Amazoniac
Member
Generation that empathize more with the prey than the predator when watching NatGeo videos, allegedly because we're choosing between one less life or one more fast,
The following observations are very clear on acute infections, which is probably why they are easier to study compared to chronic infections, in which something similar but more subtle must happen. Some of those economical, preservative and protective principles/responses can be extended to inflammation in geleran.
The majority of the reviews linked here are extense and filled with details, I've only selected some parts but left the details and technical information out. I highly recommend reading them yourselves instead of relying on my capacity to abstract..
Context from one abstract:
The most commonly recognized behavioral patterns of animals and people at the onset of febrile infectious diseases are lethargy, depression, anorexia, and reduction in grooming. Findings from recent lines of research are reviewed to formulate the perspective that the behavior of sick animals and people is not a maladaptive response or the effect of debilitation, but rather an organized, evolved behavioral strategy to facilitate the role of fever in combating viral and bacterial infections. The sick individual is viewed as being at a life or death juncture and its behavior is an all-out effort to overcome the disease.
Biological basis of the behavior of sick animals
"The coevolution of the host-pathogen or host-parasite relationship is by now well established in evolutionary biology [59,138]. Indeed exceedingly complex nonspecific and specific immunologic systems of mammals [160] provide documentation of the evolved strategy of animals to prevent infections by pathogens or to survive established infections. It is quite logical to expect animals and people to also have evolved nonimmunologic disease-fighting strategies, including behavioral patterns, that might serve as a first line of defense before the nonspecific and specific immunologic systems are activated and that would complement or potentiate immunolgical processes."
"When a wild animal is acutely ill with a pathogen it is at a life-or-death juncture. The behavior associated with being sick can be viewed as an all-out effort to overcome the disease, putting virtually all the animal's resources into killing off the invading pathogen. The behavior associated with being sick centers around the fever response. When animals are initially infected with a pathogen the febrile response, coupled with a reduction of plasma levels of iron, has the effect of inhibiting the growth of at least some viral and bacterial pathogens and is associated with activating elements in the immunological system. The concept to be developed here is that because fever is costly from the standpoint of metabolic activity associated with the rise in body temperature, the depression and anorexia typically seen in sick animals constitute a programmed behavioral mode to facilitate the body's attempt to raise and maintain a febrile temperature and lower blood iron concentration."
"Although elevated body temperature has long been viewed as a symptom of illness in both people and animals, until recently, fever has typically been thought of as an undesirable side effect of illness to be reduced by antipyretics such as aspirin."
"The fever response is initiated by the release of activators, such as the components of the cell walls of bacteria, which induce the synthesis of what have been commonly known as endogenous pyrogens from fixed tissue macrophages, blood monocytes, phagocytic cells of the liver and spleen, and granular lymphocytes. The activated cells release such endogenous pyrogens (EPs) with infections from many types of viruses, bacteria, and protozoa, as well as with some hypersensitivities and tissue necroses. One of the EPs, and perhaps the primary one, is interleukin-1 (IL-I) which as been known before as leukocytic endogenous mediator and lymphocyte-activating factor [47,98]. IL-I is not only involved in causing fever but also in inducing other fever-related responses such as lowering plasma concentrations of iron (hypoferremia) and zinc (hypozincemia), increasing the excretion of sodium and in activating nonspecific resistance to pathogens [47,50]. IL-1 causes the release of adrenocorticotropic hormone and glucocorticoids [23], which presumably play a role in helping the animal to meet the stress and energy demands associated with illness."
"Tumor necrosis factor is another EP and shares many of the biological properties of IL-I [24, 49, 102]. Another EP is interferon-fl..,, recently identified as interleukin-6 and which is released from some of the same cellular elements as IL-I [I, 115, 132]. Interleukin-6 is identical to what was previously known as hepatocyte stimulating factor and together with IL-I and tumor necrosis factor, promotes the release of proteins from the liver including C-reactive protein, serum amyloid A, ceruloplasmin, haptoglobin, antiproteinase and fibrinogen [65,136]."
"A possible mechanism by which EPs stimulate the hypothalamus to raise the set point is to promote increased synthesis of prostaglandins [120]. Drugs that are used to reduce fever such as salicylic acid are known to block prostaglandin synthesis."
"One of the earliest experimental reports of the importance of body temperature in the control of infections was by Muschenheim et al. [129] who studied dermal pneumococcus infections in rabbits that were subjected to environmentally induced hypothermia. Infection with a strain ofpneumococcus that was nonlethal under ordinary conditions produced an overwhelming bacteremia and death in hypothermic rabbits."
"It should not be assumed a higher temperature is always better in terms of host resistance to a pathogen. In one experiment rats, which were infected with Salmonella enteritidis and induced to develop an artificially high fever through hypothalamic cooling, had a higher mortality rate than controls [7]. Perhaps, as conjectured by the investigator, a moderate fever would have beneficial effects but a higher fever was detrimental because of metabolic or endocrine responses induced by the high temperature."
"The second mechanism by which fever benefits acute ill animals relates to the fact that some pathogens have an optimal temperature for growth that is the same as or below the normal body temperature of the animals they infect. There is now evidence that both in vitro and in vivo studies that there is a direct suppressive effect of temperature elevation on the growth of some pathogenic viruses and bacteria."
"One of the physiological changes that accompany the fever response is a reduction in plasma iron and zinc concentrations. This is true of most infections accompanied by fever in people and laboratory animals [175]. Among domestic animals a fall in plasma iron and zinc is reported for cattle infected with rhinotracheitis virus or E. coli endotoxin [46] and in cattle with mastitis [ 172]. Iron is an essential element for many bacteria and they obtain iron needed for their own multiplication by chelating the small amount of free iron in the blood that is bound to serum transferrin [30, 57, 175]. Transferrin is a glycoprotein which plays a role in the transport of iron among its sites of absorption, storage and utilization. The reduction of iron is due to redistribution of iron in the body rather than excretion [90]."
