Microbial endocrinology: how stress influences susceptibility to infection

A holistic approach to understanding the mechanisms by which stress influences the pathogenesis of infectious disease has resulted in the development of the field of microbial endocrinology. This transdisciplinary field represents the intersection of microbiology with mammalian endocrinology and neurophysiology, and is based on the tenet that microorganisms have evolved systems for using neurohormones, which are widely distributed throughout nature, as environmental cues to initiate growth and pathogenic processes. This review reveals that responsiveness to human stress hormones is widespread in the microbial world and documents recent advances in microbial endocrinology.     

Stress and microbial endocrinology: prospects for ruminant nutrition

The feed efficiency of ruminant meat and dairy livestock can be significantly influenced by factors within their living environments. In particular, events perceived by the animals as stressful (such as parturition, transport or handling) have been found to affect susceptibility to infection. It has been well documented that even minor stress such as weighing can result in an increase in colonisation and faecal shedding of enteric pathogens such as Salmonella enterica and Escherichia coli O157:H7. Such infections affect both ruminant overall health and therefore performance, and are a particular problem for the meat production industries. Prior explanations for stress enhancing the likelihood of infection is that activation of the sympathetic nervous system under stress leads to the release of neuroendocrine mediators such as the catecholamine stress hormones noradrenaline and adrenaline, which may impair innate and adaptive immunity. More recently, however, another equally compelling explanation, viewed through the lens of the newly recognised microbiological discipline of microbial endocrinology is that the myriad of bacteria within the ruminant digestive tract are as responsive to the hormonal output of stress as the cells of their host. Work from our laboratories has shown that enteric pathogens have evolved systems for directly sensing stress hormones. We have demonstrated that even brief exposure of enteric pathogens to physiological concentrations of stress hormones can result in massive increases in growth and marked changes in expression of virulence factors such as adhesins and toxins. Happy, less stressed ruminants may therefore be better-nourished animals and safer sources of meat. This article reviews evidence that stress, as well as affecting nutrition, in ruminants is correlated with increased risk of enteric bacterial infections, and examines the molecular mechanisms that may be at work in both processes.     

Review: Microbial endocrinology: intersection of microbiology and neurobiology matters to swine health from infection to behavior

From birth to slaughter, pigs are in constant interaction with microorganisms. Exposure of the skin, gastrointestinal and respiratory tracts, and other systems allows microorganisms to affect the developmental trajectory and function of porcine physiology as well as impact behavior. These routes of communication are bi-directional, allowing the swine host to likewise influence microbial survival, function and community composition. Microbial endocrinology is the study of the bi-directional dialogue between host and microbe. Indeed, the landmark discovery of host neuroendocrine systems as hubs of host–microbe communication revealed neurochemicals act as an inter-kingdom evolutionary-based language between microorganism and host. Several such neurochemicals are stress catecholamines, which have been shown to drastically increase host susceptibility to infection and augment virulence of important swine pathogens, including Clostridium perfringens. Catecholamines, the production of which increase in response to stress, reach the epithelium of multiple tissues, including the gastrointestinal tract and lung, where they initiate diverse responses by members of the microbiome as well as transient microorganisms, including pathogens and opportunistic pathogens. Multiple laboratories have confirmed the evolutionary role of microbial endocrinology in infectious disease pathogenesis extending from animals to even plants. More recent investigations have now shown that microbial endocrinology also plays a role in animal behavior through the microbiota–gut–brain axis. As stress and disease are ever-present, intersecting concerns during each stage of swine production, novel strategies utilizing a microbial endocrinology-based approach will likely prove invaluable to the swine industry.     

