a physiological insult: a dramatic shift in the composition and virulence of intestinal microbes (57-59), an erosion of the mucus barrier, an increase in the permeability of the gut (i.e., "leaky gut") (60) (61) (62) , and a disruption in gut motility (63) . This intestinal injury is thought to be largely a consequence of local I/R and redox imbalance resulting from splanchnic hypoperfusion (58, 61, [64] [65] [66] [67] . Indeed, studies in the field of exercise immunology have shown that even relatively low levels of splanchnic hypoperfusion during exercise result in intestinal injury (68) . Critically, this intestinal injury may lead to bacterial translocation from the gut into circulation (i.e., endotoxemia) and/or the formation of toxic gut-derived lymph (57, 60). This in turn can induce pro-inflammatory cytokines and systemic inflammation (69, 70) . Moreover, changes in the intestinal microbiome or the mucus barrier may also impact the immune system directly (57). Thus, researchers have long considered the gut "the motor of critical illness" driving sepsis and distant organ dysfunction (71) . Some have suggested that a self-perpetuating vicious inflammatory cycle centered around intestinal injury can hinder recovery from critical illness (61, 72) . We propose that the sequence during critical illness-from splanchnic hypoperfusion to hypoxia, redox imbalance, altered gut microbiome, intestinal injury, gut-related endotoxemia, pro-inflammatory cytokines and systemic inflammatorymay also contribute to explain the emergence of ME/CFS following a physiological insult. Our proposal is in alignment with others' findings that intestinal injury and resulting inflammation are central to ME/CFS (73) (74) (75) (76) (77) (78) (79) (80) (81) and consistent with findings linking the gut microbiome to inflammation (82) (83) (84) (85) and to fatigue symptoms in ME/CFS (86) . If verified, the existence of a vicious inflammatory cycle centered around intestinal injury could contribute to explain the perpetuation of ME/CFS. Post-exertional malaise-a key symptom of ME/CFScould be the manifestation of an accentuation in intestinal injury following exertion. Moreover, the translocation of gut microbes or toxin from the intestines to the brain (55) might contribute to explain central nervous system inflammation in ME/CFS (87) (88) (89) . Finally, leaky gut is also associated with auto-immunity (90, 91)-an important factor in ME/CFS pathology (92) (93) (94) . Almost immediately after a physiological insult, endocrine axes experience profound alterations considered a vital response to severe stress or injury to allow for a shift in energy and resources to essential organs and repair (95) (96) (97) . Whereas, in critically ill patients who begin to recover, endocrine axes essentially normalize within 28 days of illness, in cases of prolonged critical illness the pituitary's pulsatile secretion of tropic hormones (unexpectedly) remains suppressed. Why and how this central suppression is maintained in prolonged critical illness continues to be debated. Inflammatory pathways likely play a role irrespective of the nature of the original injury or infection. For example, cytokines increase the abundance and affinity of glucocorticoid receptors (GR) at the level of the hypothalamus / pituitary, thereby enhancing the negative feedback loop of the hypothalamic-pituitary-adrenal (HPA) axis, and consequently suppressing pituitary release of adrenocorticotropic hormone (ACTH) (95, 98) . Similarly, cytokines up-regulate deiodinase enzymes in the hypothalamus resulting in higher local levels of the active thyroid hormone (T3), thereby enhancing the hypothalamic-pituitary-thyroid (HPT) axis' negative feedback loop and consequently suppressing pituitary secretion of thyroid stimulating hormone (TSH) irrespective of circulating thyroid hormone concentrations (99) (100) (101) . Cytokines may also suppress the release of TSH by the pituitary directly (102, 103) contributing to a virtual complete loss of pulsatile TSH secretion (96) . The loss of pulsatile pituitary secretions has important implications for the autonomic nervous system, metabolism, and the immune system. Without sufficient pulsatile stimulation by ACTH, adrenal glands begin to atrophy (104, 105) , compromising patients' ability to cope with external stressors and permitting excessive inflammatory responses. Erratic rather than pulsatile pituitary production of growth hormone (GH) leads to an imbalance between catabolic and anabolic hormones, resulting in loss of muscle and bone mass, muscle weakness, and changes in glucose and fat metabolism (106) (107) (108) . Finally, suppression of the HPT axis is associated with tiredness and other hypothyroid-like symptoms (109, 110) . We propose that the sequence during critical illness-from increased release of pituitary hormones during the acute phase to suppression of the pituitary gland's pulsatile secretion in the prolonged phase-could also contribute to explain the emergence of ME/CFS following a physiological insult. This proposal is consistent with descriptions of ME/CFS as a progression from a hypermetabolic to hypometabolic state (21). It also aligns with a recent hypothesis relating many of the symptoms in severe ME/CFS to impaired pituitary function (111) . Further support for this proposal is provided by the many previous ME/CFS studies that have documented dysfunctions in the hypothalamic-pituitary-somatotropic (HPS) axis (112) (113) (114) , the HPT axis (115) (116) (117) (118) (119) (120) , and the HPA axis (121-136)-notably associated with inflammation and oxidative & nitrosative stress (O&NS) (137) (138) (139) (140) . Strikingly, models relating the persistence of a suppressed HPA axis in ME/CFS to a change in central GRs concentrations resemble the explanations provided for pituitary suppression in critical illness (141) (142) (143) (144) (145) (146) . Moreover, suppression of ACTH release would explain why in a small study ME/CFS patients were found to have 50% smaller adrenals than controls (147) , resembling adrenal atrophy in prolonged critical illness. However, the relationship between the pituitary's pulsatile secretions, physiological alterations and severity of illnesswhich proved revelatory in understanding prolonged critical illness-remains unexplored in ME/CFS. Peripheral mechanisms involving cytokines lead to the rapid depression of thyroid hormone activity following a severe physiological insult (148) (149) (150) (151) (152) . This is termed "non-thyroidal illness syndrome" (NTIS), "euthyroid sick syndrome" or "low T3 syndrome" and is thought to be an adaptive response to conserve energy resources during critical illness (152) (153) (154) . The mechanisms involved include alterations in the half-life of thyroid hormone in circulation (155) (156) (157) ; modifications in the uptake of thyroid hormone by cells (158, 159) ; down-and up-regulation of deiodinase enzymes that convert the thyroid hormone into active and inactive forms respectively (156, 160) ; and alterations in sensitivity of cells to thyroid hormones (161) (162) (163) . These alterations can lead to important tissue-specific depression in thyroid hormone function (164, 165) which is, however, often missed altogether in clinical settings (166) because most of the alterations do not translate into changes in the blood concentrations of thyroid hormones (164, 167, 168) . Indeed, the decrease in the ratio of the active form of thyroid hormone (T3) relative to the inactivated thyroid hormone (rT3) (150, 152, 169) -considered the most sensitive marker of NTIS-may be just the "tip of the iceberg" of the depressed thyroid hormone function in target tissues (120, 170) . While NTIS may be beneficial in the acute phase of critical illness, it is increasingly seen as maladaptive and hampering the recovery of patients in the case of prolonged critical illness (96, 101, 152, 169, (171) (172) (173) . Low thyroid hormone function may hamper the function of organs (170) and the activity of immune cells, including natural killer cells (174) (175) (176) (177) (178) (179) (180) (181) (182) (183) (184) (185) . Immune dysfunctions might in turn explain other pathologies, such as viral reactivation observed in ICU patients (186) (187) (188) . Some critical illness researchers have proposed a model that describes how NTIS is maintained by reciprocal relationships between inflammation (notably pro-inflammatory cytokines), O&NS and reduced thyroid hormone function, forming a "vicious cycle" (101, 173) . This model can help to explain the perplexing failure to recover of some critically ill patients in ICUs that survive their initial severe illness or injury. We propose that low thyroid hormone function could also contribute to explain the emergence of ME/CFS following a physiological insult. An immune-mediated loss of thyroid hormone function in ME/CFS has long been suspected (117) . A recent study showed that the thyroid panel of ME/CFS patients resembles that of critical illness patients, including significantly lower ratio of T3 to rT3 hormones (120) . Moreover, the other elements for a "vicious cycle" which researchers have suggested perpetuate a hypometabolic and inflammatory state in critical illness