"Circumstantial evidence of the influence of iron reduction in combatting infectious disease was found in a study of Somali nomads that are typically iron deficient for dietary reasons. Somali patients which were treated with iron supplement had 4 times as many episodes of infectious diseases, including brucellosis, tuberculosis, pneumonia and malaria, as patients receiving a placebo [128]."
"If an animal stays in one spot, it engages in much less muscular activity and thus can save on body energy reserves needed for the increased metabolic costs of fever. Perhaps more important, by staying in one place it is able to reduce heat loss which would otherwise occur from increased convection and enhanced body surface exposure if the animal was moving about."
"The food intake suppression seen in fasted laboratory rats injected with endotoxin of IL-l is not absolute, but is rather about 60-70% of ad lib normal intake [107]."
"For hibernating mammals, foraging for food or consuming water during occasional winter arousals would be counterproductive because the kidneys do not function well when hypothermic and to eliminate metabolic end products the kidney would have to warm up which is contrary to the winter survival strategy [123]."
"According to the perspective presented here, the sleepy or depressed or inactive animal is less motivated to move about using energy that could fuel metabolic increases associated with fever. In addition, the animal will also curl up or otherwise insulate itself for conservation of body heat, making shivering less necessary. Thus, excessive sleepiness is complementary to anorexia in inducing the animal or person to remain in a heat conservation mode."
"Relevant to the discussion of increased sleepiness, decreased activity and depression is the fact that there are some animal models of depression serving as a precedent for the notion that depression may occur as an adaptive syndrome for last ditch survival which is put into play before an animal's resources are exhausted. For example, work on separation of infants from their mothers [71, 89, 121], or on animals facing a problem of survival with no apparent solution [161], reveals that the depressed state may be viewed as adaptive behavior. According to these models, an animal's chances for survival are better in a depressionconservation- withdrawal mode than in an active fight-flightenergy-expenditure mode."
"Sick animals often assume a posture that we associate with being sick. For those animals that can easily curl up, such as carnivores, we can see the adaptive value in reducing surface area of the body exposed to the environment for heat loss by convection and radiation. The curled up posture, particularly with accompanying piloerection, is a common sight in sick animals. In large herbivores, the posture is often that of being humped over or even lying down accompanied by piloerection. Given the rather limited flexibility of large herbivores, this is probably the best they can do to conserve body heat."
"Wild animals that are sick are threatened by increased susceptibility to predation, loss of social position, or removal from territorial holdings. As serious as these consequences may be, death by disease can be even a more immediate threat. The fever response accompanied by anorexia and depression puts virtually all of an animal's resources into recovering from the disease. For an animal unfortunate enough to be infected by microorganisms associated with a deadly disease, taking on the pattern of sick behavior is the most extreme and only strategy an animal in the wild has for surviving."
--
http://www.sciencedirect.com/science/article/pii/S0092867416309722
"It has been long appreciated that sickness behaviors are motivational states rather than a result of debilitation of physiological functions (Miller, 1964). Furthermore, sickness behaviors have been conceptualized as adaptive programs that promote survival of acute infections (Hart, 1988; Kluger et al., 1975)."
"Importantly, Ayres and Schneider (2009) found that, in Drosophila, anorexia was beneficial in some, but not all, infections. Similarly, it was recently shown that the fasting metabolic state was critical to surviving bacterial sepsis (Feingold et al., 2012)."
"..survival of infections can be promoted by either reducing pathogen burden or by increasing host tolerance to the damage of infection (Ayres and Schneider, 2012; Soares et al., 2014)."
“In addition to the well-studied but contentious role of glucose homeostasis in managing sepsis in the intensive care units (NICE-SUGAR Study Investigators et al., 2009; van den Berghe et al., 2001), the largest proteomic and metabolomic screen of patients with sepsis to date identified fatty acid, glucose, and beta-oxidation pathways as being discriminatory between survivors and non-survivors (Langley et al., 2013). Bacterial sepsis leads to a pro-lipolytic state, which affects the ability of target tissues to utilize glucose via glycolysis and alternative fuel sources, such as ketone bodies (KBs) and free fatty acids (FFAs) via oxidative phosphorylation (Agwunobi et al., 2000). Growing evidence suggests that a shift from glucose to KB/FFA utilization is protective in bacterial sepsis”
"We found that, whereas glucose was necessary for adaptation to and survival from the stress of antiviral inflammation by preventing initiation of endoplasmic reticulum (ER) stress-mediated apoptotic pathways, glucose prevented adaptation to the stress of bacterial inflammation by inhibiting ketogenesis, which was necessary for limiting reactive oxygen species (ROS) induced by anti-bacterial inflammation."
"Collectively, these data suggest that glucose is the component of food that is necessary and sufficient to mediate lethality in listeriosis when anorexia is blocked by force feeding."
"We found that gavaging mice with enteral nutrition starting 1 hr post-LPS injection led to significantly increased mortality, whereas fluid resuscitation improved survival (Figure 2A)."
"These findings suggest that glucose utilization does not affect the magnitude of the inflammatory response in endotoxic shock but rather the ability of the tissues to tolerate inflammatory damage."
"It is increasingly appreciated that inflammatory responses must be coupled to specific metabolic programs to support their energetic demands (Buck et al., 2015; Galván-Peña and O’Neill, 2014). In this study, we observed that systemic metabolism appears to be coordinated to support tolerance to different inflammatory states. We found that, whereas glucose utilization was required for survival in models of viral inflammation, it was lethal in models of bacterial inflammation."
"In the case of bacterial inflammation, lethality subsequent to glucose administration appeared to be mediated by suppression of ketogenesis, which led to impaired resistance to ROS-mediated damage in the brain (Figure 7)."