Hormonal mechanisms of cooperative behaviour

Research on the diversity, evolution and stability of cooperative behaviour has generated a considerable body of work. As concepts simplify the real world, theoretical solutions are typically also simple. Real behaviour, in contrast, is often much more diverse. Such diversity, which is increasingly acknowledged to help in stabilizing cooperative outcomes, warrants detailed research about the proximate mechanisms underlying decision-making. Our aim here is to focus on the potential role of neuroendocrine mechanisms on the regulation of the expression of cooperative behaviour in vertebrates. We first provide a brief introduction into the neuroendocrine basis of social behaviour. We then evaluate how hormones may influence known cognitive modules that are involved in decision-making processes that may lead to cooperative behaviour. Based on this evaluation, we will discuss specific examples of how hormones may contribute to the variability of cooperative behaviour at three different levels: (i) within an individual; (ii) between individuals and (iii) between species. We hope that these ideas spur increased research on the behavioural endocrinology of cooperation.     

Microbial Endocrinology

Microbial Endocrinology is a new microbiology research discipline that represents the intersection of microbiology and endocrinology with neurophysiology. It has as its main tenet that through their long co-existence with animals and plants, micro-organisms have evolved sensory systems for detecting host-associated hormones. These sensing systems allow the microbe to determine that they are within proximity of a suitable host, and that is time to initiate expression of genes involved in host colonisation. Microbial Endocrinology therefore provides a new paradigm with which to examine and understand the interactions of micro-organisms with their host under conditions present in both health and disease. This article will focus on microbial interactions with the fight and flight family of catecholamine stress hormones.     

Hormonal stimulation of adenosine 3',5'-cyclic monophosphate formation in cell-free particles and intact cells of smooth muscle in the aorta and femoral artery of rats during immubilization stress]

The ability of adrenaline and histamine to stimulate the formation of cyclic AMP was investigated in broken cell preparation and intact cells of smooth muscle of the aorta and femoral artery of rats which had been subjected to daily intermittent immobilization for 1, 3, and 17 weeks. It was found that this type of stress led to an instability of the blood pressure which was associated with an increase in the sensitivity of adenylate cyclase in the broken cell preparations from the arteries to adrenaline and histamine and with a heightened cyclic AMP response to the two hormones in the intact arterial smooth muscle cells. The sensitivity of cardiac adenylate cyclase for adrenaline remained unchanged.     

Update: brain and pituitary hormones of lampreys

Lampreys and hagfish of the class Agnatha are of particular importance in understanding endocrinological relationships since they represent the oldest lineages of extant vertebrates which evolved over 550 million years ago. This review briefly summarizes the latest findings on the reproductive endocrinology of the sea lampreys. Since the First International Symposium of Fish Endocrinology in 1988, when virtually little was known of the hypothalamic-pituitary-gonadal axis, substantial new biochemical, molecular, physiological and immunological evidence has now clearly shown that lamprey reproduction is controlled by the neuroendocrine axis. In addition, five brain and six pituitary hormones of lampreys have been identified mainly by Sower and Kawauchi and colleagues between 1986 and 2000. We now hypothesize that lamprey reproduction is a highly synchronized process that is initiated or mediated by a coordination of complex integration of environmental cues and hormonal mechanisms which is broadly similar to that exhibited by gnathostome vertebrates.     

Sex-role reversal in vertebrates: behavioural and endocrinological accounts

Sex-role reversal occurs when females compete more intensely than males for access to mates. In this paper, we survey the occurrence of sex-role reversal in vertebrates: we focus on behavioural aspects of sex-role reversal and we examine possible endocrinological correlates of this phenomenon. The best documented cases among vertebrates of sex-role reversal occur in fish and birds. In nearly all sex-role reversed species or populations, females have higher potential reproductive rates than males. Some species in which females were previously thought to be the predominant competitors for mates (for instance seahorses and a dendrobatid frog), appear not to be sex-role reversed according to recent studies. The endocrinology of sex-role reversal has been studied in only a few species and therefore remains poorly understood. In birds, which probably have been studied the most in this respect, steroid hormones appear to follow the typical ancestral conditions (for instance no reversal of testosterone levels) in sex-role reversed species, whereas prolactin, a principal regulator of the onset and maintenance of incubation, departs from the usual avian pattern in that it is higher in males than in females. The study of sex-role reversed behaviour offers unique opportunities not only to test sexual selection theory, but also to enhance our understanding of the neuroendocrine mechanisms mediating behavioural sex differences.     