are also present in ME/CFS, including inflammation (140, 189) , increased O&NS (190) (191) (192) and altered cytokine profiles (193, 194) . Hypoperfusion and endotheliopathy, intestinal injury, pituitary suppression, and low thyroid hormone function are each central to prolonged critical illness regardless of the nature of the initial severe injury or infection (101, 173, 195, 196) . We propose that, similarly, these mechanisms and their reciprocal relationships with inflammation could underlie ME/CFS regardless of the nature of the peri-onset event (i.e., infection, stressful incident, exposure to environmental toxins or other) ( Table 1) . Moreover, the severity of ME/CFS may be a function of the strength of these mechanisms. However, each of these pathological mechanisms has largely been studied in isolation and rarely have the linkages between them been explored. Yet, the aggregate of these mechanisms is likely necessary to fully explain the perpetuation of critical illness-and to inform the understanding of ME/CFS (Figure 1) . Additional areas for inquiry thus include the following: Intestinal injury during critical illness results in decreased secretion of gastrointestinal hormones including ghrelin (63, 197) . Decreased stimulation of the pituitary and hypothalamus by ghrelin during prolonged critical illness in turn results in lower secretion of GH by the pituitary (199) . Researchers have found that the administration of an artificial ghrelin in chronic ICU patients reactivated the pulsatile secretion of GH by the pituitary and-when done in combination with thyrotropinreleasing hormones (TRH)-had beneficial metabolic effects (96, 108, 198) . Similarly, the administration of ghrelin to the I/R rats "inhibited pro-inflammatory cytokine release, reduced neutrophil infiltration, ameliorated intestinal barrier dysfunction, attenuated organ injury, and improved survival" (200) . The sequence between intestinal injury, ghrelin secretion and GH release by the pituitary could be particularly relevant for solving ME/CFS given that "several of the main typical symptoms in severe ME/CFS, such as fatigue, myalgia, contractility, delaying muscle recovery and function, exertional malaise, neurocognitive dysfunction, and physical disability may be related to severe GH deficiency" (111) . There are several pathways linking the activity of the pituitary with that of thyroid hormones. Firstly, GH secreted by the pituitary co-regulates the activity of the deiodinase enzyme (D3) responsible for the conversion of thyroid hormones into inactive forms (i.e., rT3 and inactivate forms of T2) (106, 201) . Researchers showed that normalization of the GH secretion in prolonged critically ill patients is necessary to inhibit the increase in plasma rT3 concentrations (96, 108, 198) . In other words, dampened GH release by the pituitary during prolonged critical illness enables low thyroid hormone function. Secondly, the lack of stimulation of the adrenals by ACTH could (by causing an atrophy of adrenals) create the condition necessary for persistent inflammation which depresses the activity of thyroid hormones during critical illness (148) (149) (150) (151) (152) . In other words, dampened ACTH release by the pituitary during prolonged critical illness might permit the vicious inflammatory cycles described above. Thirdly, there is evidence that thyroid hormone conversely also stimulates ACTH secretion (202, 203) . In summary, the bidirectional relationships between the endocrine axes and thyroid hormone function (in addition to reciprocal relationships with inflammation) could contribute to explain the persistence of chronic ICU and ME/CFS. Upon binding to specific receptors on endothelial cells, thyroid hormones (T3 and T4) activate the endothelial nitric oxide synthase (eNOS) responsible for nitric oxide (NO) production (204) , which in turn impacts vasodilation and inflammation (205) (206) (207) . A further line of inquiry may thus be the role of thyroid hormone function in endotheliopathy in ME/CFS, including as it relates to the new finding that plasma from ME/CFS patients inhibits eNOS and NO production in endothelial cells (208) . Relatedly, critical illness researchers have found that serum from patients with NTIS inhibits the uptake of thyroid hormone (209, 210) ; the mechanisms remain unresolved (165) . The impaired perfusion, redox imbalance, lower thyroid hormone function and inflammation appear to collectively affect mitochondrial activity in critical illness (via inhibition, damage, and/or decreased turnover of new mitochondrial protein) (30, [211] [212] [213] . Mitochondrial