"Thus, our results suggest that distinct inflammatory responses may be coupled with specific metabolic programs in order to support unique tissue tolerance mechanisms that, when uncoupled, lead to enhanced immunopathology, leading to death."
"Tissue protection is likely a function of cellular stress adaptation pathways, which allow cells to survive noxious states, such as increased free radicals and accumulation of unfolded proteins (Figueiredo et al., 2013; Larsen et al., 2010). When these adaptation pathways are overwhelmed, cells can undergo apoptotic cell death (Boison, 2013; Tabas and Ron, 2011). Thus, one important determinant of host tolerance may be related to the ability of cellular adaptation programs to tolerate noxious states found in infections (Medzhitov et al., 2012). Because different infections generate different inflammatory responses and noxious states, specific cellular adaption programs would need to be activated in distinct infectious contexts."
"ROS-mediated cytotoxicity is a well-appreciated phenomenon in bacterial sepsis (Hoetzenecker et al., 2012; Kolls, 2006), and ROS-detoxification pathways have been implicated in mitigating tissue damage and mortality."
"Furthermore, we found that the timing of ketogenesis, an adequately nourished host, or both are necessary for the protective effect of fasting that occurs as a coordinated response to bacterial inflammation. Instead of rescuing mice from LPS mortality, fasting and ketogenic pre-conditioning potentiated death. Taken together, we present evidence that the fasting response that occurs as part of the inflammatory response is required to maintain resistance to oxidative stress in LPS sepsis."
"Although anorexia is a common response in both bacterial and viral infections, we find the opposite consequence of fasting metabolism in our models of bacterial and viral inflammation. Whereas in bacterial infection and LPS-induced inflammation, we found a detrimental effect of glucose, a protective effect of 2DG, and a requirement for ketogenesis in order to maintain tolerance, in viral infection and poly(I:C)-induced inflammation, these effects were opposite."
--
http://www.sciencedirect.com/science/article/pii/S009286741631131X
by @Janelle525
"Energetic demands of pathogens are dependent in large part on food intake of their hosts, and any benefits afforded by the anorexic response are also dependent on how the fasted state influences pathogen behavior. Thus, future work is warranted to assess how nutritional status of the host and sicknessinduced anorexia regulates pathogen virulence and transmission. It is also important to understand the mechanisms that microbes have evolved to manipulate anorexia and other sickness behaviors to promote their fitness. In infection settings in which anorexia results in a negative impact on pathogen fitness, for example, by promoting host resistance mechanisms or inhibiting pathogen transmission, one would predict that anorexia could drive the selection of antagonistic traits in pathogen populations that inhibit infection-induced anorexia. By contrast, in settings where anorexia promotes disease tolerance, it is intriguing to ask whether, and if so how, microbes may evolve traits to promote the anorexic response."
--
Depression and sickness behavior are Janus-faced responses to shared inflammatory pathways
"Combating pathogen threats consumes large amounts of energy and, therefore, rations available energy [22]. PIC [pro-inflammatory cytokine] signals, for example, TNFα signals, modulate the balance between this increased energy demand and energy supply and control food intake, energy expenditure and substrate utilization [23,24]. PICs play a key role in this highly increased energy request characterized by a negative energy balance (increased lipolysis, loss of tissue proteins and lowered muscle protein synthesis, gluconeogenesis) and decreased voluntary energy utilization [22]. The central nervous system (CNS) receives neural and humoral signals about the peripheral inflammatory response through PIC-induced activation of afferent vagal signals, effects of TNFα at the sensory nuclei of the solitary tract, and all three PICs entering the brain though different pathways [22,25]. These PICs, in turn, will shut off energy-consuming processes, such as locomotor, neurocognitive and reproductive activity. Thus, metabolic energy is withdrawn from the brain and some peripheral organs and redirected to counteract the adverse effects of the invading pathogens. The energy saved by this process contributes to pyrexia and to the enhancement of the inflammatory state of immune cells [22]. Many of the sickness behavior symptoms, such as anergia, malaise, somnolence, psychomotor retardation, cognitive deficits and loss of libido serve to limit motor, sexual and brain activity and thereby direct metabolic energy to combating the primary infection [4,7,22,26]. Immune responses are highly calorie dependent and increase resting energy expenditure, while sickness behavior responses, for example, motor inhibition, may conserve critical energy [27]."
"Mild to moderate pyrexia [hyperthermia] (in contrast to high fever) is a positive adaptive response as it strengthens the host defenses and resistance to infection, for example, by enhancing the phagocytosis and mobility of polymorphonuclear leukocytes and killing of bacteria and preventing viral replication [28-30]. In addition, PICs and cytokines, such as IFNs are more active during fever [31]."
"Inflammation-induced anorexia is directly proportional to the magnitude of the insult and is also inversely related to body weight prior to the insult [33]. It is suggested that anorexia may limit the intake of iron, which otherwise would activate bacterial production [34]. Iron is one of the nutrients employed by bacteria for bacterial growth. This reasoning is, however, highly speculative as only less than 1% of dietary iron is absorbed and iron status changes slowly over time. A more plausible adaptive function is that anorexia through calorie restriction attenuates different intracellular signaling pathways leading to inflammation and even sickness behavior [35,36]. Thus, a two-week calorie restriction period significantly reduces inflammatory pathways, including IL-6 [37]. Calorie-restriction results in a dose-dependent suppression of lipopolysaccharide (LPS)-induced sickness behavior by inducing an anti-inflammatory state [36]."
"The malaise theory regards lowered mood and the more distinctive existential state of depression as a product of malaise. Thus, humans who suffer from sickness behavior and do not know they are ill, may interpret their lack of energy and neurocognitive disorders as a personal failure, causing feelings of guilt and unworthiness [26]."
"Depression is linked to reductions in brain energy generation and mania to increased energy expenditure [51], while sickness behavior is a behavioral response, which conserves energy."