Pathogen espionage: multiple bacterial adrenergic sensors eavesdrop on host communication systems

The interactions between bacterial pathogens and their eukaryotic hosts are vital in determining the outcome of infections. Bacterial pathogens employ molecular sensors to detect and facilitate adaptation to changes in their niche. The sensing of these extracellular signals enables the pathogen to navigate within mammalian hosts. Intercellular bacterial communication is facilitated by the production and sensing of autoinducer (AI) molecules via quorum sensing. More recently, AI‐3 and the host neuroendocrine (NE) hormones adrenaline and noradrenaline were reported to display cross‐talk for the activation of the same signalling pathways. Remarkably, there is increasing evidence to suggest that enteric bacteria sense and respond to the host NE stress hormones adrenaline and noradrenaline to modulate virulence. These responses can be inhibited by α and β‐adrenergic receptor antagonists implying a bacterial receptor‐based sensing and signalling cascade. In Escherichia coli O157:H7 and Salmonella, QseC has been proposed as the adrenergic receptor. Strikingly, there is an increasing body of evidence that not all the bacterial adrenergic responses require signalling through QseC. Here we provide additional hypotheses to reconcile these observations implicating the existence of alternative adrenergic receptors including BasS, QseE and CpxA and their associated signalling cascades with major roles in interkingdom communication.     

Interaction of the endocrine system with inflammation: a function of energy and volume regulation

During acute systemic infectious disease, precisely regulated release of energy-rich substrates (glucose, free fatty acids, and amino acids) and auxiliary elements such as calcium/phosphorus from storage sites (fat tissue, muscle, liver, and bone) are highly important because these factors are needed by an energy-consuming immune system in a situation with little or no food/water intake (sickness behavior). This positively selected program for short-lived infectious diseases is similarly applied during chronic inflammatory diseases. This review presents the interaction of hormones and inflammation by focusing on energy storage/expenditure and volume regulation. Energy storage hormones are represented by insulin (glucose/lipid storage and growth-related processes), insulin-like growth factor-1 (IGF-1) (muscle and bone growth), androgens (muscle and bone growth), vitamin D (bone growth), and osteocalcin (bone growth, support of insulin, and testosterone). Energy expenditure hormones are represented by cortisol (breakdown of liver glycogen/adipose tissue triglycerides/muscle protein, and gluconeogenesis; water retention), noradrenaline/adrenaline (breakdown of liver glycogen/adipose tissue triglycerides, and gluconeogenesis; water retention), growth hormone (glucogenic, lipolytic; has also growth-related aspects; water retention), thyroid gland hormones (increase metabolic effects of adrenaline/noradrenaline), and angiotensin II (induce insulin resistance and retain water). In chronic inflammatory diseases, a preponderance of energy expenditure pathways is switched on, leading to typical hormonal changes such as insulin/IGF-1 resistance, hypoandrogenemia, hypovitaminosis D, mild hypercortisolemia, and increased activity of the sympathetic nervous system and the renin-angiotensin-aldosterone system. Though necessary during acute inflammation in the context of systemic infection or trauma, these long-standing changes contribute to increased mortality in chronic inflammatory diseases.     

Regulation of IGF-I function by proinflammatory cytokines: at the interface of immunology and endocrinology

During the past decade, the immune and endocrine systems have been discovered to interact in controlling physiologic processes as diverse as cell growth and differentiation, metabolism, and even human and animal behavior. The interaction between these two major physiological systems is a bi-directional process. While it has been well documented that hormones, including prolactin (PRL), growth hormone (GH), insulin-like growth factor-I (IGF-I), and thyroid-stimulating hormone (TSH), regulate a variety of immune events, a great deal of data have accumulated supporting the notion that cytokines from the innate immune system also affect the neuroendocrine system. Communication between these two systems coordinates processes that are necessary to maintain homeostasis. Proinflammatory cytokines often act as negative regulatory signals that temper the action of hormones and growth factors. This system of 'checks and balances' is an active, ongoing process, even in healthy individuals. Dysregulation of this process has been implicated as a potential pathogenic factor in the development of co-morbid conditions associated with several chronic inflammatory diseases, including type 2 diabetes, cardiovascular disease, cerebrovascular disease, inflammatory bowel disease, rheumatoid arthritis, major depression, and even normal aging. Over the past decade, research in our laboratory has focused on the ability of the major proinflammatory cytokines, tumor necrosis factor (TNF)alpha and interleukin (IL)-1beta, to induce a state of IGF resistance. This review will highlight these and other new findings by explaining how proinflammatory cytokines induce resistance to the major growth factor, insulin-like growth factor-I (IGF-I). We also highlight that IGF-I can induce resistance or reduce sensitivity to brain TNFalpha and discuss how TNFalpha, IL-1beta, and IGF-I interact to regulate several aspects of behavior and cognition.     