activity may be similarly affected in ME/CFS (190) . Some have suggested that this down-regulation of mitochondrial activity (and oxygen utilization) in critical illness may be an adaptive form of "hibernation" to protect cells from death pathways (30, 213). This suggestion echoes the hypothesis TABLE 1 | Central pathophysiological mechanisms in prolonged critical illness, probable drivers and implications, and initial evidence suggesting similar mechanisms in ME/CFS. In prolonged critical illness (Probable drivers and implications) In ME/CFS (Initial evidence) In ME/CFS (Initial evidence) Initial evidence • Immune-mediated loss of thyroid hormone function in ME/CFS (suspected) (117) • Significantly lower ratio of T3 to rT3 hormones (120) FIGURE 1 | Central pathophysiological mechanisms in critical illness including selected consequences and inter-linkages. Hypoperfusion and endotheliopathy, intestinal injury, pituitary suppression, and low thyroid hormone function are each central to prolonged critical illness regardless of the nature of the initial severe injury or infection. These pathophysiological mechanisms are in reciprocal relationships with inflammation; specifically, researchers have proposed vicious cycles involving intestinal injury and low thyroid hormone function. Moreover, linkages have been described between these pathophysiological mechanisms, including (i) hypoperfusion and intestinal injury (i.e., leaky gut resulting from ischemia/reperfusion, hypoxia and redox imbalance); (ii) intestinal injury and pituitary suppression (i.e., suppressed growth hormone release resulting from reduced ghrelin secretion by the intestines); (iii) pituitary suppression and low thyroid hormone function (i.e., increased inactivated thyroid hormone resulting from the upregulation of D3 deiodinase as a consequence of lower growth hormone); and (iv) low thyroid hormone function and pituitary suppression (i.e., decreased ACTH secretion resulting from lower levels of activated thyroid hormone). We propose that these mechanisms and the linkages between them-alongside reciprocal relationships with inflammation-could also underlie ME/CFS. that ME/CFS is a form of "dauer" or "cell danger response" (214) (215) (216) . Lower mitochondrial activity in turn affects the immune system and the gut endothelial "such that the host's immune response and physical barriers to infection are simultaneously compromised" (29). Although prolonged critical illness remains unresolved, early treatment trials-such as the reactivation of the pituitary, or interruption of the vicious inflammatory cycles centered around either gut injury or low thyroid hormone function-may provide therapeutic avenues for ME/CFS (19) . Longitudinal studies of (spontaneous) recovery from critical illness may also give clues about prerequisites for recovery from ME/CFS. Researchers have, for example, found that "supranormal TSH precedes onset of recovery" from prolonged critical illness (96) and that metabolic rate rises > 50% above normal in the recovery phase (213) . Researchers have suggested commonality in the illnesses induced by physical, infectious, and / or emotional stressors (132, 217) . These include heat stroke, fibromyalgia, ME/CFS, prolonged critical illness, PICS, cancer-related fatigue, post-viral fatigue, post-acute COVID-19 syndrome (PACS) and long-COVID. Specifically, it is necessary to explore whether the pathological mechanisms described above also underlie long COVID-a disease which resembles ME/CFS (218) (219) (220) (221) (222) (223) (224) (225) (226) (227) (228) and can arise even after mild COVID-19 cases. Decades of research in the field of critical illness medicine have demonstrated that in response to the stress of severe infection or injury, the vascular system, intestines, endocrine axes and thyroid hormone function experience profound alterations. Self-reinforcing interlinkages between these pathophysiological mechanisms as well as "vicious cycles" involving cytokines and inflammation may perpetuate illness irrespective of the initial severe infection or injury. Without excluding possible predisposing genetic or environmental factors, we propose that the pathological mechanisms-and the interlinkages between them-that prevent recovery of some critically ill patients may also underlie ME/CFS. This initial proposal is in line with and complements several existing hypotheses of ME/CFS pathogenesis. If this hypothesis is validated, past treatment trials for critical illness may provide avenues for a cure for ME/CFS. Certainly, given the similarities described above, active collaboration between critical illness and ME/CFS researchers could lead to improved understanding of not only both conditions, but also PICS, long-COVID, PACS, and fibromyalgia. The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s. DS wrote the first draft of the manuscript. All authors contributed to manuscript revision, read, and approved the submitted version. Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Redefining an Illness Updating the National Academy of Medicine ME/CFS prevalence and economic impact figures to account for population growth and inflation Available online at European Network on Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (EUROMENE): expert consensus on the diagnosis, service provision, and care of people with ME/CFS in Europe Extremely severe ME/CFSra personal account Myalgic encephalomyelitis/chronic fatigue syndrome: when suffering is multiplied Onset patterns and course of myalgic encephalomyelitis/chronic fatigue syndrome. Front Pediatr Chronic critical illness: are we saving patients or creating victims? Rev Bras Ter Intensiva Novel insights into the neuroendocrinology of critical illness Chronic critical illness Acute and prolonged critical illness are two distinct neuroendocrine paradigms The neuroendocrine response to critical illness is a dynamic process Van den Berghe G. ICU-acquired weakness Van den Berghe G. Endocrinopathy of the Critically Ill Post-intensive care syndrome: an overview Post Intensive Care Syndrome Hypothesis: mechanisms that prevent recovery in prolonged ICU patients also underlie Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) Theory: treatments for prolonged ICU patients may provide new therapeutic avenues for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) Metagenomic analysis reveals dynamic changes of whole gut microbiota in the acute phase of intensive care unit patients Redefining the gut as the motor of critical illness Gut failure in critical care: old school versus new school Increased intestinal permeability is associated with the development of multiple organ dysfunction syndrome in critically ill ICU patients Gastrointestinal function in critical illness-a complex interplay between the nervous and enteroendocrine systems Intestinal permeability-a new target for disease prevention and therapy Determinants of intestinal barrier failure in critical illness Clinical review: splanchnic ischaemia Gut dysfunction in critically ill patients: a review of the literature Exercise-induced splanchnic hypoperfusion results in gut dysfunction in healthy men Epithelial barrier dysfunction: a unifying theme to explain the pathogenesis of multiple organ dysfunction at the cellular level Intraoperative splanchnic hypoperfusion, increased intestinal permeability, down-regulation of monocyte class II major histocompatibility complex expression, exaggerated acute phase response, and sepsis Multi-organ-failure syndrome. The gastrointestinal tract: the "motor" of MOF Gut-origin sepsis: evolution of a concept Normalization of the increased translocation of endotoxin from gram negative enterobacteria (leaky gut) is accompanied by a remission of chronic fatigue syndrome The role of microbiota and intestinal permeability in the pathophysiology of autoimmune and neuroimmune processes with an emphasis on inflammatory bowel disease type 1 diabetes and chronic fatigue syndrome Myalgic encephalomyelitis or chronic fatigue syndrome: how could the illness develop? Metab Brain Dis Increased serum IgA and IgM against LPS of enterobacteria in chronic fatigue syndrome (CFS): indication for the involvement of gram-negative enterobacteria in the etiology of CFS and for the presence of an increased gut-intestinal permeability Activation of the NLRP3 inflammasome in lipopolysaccharide-induced mouse fatigue and its relevance to chronic fatigue syndrome Normalization of leaky gut in chronic fatigue syndrome (CFS) is accompanied by a clinical improvement: effects of age, duration of illness and the translocation of LPS from gram-negative bacteria Pathological mechanisms underlying myalgic encephalomyelitis/chronic fatigue syndrome Mitochondria and immunity in chronic fatigue syndrome Changes in gut and plasma microbiome following exercise challenge in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) Reduced diversity and altered composition of the gut microbiome in individuals with myalgic encephalomyelitis/chronic fatigue syndrome Gut inflammation in chronic fatigue syndrome The emerging role of gut microbiota in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): current evidence and potential therapeutic applications the gut microbiome in