"..administration of LPS, a component of the bacterial wall of gram negative bacteria, causes neuroinflammation and microglial activation, characterized by increased levels of TNFα, which may remain elevated for months and are associated with the onset of sickness behavior [8]."
"Administration of LPS elicits not only sickness behavior but also depressive- (suppression of social interaction and activity in the open-field test, food consumption and body weight, memory dysfunction), anxiety-like and physio-somatic behaviors [15]."
"Sickness behavior supports the protective inflammatory response (helps to eradicate the trigger and redirects energy to inflammatory cells), protects against possible detrimental effects of inflammation (for example, negative energy balance), while at the same time acting as an anti-inflammatory reflex (anti-inflammatory effects of calorie restriction and weight loss). Therefore, sickness behavior itself should be regarded as a CIRS ["compensatory (anti)inflammatory reflex system"] response to acute inflammation."
"There is abundant evidence that depression is characterized not only by increased reactive oxygen and nitrogen species (ROS/RNS), but also by O&NS damage to lipids, proteins, DNA, and mitochondria [131]. In these processes O&NS ["oxidative and nitrosative stress"] pathways may alter the chemical structure of membrane fatty acids and functional proteins. When these modified fatty acids and proteins become immunogenic, an autoimmune response may be mounted directed against these 'neoepitopes' thereby further damaging the function or chemical structure of these epitopes [132,133]."
"Etiologically, sickness behavior is conceptualized as an acute phase of adaptive CIRS behavior in response to acute infections and inflammatory trauma [4,7,26]. When the resolution phase, however, is not induced, for example, when the IRS [inflammatory responses system] was unable to eradicate the pathogen, inflammation may persist despite the CIRS thus causing a chronic inflammatory state [21]. Chronic inflammation may result from a failure to eradicate the acute inflammatory trigger (for example, pyogenic bacteria), innately chronic irritants (for example, fungi, sarcoidosis), or autoimmune responses [151]. Acute and chronic inflammation are distinguished in terms of immune response patterns and time course. The time point of transition of acute inflammation to chronic inflammation is also related to the time when the energy stores become empty and this is estimated to be around 19 to 43 days depending on the nature of the energy store [152]. This transition is related to a number of inflammatory sequelae, including cachexia, insulin resistance, anemia, osteopenia and hypertension [152]. Sickness behavior thus plays a critical role in preventing the transition from acute to chronic inflammation following an acute trigger by compensating for the negative energy balance, redirecting energy to the activated immune cells, and so on [152]."
"In contrast to sickness behavior, pathogens do not play a major role in clinical depression although some authors have attempted to make links between pathogens such as herpes simplex type 2 and toxoplasma gondii and psychopathology [153,154]. In a previous review, we concluded that there is no good quality evidence that acute infections and infections with Epstein-Barr Virus (EBV) may act as trigger factors associated with the onset of clinical depression [155]. Only some types of chronic infection are frequently associated with clinical depression, for example, HIV infection [156] and increased translocation of gram negative bacteria [157]."
"However, it cannot be excluded that reactivated dormant infected states and consequent infection-induced molecular pathways may be important in clinical depression. Viral infections of the brain, for example, cause neurologic and psychiatric dysfunction more often than appreciated [160]."
"..in the rodent, social defeat stress increases the reactivity of microglia to LPS, suggesting a role for social stress factors in the regulation of microglia responses [162]."
"It thus seems unlikely that depression is a maladaptive syndrome that results from prolonged 'sickness behavior' but rather the consequence of a chronic underlying immuno-inflammatory and degenerative process."
"There is also a new hypothesis that associates depression as an evolutionary product of sickness behavior with protection from infection. As such depression is regarded as an evolutionary behavioral response that helps the immune system to fight pathogens and to avoid new pathogen exposure [26,174,175]. These hypotheses, however, did not take into account that clinical depression is not a simple behavioral response, but a progressive disorder driven by a cascading neurobiology leading to a progressive course and pathophysiology. Moreover, acute lethargy, hyperalgesia, loss of interest, anxiety, and anhedonia are beneficial behaviors, but when chronic the same symptoms are typically not beneficial, but pathological and maladaptive: they may further isolate the depressed patient from social contacts creating a state of demotivation and demoralization and negative anticipation of the future [26]. Chronic illness, furthermore, requires a person to use coping and adaptive strategies to integrate the consequences of a disorder. There is a wide diversity of coping styles and beliefs on the nature of depression, some of which are adaptive while others are maladaptive [176]."
"All in all, while sickness behavior is a beneficial CIRS response, clinical depression is a disabling, progressive disorder. Inflammation thus provokes a Janus-faced response with a good 'acute' protective inflammatory side, involving CIRS responses, such as sickness behavior, and a bad 'chronic' side, that can lead to clinical depression, a chronic disorder with positive feedback loops between (neuro)inflammation and (neuro)degenerative processes following less well-defined triggers. This Janus face also represents the transition of an inflammation-induced adaptive behavioral response that is conserved through evolution to an inflammation-related chronic progressive disorder, which is increasing in prevalence in industrialized societies [187]."
--
So, gurus, in Ray's book Generative Energy he used this graph to demonstrate different states. On the horizontal axis the "intensity of stimulation" and on the other axis "energy charge". As long as your energy available is able to handle the excitation, you're fine (and above the therapeutic vector). The sickness behavior is trying to bring the animal to the protective inhibition region. Regarding the limiting curve, it probably has its concavity downwards to demonstrate that it gets harder and harder as the demands increase but are not matched by the energy available, until a critical point, when management seems unbearable and a rapid collapse starts to occur (D). I think that the curve is not symmetrical because of our effort to maintain order in adversity and will to live, so to speak..
A - Adventure
B - A baby sleeping
C - Cautious conserving of energy
D - Stressed to death
He writes:
Thread sponsored by: @Greg says and @PakPik
The following observations are very clear on acute infections, which is probably why they are easier to study compared to chronic infections, in which something similar but more subtle must happen. Some of those economical, preservative and protective principles/responses can be extended to inflammation in geleran.