Effects of catecholamines on rat myocardial metabolism. I. Influence of catecholamines on energy-rich nucleotides and phosphorylated fraction contents.

1. The influence of catecholamines (adrenaline and noradrenaline) on energy metabolism of the rat myocardium has been studied by incubating slices of this tissue with these hormones and by following the levels of the different phosphorylated fractions and adenylic nucleotides. 2. Similar effects are obtained with both hormones, adrenaline being more effective. 3. Catecholamines decrease significantly the total amount of phosphate while Pi content increases during the first 10 minutes of incubation; labile and residual phosphate contents increase at the beginning of incubation and decrease to the initial values afterwards. 4. ATP and ADP levels decrease significantly with both hormones; however, the effect of noradrenalin on the ATP level needs a longer time of incubation. The ATP/ADP ratios decrease after 5 minutes incubation and the total adenylic nucleotide content is severely decreased (35 per cent with adrenalin, after 20 minutes incubation). 5. Similar results have been obtained with other tissues; these results can explain the decrease of aerobic metabolism we observed under the same conditions.     

The Riddle of Sex: Biological Theories of Sexual Difference in the Early Twentieth-Century

At the turn of the twentieth century, biologists such as Oscar Riddle, Thomas Hunt Morgan, Frank Lillie, and Richard Goldschmidt all puzzled over the question of sexual difference, the distinction between male and female. They all offered competing explanations for the biological cause of this difference, and engaged in a fierce debate over the primacy of their respective theories. Riddle propounded a metabolic theory of sex dating from the late-nineteenth century suggesting that metabolism lay at the heart of sexual difference. Thomas Hunt Morgan insisted on the priority of chromosomes, Frank Lillie emphasized the importance of hormones, while Richard Goldschmidt supported a mixed model involving both chromosomes and hormones. In this paper, I will illustrate how the older metabolic theory of sex was displaced when those who argued for the relatively newer theories of chromosomes and hormones gradually formed an alliance that accommodated each other and excluded the metabolic theory of sex. By doing so, proponents of chromosomes and hormones established their authority over the question of sexual difference as they laid the foundations for the new disciplines of genetics and endocrinology. Their debate raised urgent questions about what constituted sexual difference, and how scientists envisioned the plasticity and controllability of this difference. These theories also had immediate political and cultural consequences at the turn of the twentieth century, especially for the eugenic and feminist movements, both of which were heavily invested in knowledge of sex and its determination, ascertainment, and command.     

Hormones,Lymphohemopoietic Cytokines and the Neuroimmune Axis

The classical distinction between hormones and cytokines has become increasingly obscure with the realization that homeostatic responses to infection involve coordinated changes in both the neuroendocrine and immune systems. The hypothesis that these systems communicate with one another is supported by the ever-accruing demonstrations of a shared molecular network of ligands and receptors. For instance, leukocytes express receptors for hormones and these receptors modulate diverse biological activities such as the growth, differentiation and effector functions. Leukocyte lineages also synthesize and secrete hormones, such as insulin-like growth factor-I (IGF-I), in response to both growth hormone (GH) and also to cytokines such as tumor necrosis factor-α (TNF-α). Since hormones share intracellular signaling substrates and biological activities with classical lymphohemopoietic cytokines, neuroendocrine and immune tissues share a common molecular language. The physiological significance of this shared molecular framework is that these homeostatic systems can intercommunicate. One important example of this interaction is the mechanism by which bacterial lipopolysaccharide, by eliciting a pro-inflammatory cytokine cascade from activated leukocytes, modulate pituitary GH secretion as well as other CNS-controlled behavioral and metabolic events. This article reviews the cellular and molecular basis for this communication system and proposes novel mechanisms by which neuroendocrine-immune interactions converge to modulate disease resistance, metabolism and growth.     