Myalgic Encephalomyelitis (ME)/Chronic Fatigue Syndrome (CFS) Deficient butyrate-producing capacity in the gut microbiome of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome patients is associated with fatigue symptoms Neuroinflammation in the brain of patients with myalgic encephalomyelitis/chronic fatigue syndrome Neuroinflammation in patients with chronic fatigue syndrome/myalgic encephalomyelitis: an (1)(1)C-(R)-PK11195 PET study Evidence of widespread metabolite abnormalities in Myalgic encephalomyelitis/chronic fatigue syndrome: assessment with wholebrain magnetic resonance spectroscopy Leaky gut as a danger signal for autoimmune diseases Leaky gut and autoimmune diseases Myalgic encephalomyelitis/chronic fatigue syndromeevidence for an autoimmune disease The emerging role of autoimmunity in myalgic encephalomyelitis/chronic fatigue syndrome (ME/cfs) Infection elicited autoimmunity and myalgic encephalomyelitis/chronic fatigue syndrome: an explanatory model New insights into the controversy of adrenal function during critical illness On the neuroendocrinopathy of critical illness. Perspectives for feeding and novel treatments Altered adrenal and gonadal steroids biosynthesis in patients with burn injury Mechanisms and clinical consequences of critical illness associated adrenal insufficiency Simultaneous changes in central and peripheral components of the hypothalamus-pituitary-thyroid axis in lipopolysaccharide-induced acute illness in mice Regulation of TRH neurons and energy homeostasis-related signals under stress Thyroid allostasis-adaptive responses of thyrotropic feedback control to conditions of strain, stress, and developmental programming Prolonged effects of tumor necrosis factor-alpha on anterior pituitary hormone release Effects of interleukin-1 beta on thyrotropin secretion and thyroid hormone uptake in cultured rat anterior pituitary cells Impact of Duration of Critical Illness on the Adrenal Glands of Human Intensive Care Patients Adrenal function and dysfunction in critically ill patients Endocrine modifications and interventions during critical illness Changes in the IGF-IGFBP axis in critical illness Reactivation of pituitary hormone release and metabolic improvement by infusion of growth hormone-releasing peptide and thyrotropin-releasing hormone in patients with protracted critical illness Mayo Clinic Family Health Book 5th Edition: Completely Revised and Updated Atlas of Endocrinology for Hormone Therapy Hypothalamic-Pituitary autoimmunity and related impairment of hormone secretions in chronic fatigue syndrome Secretion of growth hormone in patients with chronic fatigue syndrome Characterization of pituitary function with emphasis on GH secretion in the chronic fatigue syndrome Integrity of the growth hormone/insulin-like growth factor system is maintained in patients with chronic fatigue syndrome Effective Treatment of Severe Chronic Fatigue: A Report of a Series of 64 Patients Diagnosis and treatment of Hypothalamic-Pituitary-Adrenal (HPA) axis dysfunction in patients with chronic Fatigue Syndrome (CFS) and Fibromyalgia (FM) Neuroendocrine and immune network remodeling in chronic fatigue syndrome: An exploratory analysis Thyroid hormone transport into cellular tissue Peripheral thyroid hormone conversion and its impact on TSH and metabolic activity Higher prevalence of "low T3 syndrome" in patients with chronic fatigue syndrome: a case-control study Evidence for impaired activation of the hypothalamic-pituitary-adrenal axis in patients with chronic fatigue syndrome Blunted adrenocorticotropin and cortisol responses to corticotropin-releasing hormone stimulation in chronic fatigue syndrome Dehydroepiandrosterone (DHEA) response to iv ACTH in patients with chronic fatigue syndrome Hypothalamo-pituitary-adrenal axis dysfunction in chronic fatigue syndrome, and the effects of low-dose hydrocortisone therapy Hypothalamicpituitary-adrenal axis reactivity in chronic fatigue syndrome and health under psychological, physiological, and pharmacological stimulation Diurnal patterns of salivary cortisol and cortisone output in chronic fatigue syndrome Disturbed adrenal function in adolescents with chronic fatigue syndrome Combined dexamethasone/corticotropin-releasing factor test in chronic fatigue syndrome Hypothalamic-pituitary-adrenal axis function in chronic fatigue syndrome Hypothalamic-pituitary-adrenal axis dysfunction in chronic fatigue syndrome A role for homeostatic drive in the perpetuation of complex chronic illness: Gulf War Illness and chronic fatigue syndrome Associations between neuroendocrine responses to the Insulin Tolerance Test