The majority of the reviews linked here are extense and filled with details, I've only selected some parts but left the details and technical information out. I highly recommend reading them yourselves instead of relying on my capacity to abstract..
Context from one abstract:
The most commonly recognized behavioral patterns of animals and people at the onset of febrile infectious diseases are lethargy, depression, anorexia, and reduction in grooming. Findings from recent lines of research are reviewed to formulate the perspective that the behavior of sick animals and people is not a maladaptive response or the effect of debilitation, but rather an organized, evolved behavioral strategy to facilitate the role of fever in combating viral and bacterial infections. The sick individual is viewed as being at a life or death juncture and its behavior is an all-out effort to overcome the disease.
Biological basis of the behavior of sick animals
"The coevolution of the host-pathogen or host-parasite relationship is by now well established in evolutionary biology [59,138]. Indeed exceedingly complex nonspecific and specific immunologic systems of mammals [160] provide documentation of the evolved strategy of animals to prevent infections by pathogens or to survive established infections. It is quite logical to expect animals and people to also have evolved nonimmunologic disease-fighting strategies, including behavioral patterns, that might serve as a first line of defense before the nonspecific and specific immunologic systems are activated and that would complement or potentiate immunolgical processes."
"When a wild animal is acutely ill with a pathogen it is at a life-or-death juncture. The behavior associated with being sick can be viewed as an all-out effort to overcome the disease, putting virtually all the animal's resources into killing off the invading pathogen. The behavior associated with being sick centers around the fever response. When animals are initially infected with a pathogen the febrile response, coupled with a reduction of plasma levels of iron, has the effect of inhibiting the growth of at least some viral and bacterial pathogens and is associated with activating elements in the immunological system. The concept to be developed here is that because fever is costly from the standpoint of metabolic activity associated with the rise in body temperature, the depression and anorexia typically seen in sick animals constitute a programmed behavioral mode to facilitate the body's attempt to raise and maintain a febrile temperature and lower blood iron concentration."
"Although elevated body temperature has long been viewed as a symptom of illness in both people and animals, until recently, fever has typically been thought of as an undesirable side effect of illness to be reduced by antipyretics such as aspirin."
"The fever response is initiated by the release of activators, such as the components of the cell walls of bacteria, which induce the synthesis of what have been commonly known as endogenous pyrogens from fixed tissue macrophages, blood monocytes, phagocytic cells of the liver and spleen, and granular lymphocytes. The activated cells release such endogenous pyrogens (EPs) with infections from many types of viruses, bacteria, and protozoa, as well as with some hypersensitivities and tissue necroses. One of the EPs, and perhaps the primary one, is interleukin-1 (IL-I) which as been known before as leukocytic endogenous mediator and lymphocyte-activating factor [47,98]. IL-I is not only involved in causing fever but also in inducing other fever-related responses such as lowering plasma concentrations of iron (hypoferremia) and zinc (hypozincemia), increasing the excretion of sodium and in activating nonspecific resistance to pathogens [47,50]. IL-1 causes the release of adrenocorticotropic hormone and glucocorticoids [23], which presumably play a role in helping the animal to meet the stress and energy demands associated with illness."
"Tumor necrosis factor is another EP and shares many of the biological properties of IL-I [24, 49, 102]. Another EP is interferon-fl..,, recently identified as interleukin-6 and which is released from some of the same cellular elements as IL-I [I, 115, 132]. Interleukin-6 is identical to what was previously known as hepatocyte stimulating factor and together with IL-I and tumor necrosis factor, promotes the release of proteins from the liver including C-reactive protein, serum amyloid A, ceruloplasmin, haptoglobin, antiproteinase and fibrinogen [65,136]."
"A possible mechanism by which EPs stimulate the hypothalamus to raise the set point is to promote increased synthesis of prostaglandins [120]. Drugs that are used to reduce fever such as salicylic acid are known to block prostaglandin synthesis."
"One of the earliest experimental reports of the importance of body temperature in the control of infections was by Muschenheim et al. [129] who studied dermal pneumococcus infections in rabbits that were subjected to environmentally induced hypothermia. Infection with a strain ofpneumococcus that was nonlethal under ordinary conditions produced an overwhelming bacteremia and death in hypothermic rabbits."
"It should not be assumed a higher temperature is always better in terms of host resistance to a pathogen. In one experiment rats, which were infected with Salmonella enteritidis and induced to develop an artificially high fever through hypothalamic cooling, had a higher mortality rate than controls [7]. Perhaps, as conjectured by the investigator, a moderate fever would have beneficial effects but a higher fever was detrimental because of metabolic or endocrine responses induced by the high temperature."
"The second mechanism by which fever benefits acute ill animals relates to the fact that some pathogens have an optimal temperature for growth that is the same as or below the normal body temperature of the animals they infect. There is now evidence that both in vitro and in vivo studies that there is a direct suppressive effect of temperature elevation on the growth of some pathogenic viruses and bacteria."
"One of the physiological changes that accompany the fever response is a reduction in plasma iron and zinc concentrations. This is true of most infections accompanied by fever in people and laboratory animals [175]. Among domestic animals a fall in plasma iron and zinc is reported for cattle infected with rhinotracheitis virus or E. coli endotoxin [46] and in cattle with mastitis [ 172]. Iron is an essential element for many bacteria and they obtain iron needed for their own multiplication by chelating the small amount of free iron in the blood that is bound to serum transferrin [30, 57, 175]. Transferrin is a glycoprotein which plays a role in the transport of iron among its sites of absorption, storage and utilization. The reduction of iron is due to redistribution of iron in the body rather than excretion [90]."