L to D amino acid isomerization in a peptide hormone is a late post-translational event occurring in specialized neurosecretory cells

Modification of the chirality of a single amino acid residue within a peptide chain appears to be novel additional mechanism leading to structural and functional diversification of eukaryotic bioactive peptides. This phenomenon has been studied at the cellular level in a neuroendocrine organ which elaborates a mixture of diastereoisomers of a 72-residue neuropeptide, crustacean hyperglycemic hormone. For the first time, amino acid isomerization has been shown to occur in the perikarya of fully specialized neurosecretory cells, as a late step of the maturation of the hyperglycemic hormone precursor and after propeptide cleavage. The specificity and efficiency of this phenomenon indicates the existence of a new enzyme family involved in the biogenesis of peptide hormones.     

Recent Developments in Invertebrate Endocrinology

In recent years the field of invertebrate endocrinology haswitnessed considerable progress in certain areas while littleor no advancement has been made in others. The great majorityof work continues to be done with insects. In this brief reviewattention is focused primarily on three areas of insect endocrinology:intermediary metabolism, osmoregulation, and growth and development. Some comments are made about the intimacy of the neural andendocrine systems of invertebrates. The apparent productionof hormones throughout the nervous system of arthropods is noted,and evidence is cited that direct delivery of neurosecretoryhormones to target organs may be common.     

Desensitization of adenylate cyclase and cyclic AMP flux during the early stages of liver regeneration

Liver regeneration is controlled by a complex network of interactions between hormones, growth factors, and a variety of hepatotrophic factors. Transient increases in cAMP in the early stages of liver regeneration that are necessary for DNA synthesis and subsequent mitosis have been reported; however, studies on the mechanisms that control cellular cAMP levels during liver regeneration, namely adenylate cyclase activity, cAMP-dependent phosphodiesterase activity, and cAMP efflux from the cell, have been generally incomplete. In this study we have shown that although there are three peaks in intracellular cAMP levels in the first 24 hours after partial hepatectomy, the adenylate cyclase activity stimulated by glucagon, prostaglandin E2, adrenaline, and fluoride in vitro decreases with time. KD and BMAX of hepatocyte glucagon and beta receptors were similar to the sham controls. Our results are consistent with a mixed homologous/heterologous desensitization of the adenylate cyclase system. There was also a loss of cAMP-dependent phosphodiesterase activity after partial hepatectomy. We speculate that even though the hormone-stimulated adenylate cyclase system has been desensitized, the system retains the ability to respond to the transient pulses of the variety of hormones secreted after partial hepatectomy and thus raise the intracellular concentration of cAMP. The decrease in cAMP-dependent phosphodiesterase may be necessary to prevent rapid breakdown of cAMP.     

Stimulation with LH of progesterone production by rabbit corpora lutea in vitro

Quartered CL from 7-day pseudopregnant rabbits were incubated at 37 degrees C for 0-180 min in the presence of BSA, LH or adrenaline in Krebs-Ringer-bicarbonate buffer. Total progesterone at each time point was quantified in homogenates of tissue plus incubation media and expressed relative to CL protein. Progesterone increased linearly with time during the first 30 min of incubation in the presence of BSA. LH and adrenaline markedly accelerated progesterone accumulations relative to the BSA control. At 10 min, progesterone accumulation in the presence of LH and adrenaline were 2.4 and 5.9 times that in the absence of stimulators, respectively. Both hormones caused concentration-dependent increases in progesterone and the apparent ED50 was 0.75 microgram/ml for LH and adrenaline. The CL obtained from ovaries of 7-day pseudopregnant rabbits are therefore capable of an acute steroidogenic synthetic response to LH as well as adrenaline.