and patient characteristics in chronic fatigue syndrome review of hypothalamic-pituitaryadrenal axis function in chronic fatigue syndrome 24-hour pituitary and adrenal hormone profiles in chronic fatigue syndrome Characterization of cortisol dysregulation in fibromyalgia and chronic fatigue syndromes: a state-space approach Hypothalamic-pituitary-adrenal hypofunction in Myalgic Encephalomyelitis (ME)/Chronic Fatigue Syndrome (CFS) as a consequence of activated immune-inflammatory and oxidative and nitrosative pathways Myalgic encephalomyelitis/chronic fatigue syndrome-metabolic disease or disturbed homeostasis due to focal inflammation in the hypothalamus? Kindling and oxidative stress as contributors to myalgic encephalomyelitis/chronic fatigue syndrome Oxidative and nitrosative stress and immuneinflammatory pathways in patients with Myalgic Encephalomyelitis (ME)/Chronic Fatigue Syndrome (CFS) Inclusion of the glucocorticoid receptor in a hypothalamic pituitary adrenal axis model reveals bistability Model-based therapeutic correction of hypothalamic-pituitary-adrenal axis dysfunction Highfidelity discrete modeling of the HPA axis: a study of regulatory plasticity in biology Modeling the hypothalamus-pituitary-adrenal axis: A review and extension Achieving remission in gulf war illness: a simulation-based approach to treatment design Leveraging prior knowledge of endocrine immune regulation in the therapeutically relevant phenotyping of women with chronic fatigue syndrome Small adrenal glands in chronic fatigue syndrome: a preliminary computer tomography study Association between serum interleukin-6 and serum 3,5,3'-triiodothyronine in nonthyroidal illness Relation between serum interleukin-6 and thyroid hormone concentrations in 270 hospital in-patients with non-thyroidal illness Mechanisms behind the nonthyroidal illness syndrome: an update IL-6 promotes nonthyroidal illness syndrome by blocking thyroxine activation while promoting thyroid hormone inactivation in human cells New insights toward the acute non-thyroidal illness syndrome Effect of severe, chronic illness on thyroid function Novel insights in the HPA-axis during critical illness Effects of interleukin-6 on the expression of thyroid hormone-binding protein genes in cultured human hepatoblastoma-derived (Hep G2) cells Role of cytokines in the pathogenesis of the euthyroid sick syndrome Concordant decreases of thyroxine and thyroxine binding protein concentrations during sepsis Variations in thyroid hormone transport proteins and their clinical implications Expression of thyroid hormone transporters during critical illness Transforming growth factor-beta promotes inactivation of extracellular thyroid hormones via transcriptional stimulation of type 3 iodothyronine deiodinase Interleukin-1beta modulates endogenous thyroid hormone receptor alpha gene transcription in liver cells Identification of molecular mechanisms related to nonthyroidal illness syndrome in skeletal muscle and adipose tissue from patients with septic shock Thyroid hormone receptors are down-regulated in skeletal muscle of patients with non-thyroidal illness syndrome secondary to nonseptic shock Cellular and molecular basis of deiodinase-regulated thyroid hormone signaling The non-thyroidal illness syndrome Calculated parameters of thyroid homeostasis: emerging tools for differential diagnosis and clinical research New insights into thyroid hormone action Metabolic effects of the intracellular regulation of thyroid hormone: old players, new concepts Dangerous dogmas in medicine: the nonthyroidal illness syndrome Effect of hypothyroidism and hyperthyroidism on tissue thyroid hormone concentrations in rat Frequency and outcome of patients with nonthyroidal illness syndrome in a medical intensive care unit Beyond low plasma T3: local thyroid hormone metabolism during inflammation and infection Thyroid hormones, oxidative stress, and inflammation Stimulating effect of triiodothyronine on cell-mediated immunity Congenital hypothyroidism and immunodeficiency: evidence for an endocrine-immune interaction Integrative study of hypothalamus-pituitarythyroid-immune system interaction: thyroid hormone-mediated modulation of lymphocyte activity through the protein kinase C signaling pathway The immune system as a regulator of thyroid hormone activity Low T3 syndrome in head-injured patients is associated with prolonged suppression of markers of cell-mediated immune response Preliminary evidence of immune function modulation by thyroid hormones in healthy men and women aged 55-70 years Energy regulation and neuroendocrine-immune control in chronic inflammatory