"Circumstantial evidence of the influence of iron reduction in combatting infectious disease was found in a study of Somali nomads that are typically iron deficient for dietary reasons. Somali patients which were treated with iron supplement had 4 times as many episodes of infectious diseases, including brucellosis, tuberculosis, pneumonia and malaria, as patients receiving a placebo [128]."
"If an animal stays in one spot, it engages in much less muscular activity and thus can save on body energy reserves needed for the increased metabolic costs of fever. Perhaps more important, by staying in one place it is able to reduce heat loss which would otherwise occur from increased convection and enhanced body surface exposure if the animal was moving about."
"The food intake suppression seen in fasted laboratory rats injected with endotoxin of IL-l is not absolute, but is rather about 60-70% of ad lib normal intake [107]."
"For hibernating mammals, foraging for food or consuming water during occasional winter arousals would be counterproductive because the kidneys do not function well when hypothermic and to eliminate metabolic end products the kidney would have to warm up which is contrary to the winter survival strategy [123]."
"According to the perspective presented here, the sleepy or depressed or inactive animal is less motivated to move about using energy that could fuel metabolic increases associated with fever. In addition, the animal will also curl up or otherwise insulate itself for conservation of body heat, making shivering less necessary. Thus, excessive sleepiness is complementary to anorexia in inducing the animal or person to remain in a heat conservation mode."
"Relevant to the discussion of increased sleepiness, decreased activity and depression is the fact that there are some animal models of depression serving as a precedent for the notion that depression may occur as an adaptive syndrome for last ditch survival which is put into play before an animal's resources are exhausted. For example, work on separation of infants from their mothers [71, 89, 121], or on animals facing a problem of survival with no apparent solution [161], reveals that the depressed state may be viewed as adaptive behavior. According to these models, an animal's chances for survival are better in a depressionconservation- withdrawal mode than in an active fight-flightenergy-expenditure mode."
"Sick animals often assume a posture that we associate with being sick. For those animals that can easily curl up, such as carnivores, we can see the adaptive value in reducing surface area of the body exposed to the environment for heat loss by convection and radiation. The curled up posture, particularly with accompanying piloerection, is a common sight in sick animals. In large herbivores, the posture is often that of being humped over or even lying down accompanied by piloerection. Given the rather limited flexibility of large herbivores, this is probably the best they can do to conserve body heat."
"Wild animals that are sick are threatened by increased susceptibility to predation, loss of social position, or removal from territorial holdings. As serious as these consequences may be, death by disease can be even a more immediate threat. The fever response accompanied by anorexia and depression puts virtually all of an animal's resources into recovering from the disease. For an animal unfortunate enough to be infected by microorganisms associated with a deadly disease, taking on the pattern of sick behavior is the most extreme and only strategy an animal in the wild has for surviving."
--
http://www.sciencedirect.com/science/article/pii/S0092867416309722
"It has been long appreciated that sickness behaviors are motivational states rather than a result of debilitation of physiological functions (Miller, 1964). Furthermore, sickness behaviors have been conceptualized as adaptive programs that promote survival of acute infections (Hart, 1988; Kluger et al., 1975)."
"Importantly, Ayres and Schneider (2009) found that, in Drosophila, anorexia was beneficial in some, but not all, infections. Similarly, it was recently shown that the fasting metabolic state was critical to surviving bacterial sepsis (Feingold et al., 2012)."
"..survival of infections can be promoted by either reducing pathogen burden or by increasing host tolerance to the damage of infection (Ayres and Schneider, 2012; Soares et al., 2014)."
“In addition to the well-studied but contentious role of glucose homeostasis in managing sepsis in the intensive care units (NICE-SUGAR Study Investigators et al., 2009; van den Berghe et al., 2001), the largest proteomic and metabolomic screen of patients with sepsis to date identified fatty acid, glucose, and beta-oxidation pathways as being discriminatory between survivors and non-survivors (Langley et al., 2013). Bacterial sepsis leads to a pro-lipolytic state, which affects the ability of target tissues to utilize glucose via glycolysis and alternative fuel sources, such as ketone bodies (KBs) and free fatty acids (FFAs) via oxidative phosphorylation (Agwunobi et al., 2000). Growing evidence suggests that a shift from glucose to KB/FFA utilization is protective in bacterial sepsis”
"We found that, whereas glucose was necessary for adaptation to and survival from the stress of antiviral inflammation by preventing initiation of endoplasmic reticulum (ER) stress-mediated apoptotic pathways, glucose prevented adaptation to the stress of bacterial inflammation by inhibiting ketogenesis, which was necessary for limiting reactive oxygen species (ROS) induced by anti-bacterial inflammation."
"Collectively, these data suggest that glucose is the component of food that is necessary and sufficient to mediate lethality in listeriosis when anorexia is blocked by force feeding."
"We found that gavaging mice with enteral nutrition starting 1 hr post-LPS injection led to significantly increased mortality, whereas fluid resuscitation improved survival (Figure 2A)."
"These findings suggest that glucose utilization does not affect the magnitude of the inflammatory response in endotoxic shock but rather the ability of the tissues to tolerate inflammatory damage."
"It is increasingly appreciated that inflammatory responses must be coupled to specific metabolic programs to support their energetic demands (Buck et al., 2015; Galván-Peña and O’Neill, 2014). In this study, we observed that systemic metabolism appears to be coordinated to support tolerance to different inflammatory states. We found that, whereas glucose utilization was required for survival in models of viral inflammation, it was lethal in models of bacterial inflammation."
"In the case of bacterial inflammation, lethality subsequent to glucose administration appeared to be mediated by suppression of ketogenesis, which led to impaired resistance to ROS-mediated damage in the brain (Figure 7)."
"Thus, our results suggest that distinct inflammatory responses may be coupled with specific metabolic programs in order to support unique tissue tolerance mechanisms that, when uncoupled, lead to enhanced immunopathology, leading to death."
"Tissue protection is likely a function of cellular stress adaptation pathways, which allow cells to survive noxious states, such as increased free radicals and accumulation of unfolded proteins (Figueiredo et al., 2013; Larsen et al., 2010). When these adaptation pathways are overwhelmed, cells can undergo apoptotic cell death (Boison, 2013; Tabas and Ron, 2011). Thus, one important determinant of host tolerance may be related to the ability of cellular adaptation programs to tolerate noxious states found in infections (Medzhitov et al., 2012). Because different infections generate different inflammatory responses and noxious states, specific cellular adaption programs would need to be activated in distinct infectious contexts."
"ROS-mediated cytotoxicity is a well-appreciated phenomenon in bacterial sepsis (Hoetzenecker et al., 2012; Kolls, 2006), and ROS-detoxification pathways have been implicated in mitigating tissue damage and mortality."
"Furthermore, we found that the timing of ketogenesis, an adequately nourished host, or both are necessary for the protective effect of fasting that occurs as a coordinated response to bacterial inflammation. Instead of rescuing mice from LPS mortality, fasting and ketogenic pre-conditioning potentiated death. Taken together, we present evidence that the fasting response that occurs as part of the inflammatory response is required to maintain resistance to oxidative stress in LPS sepsis."
"Although anorexia is a common response in both bacterial and viral infections, we find the opposite consequence of fasting metabolism in our models of bacterial and viral inflammation. Whereas in bacterial infection and LPS-induced inflammation, we found a detrimental effect of glucose, a protective effect of 2DG, and a requirement for ketogenesis in order to maintain tolerance, in viral infection and poly(I:C)-induced inflammation, these effects were opposite."
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http://www.sciencedirect.com/science/article/pii/S009286741631131X
by @Janelle525
"Energetic demands of pathogens are dependent in large part on food intake of their hosts, and any benefits afforded by the anorexic response are also dependent on how the fasted state influences pathogen behavior. Thus, future work is warranted to assess how nutritional status of the host and sicknessinduced anorexia regulates pathogen virulence and transmission. It is also important to understand the mechanisms that microbes have evolved to manipulate anorexia and other sickness behaviors to promote their fitness. In infection settings in which anorexia results in a negative impact on pathogen fitness, for example, by promoting host resistance mechanisms or inhibiting pathogen transmission, one would predict that anorexia could drive the selection of antagonistic traits in pathogen populations that inhibit infection-induced anorexia. By contrast, in settings where anorexia promotes disease tolerance, it is intriguing to ask whether, and if so how, microbes may evolve traits to promote the anorexic response."
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Depression and sickness behavior are Janus-faced responses to shared inflammatory pathways
"Combating pathogen threats consumes large amounts of energy and, therefore, rations available energy [22]. PIC [pro-inflammatory cytokine] signals, for example, TNFα signals, modulate the balance between this increased energy demand and energy supply and control food intake, energy expenditure and substrate utilization [23,24]. PICs play a key role in this highly increased energy request characterized by a negative energy balance (increased lipolysis, loss of tissue proteins and lowered muscle protein synthesis, gluconeogenesis) and decreased voluntary energy utilization [22]. The central nervous system (CNS) receives neural and humoral signals about the peripheral inflammatory response through PIC-induced activation of afferent vagal signals, effects of TNFα at the sensory nuclei of the solitary tract, and all three PICs entering the brain though different pathways [22,25]. These PICs, in turn, will shut off energy-consuming processes, such as locomotor, neurocognitive and reproductive activity. Thus, metabolic energy is withdrawn from the brain and some peripheral organs and redirected to counteract the adverse effects of the invading pathogens. The energy saved by this process contributes to pyrexia and to the enhancement of the inflammatory state of immune cells [22]. Many of the sickness behavior symptoms, such as anergia, malaise, somnolence, psychomotor retardation, cognitive deficits and loss of libido serve to limit motor, sexual and brain activity and thereby direct metabolic energy to combating the primary infection [4,7,22,26]. Immune responses are highly calorie dependent and increase resting energy expenditure, while sickness behavior responses, for example, motor inhibition, may conserve critical energy [27]."
"Mild to moderate pyrexia [hyperthermia] (in contrast to high fever) is a positive adaptive response as it strengthens the host defenses and resistance to infection, for example, by enhancing the phagocytosis and mobility of polymorphonuclear leukocytes and killing of bacteria and preventing viral replication [28-30]. In addition, PICs and cytokines, such as IFNs are more active during fever [31]."
"Inflammation-induced anorexia is directly proportional to the magnitude of the insult and is also inversely related to body weight prior to the insult [33]. It is suggested that anorexia may limit the intake of iron, which otherwise would activate bacterial production [34]. Iron is one of the nutrients employed by bacteria for bacterial growth. This reasoning is, however, highly speculative as only less than 1% of dietary iron is absorbed and iron status changes slowly over time. A more plausible adaptive function is that anorexia through calorie restriction attenuates different intracellular signaling pathways leading to inflammation and even sickness behavior [35,36]. Thus, a two-week calorie restriction period significantly reduces inflammatory pathways, including IL-6 [37]. Calorie-restriction results in a dose-dependent suppression of lipopolysaccharide (LPS)-induced sickness behavior by inducing an anti-inflammatory state [36]."
"The malaise theory regards lowered mood and the more distinctive existential state of depression as a product of malaise. Thus, humans who suffer from sickness behavior and do not know they are ill, may interpret their lack of energy and neurocognitive disorders as a personal failure, causing feelings of guilt and unworthiness [26]."
"Depression is linked to reductions in brain energy generation and mania to increased energy expenditure [51], while sickness behavior is a behavioral response, which conserves energy."
"..administration of LPS, a component of the bacterial wall of gram negative bacteria, causes neuroinflammation and microglial activation, characterized by increased levels of TNFα, which may remain elevated for months and are associated with the onset of sickness behavior [8]."