diseases A role for iodide and thyroglobulin in modulating the function of human immune cells Regulation of intracellular triiodothyronine is essential for optimal macrophage function Thyroid hormones as modulators of immune activities at the cellular level Thyroid hormones interaction with immune response, inflammation and non-thyroidal illness syndrome Immunosuppression and herpes viral reactivation in intensive care unit patients: one size does not fit all Cytomegalovirus and Epstein-Barr virus reactivation in the intensive care unit Reactivation of multiple viruses in patients with sepsis The NO/ONOO-cycle mechanism as the cause of chronic fatigue syndrome/myalgia encephalomyelitis Mitochondrial dysfunctions in myalgic encephalomyelitis/chronic fatigue syndrome explained by activated immuno-inflammatory, oxidative and nitrosative stress pathways Metabolic profiling reveals anomalous energy metabolism and oxidative stress pathways in chronic fatigue syndrome patients Increased ventricular lactate in chronic fatigue syndrome. III Relationships to cortical glutathione and clinical symptoms implicate oxidative stress in disorder pathophysiology Cytokine signature associated with disease severity in chronic fatigue syndrome patients Distinct plasma immune signatures in ME/CFS are present early in the course of illness Hypothalamic-pituitary hormones during critical illness: a dynamic neuroendocrine response Endocrine responses to critical illness: novel insights and therapeutic implications Bench-to-bedside review: the gut as an endocrine organ in the critically ill Neuroendocrinology of prolonged critical illness: effects of exogenous thyrotropin-releasing hormone and its combination with growth hormone secretagogues Changes within the growth hormone/insulin-like growth factor I/IGF binding protein axis during critical illness Orexigenic hormone ghrelin attenuates local and remote organ injury after intestinal ischemia-reperfusion Van den Berghe G. Regulation of tissue iodothyronine deiodinase activity in a model of prolonged critical illness Thyroid hormone therapy modulates hypothalamo-pituitary-adrenal axis Thyroid hormone action on ACTH secretion Rapid nongenomic actions of thyroid hormone Role of nitric oxide in inflammatory diseases Role of endothelial nitric oxide synthasederived nitric oxide in activation and dysfunction of cerebrovascular endothelial cells during early onsets of sepsis Regulation of nitric oxide production in hypothyroidism Decreased NO production in endothelial cells exposed to plasma from ME/CFS patients Inhibition of thyroxine transport into cultured rat hepatocytes by serum of nonuremic critically ill patients: effects of bilirubin and nonesterified fatty acids Impaired thyroxine and 3,5,3'-triiodothyronine handling by rat hepatocytes in the presence of serum of patients with nonthyroidal illness Metabolic response to the stress of critical illness The metabolic basis of immune dysfunction following sepsis and trauma Critical illness and flat batteries Metabolic features of chronic fatigue syndrome Perspective: Cell danger response Biology-The new science that connects environmental health with mitochondria and the rising tide of chronic illness Metabolic features and regulation of the healing cycle-a new model for chronic disease pathogenesis and treatment Inflammatory fatigue and sickness behaviour -lessons for the diagnosis and management of chronic fatigue syndrome Management of post-acute covid-19 in primary care Autonomic dysfunction in 'long COVID': rationale, physiology and management strategies 6-month consequences of COVID-19 in patients discharged from hospital: a cohort study Persistent fatigue following SARS-CoV-2 infection is common and independent of severity of initial infection Will COVID-19 lead to myalgic encephalomyelitis/chronic fatigue syndrome? Front Med The neurological symptoms of COVID-19: a systematic overview of systematic reviews, comparison with other neurological conditions and implications for healthcare services Long COVID or post-acute sequelae of COVID-19 (PASC): an overview of biological factors that may contribute to persistent symptoms Paradigm for post-Covid-19 fatigue syndrome analogous to ME Insights from myalgic encephalomyelitis/chronic fatigue syndrome may help unravel the pathogenesis of postacute COVID-19 syndrome A Molecular network approach reveals shared cellular and molecular signatures between chronic fatigue syndrome and other fatiguing illnesses Redox imbalance links COVID-19 and myalgic encephalomyelitis/chronic fatigue syndrome The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.