"Administration of LPS elicits not only sickness behavior but also depressive- (suppression of social interaction and activity in the open-field test, food consumption and body weight, memory dysfunction), anxiety-like and physio-somatic behaviors [15]."
"Sickness behavior supports the protective inflammatory response (helps to eradicate the trigger and redirects energy to inflammatory cells), protects against possible detrimental effects of inflammation (for example, negative energy balance), while at the same time acting as an anti-inflammatory reflex (anti-inflammatory effects of calorie restriction and weight loss). Therefore, sickness behavior itself should be regarded as a CIRS ["compensatory (anti)inflammatory reflex system"] response to acute inflammation."
"There is abundant evidence that depression is characterized not only by increased reactive oxygen and nitrogen species (ROS/RNS), but also by O&NS damage to lipids, proteins, DNA, and mitochondria [131]. In these processes O&NS ["oxidative and nitrosative stress"] pathways may alter the chemical structure of membrane fatty acids and functional proteins. When these modified fatty acids and proteins become immunogenic, an autoimmune response may be mounted directed against these 'neoepitopes' thereby further damaging the function or chemical structure of these epitopes [132,133]."
"Etiologically, sickness behavior is conceptualized as an acute phase of adaptive CIRS behavior in response to acute infections and inflammatory trauma [4,7,26]. When the resolution phase, however, is not induced, for example, when the IRS [inflammatory responses system] was unable to eradicate the pathogen, inflammation may persist despite the CIRS thus causing a chronic inflammatory state [21]. Chronic inflammation may result from a failure to eradicate the acute inflammatory trigger (for example, pyogenic bacteria), innately chronic irritants (for example, fungi, sarcoidosis), or autoimmune responses [151]. Acute and chronic inflammation are distinguished in terms of immune response patterns and time course. The time point of transition of acute inflammation to chronic inflammation is also related to the time when the energy stores become empty and this is estimated to be around 19 to 43 days depending on the nature of the energy store [152]. This transition is related to a number of inflammatory sequelae, including cachexia, insulin resistance, anemia, osteopenia and hypertension [152]. Sickness behavior thus plays a critical role in preventing the transition from acute to chronic inflammation following an acute trigger by compensating for the negative energy balance, redirecting energy to the activated immune cells, and so on [152]."
"In contrast to sickness behavior, pathogens do not play a major role in clinical depression although some authors have attempted to make links between pathogens such as herpes simplex type 2 and toxoplasma gondii and psychopathology [153,154]. In a previous review, we concluded that there is no good quality evidence that acute infections and infections with Epstein-Barr Virus (EBV) may act as trigger factors associated with the onset of clinical depression [155]. Only some types of chronic infection are frequently associated with clinical depression, for example, HIV infection [156] and increased translocation of gram negative bacteria [157]."
"However, it cannot be excluded that reactivated dormant infected states and consequent infection-induced molecular pathways may be important in clinical depression. Viral infections of the brain, for example, cause neurologic and psychiatric dysfunction more often than appreciated [160]."
"..in the rodent, social defeat stress increases the reactivity of microglia to LPS, suggesting a role for social stress factors in the regulation of microglia responses [162]."
"It thus seems unlikely that depression is a maladaptive syndrome that results from prolonged 'sickness behavior' but rather the consequence of a chronic underlying immuno-inflammatory and degenerative process."
"There is also a new hypothesis that associates depression as an evolutionary product of sickness behavior with protection from infection. As such depression is regarded as an evolutionary behavioral response that helps the immune system to fight pathogens and to avoid new pathogen exposure [26,174,175]. These hypotheses, however, did not take into account that clinical depression is not a simple behavioral response, but a progressive disorder driven by a cascading neurobiology leading to a progressive course and pathophysiology. Moreover, acute lethargy, hyperalgesia, loss of interest, anxiety, and anhedonia are beneficial behaviors, but when chronic the same symptoms are typically not beneficial, but pathological and maladaptive: they may further isolate the depressed patient from social contacts creating a state of demotivation and demoralization and negative anticipation of the future [26]. Chronic illness, furthermore, requires a person to use coping and adaptive strategies to integrate the consequences of a disorder. There is a wide diversity of coping styles and beliefs on the nature of depression, some of which are adaptive while others are maladaptive [176]."
"All in all, while sickness behavior is a beneficial CIRS response, clinical depression is a disabling, progressive disorder. Inflammation thus provokes a Janus-faced response with a good 'acute' protective inflammatory side, involving CIRS responses, such as sickness behavior, and a bad 'chronic' side, that can lead to clinical depression, a chronic disorder with positive feedback loops between (neuro)inflammation and (neuro)degenerative processes following less well-defined triggers. This Janus face also represents the transition of an inflammation-induced adaptive behavioral response that is conserved through evolution to an inflammation-related chronic progressive disorder, which is increasing in prevalence in industrialized societies [187]."
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So, gurus, in Ray's book Generative Energy he used this graph to demonstrate different states. On the horizontal axis the "intensity of stimulation" and on the other axis "energy charge". As long as your energy available is able to handle the excitation, you're fine (and above the therapeutic vector). The sickness behavior is trying to bring the animal to the protective inhibition region. Regarding the limiting curve, it probably has its concavity downwards to demonstrate that it gets harder and harder as the demands increase but are not matched by the energy available, until a critical point, when management seems unbearable and a rapid collapse starts to occur (D). I think that the curve is not symmetrical because of our effort to maintain order in adversity and will to live, so to speak..
A - Adventure
B - A baby sleeping
C - Cautious conserving of energy
D - Stressed to death
He writes:
Thread sponsored by: @Greg says and @PakPik
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Because you don't have enough energy for a proper response and to thrive, and not low enough energy to get into a numbing state; you are still reactive and living life normally but with inadequate energy. So, it can happen even if there's just a tiny stimulus, as long as you don't have adequate energy but are not yet in the protective inhibition state. #damngoodcoffee
