Dietary Effects on the Gut Phageome.

As knowledge of the gut microbiome has expanded our understanding of the symbiotic and dysbiotic relationships between the human host and its microbial constituents, the influence of gastrointestinal (GI) microbes both locally and beyond the intestine has become evident. Shifts in bacterial populations have now been associated with several conditions including Crohn's disease (CD), Ulcerative Colitis (UC), irritable bowel syndrome (IBS), Alzheimer's disease, Parkinson's Disease, liver diseases, obesity, metabolic syndrome, anxiety, depression, and cancers. As the bacteria in our gut thrive on the food we eat, diet plays a critical role in the functional aspects of our gut microbiome, influencing not only health but also the development of disease. While the bacterial microbiome in the context of disease is well studied, the associated gut phageome-bacteriophages living amongst and within our bacterial microbiome-is less well understood. With growing evidence that fluctuations in the phageome also correlate with dysbiosis, how diet influences this population needs to be better understood. This review surveys the current understanding of the effects of diet on the gut phageome.

The pandemic exposes human nature: 10 evolutionary insights.

Humans and viruses have been coevolving for millennia. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, the virus that causes COVID-19) has been particularly successful in evading our evolved defenses. The outcome has been tragic-across the globe, millions have been sickened and hundreds of thousands have died. Moreover, the quarantine has radically changed the structure of our lives, with devastating social and economic consequences that are likely to unfold for years. An evolutionary perspective can help us understand the progression and consequences of the pandemic. Here, a diverse group of scientists, with expertise from evolutionary medicine to cultural evolution, provide insights about the pandemic and its aftermath. At the most granular level, we consider how viruses might affect social behavior, and how quarantine, ironically, could make us susceptible to other maladies, due to a lack of microbial exposure. At the psychological level, we describe the ways in which the pandemic can affect mating behavior, cooperation (or the lack thereof), and gender norms, and how we can use disgust to better activate native "behavioral immunity" to combat disease spread. At the cultural level, we describe shifting cultural norms and how we might harness them to better combat disease and the negative social consequences of the pandemic. These insights can be used to craft solutions to problems produced by the pandemic and to lay the groundwork for a scientific agenda to capture and understand what has become, in effect, a worldwide social experiment.

Norepinephrine induces growth of Desulfovibrio vulgaris in an iron dependent manner.

Desulfovibrio spp. is a commensal sulfate reducing bacterium that is present in small numbers in the gastrointestinal tract. Increased concentrations of Desulfovibrio spp. (blooms) have been reported in patients with inflammatory bowel disease and irritable bowel syndrome. Since stress has been reported to exacerbate symptoms of these chronic diseases, this study examined whether the stress catecholamine norepinephrine (NE) promotes Desulfovibrio growth. Norepinephrine-stimulated growth has been reported in other bacterial taxa, and this effect may depend on the availability of the micronutrient iron. OBJECTIVES: This study tested whether norepinephrine exposure affects the in vitro growth of Desulfovibrio vulgaris in an iron dependent manner. METHODS: DSV was incubated in a growth medium with and without 1 µm of norepinephrine. An additional growth assay added the iron chelator deferoxamine in NE exposed DSV. Iron regulatory genes were assessed with and without the treatment of NE and Deferoxamine. RESULTS: We found that norepinephrine significantly increased growth of D. vulgaris. Norepinephrine also increased bacterial production of hydrogen sulfide. Additionally, norepinephrine significantly increased bacterial expression in three of the four tested iron regulatory genes. The iron chelator deferoxamine inhibited growth of D. vulgaris in a dose-dependent manner and reversed the effect of norepinephrine on proliferation of D. vulgaris and on bacterial expression of iron regulatory genes. CONCLUSION: The data presented in this work suggests that promotion of D. vulgaris growth by norepinephrine is iron dependent.

Is eating behavior manipulated by the gastrointestinal microbiota? Evolutionary pressures and potential mechanisms.

Microbes in the gastrointestinal tract are under selective pressure to manipulate host eating behavior to increase their fitness, sometimes at the expense of host fitness. Microbes may do this through two potential strategies: (i) generating cravings for foods that they specialize on or foods that suppress their competitors, or (ii) inducing dysphoria until we eat foods that enhance their fitness. We review several potential mechanisms for microbial control over eating behavior including microbial influence on reward and satiety pathways, production of toxins that alter mood, changes to receptors including taste receptors, and hijacking of the vagus nerve, the neural axis between the gut and the brain. We also review the evidence for alternative explanations for cravings and unhealthy eating behavior. Because microbiota are easily manipulatable by prebiotics, probiotics, antibiotics, fecal transplants, and dietary changes, altering our microbiota offers a tractable approach to otherwise intractable problems of obesity and unhealthy eating.

Birth weight predicted baseline muscular efficiency, but not response of energy expenditure to calorie restriction: An empirical test of the predictive adaptive response hypothesis.

OBJECTIVES: Aiming to test the evolutionary significance of relationships linking prenatal growth conditions to adult phenotypes, this study examined whether birth size predicts energetic savings during fasting. We specifically tested a Predictive Adaptive Response (PAR) model that predicts greater energetic saving among adults who were born small. METHODS: Data were collected from a convenience sample of young adults living in Albuquerque, NM (n = 34). Indirect calorimetry quantified changes in resting energy expenditure (REE) and active muscular efficiency that occurred in response to a 29-h fast. Multiple regression analyses linked birth weight to baseline and postfast metabolic values while controlling for appropriate confounders (e.g., sex, body mass). RESULTS: Birth weight did not moderate the relationship between body size and energy expenditure, nor did it predict the magnitude change in REE or muscular efficiency observed from baseline to after fasting. Alternative indicators of birth size were also examined (e.g., low v. normal birth weight, comparison of tertiles), with no effects found. However, baseline muscular efficiency improved by 1.1% per 725 g (S.D.) increase in birth weight (P = 0.037). CONCLUSIONS: Birth size did not influence the sensitivity of metabolic demands to fasting-neither at rest nor during activity. Moreover, small birth size predicted a reduction in the efficiency with which muscles convert energy expended into work accomplished. These results do not support the ascription of adaptive function to phenotypes associated with small birth size. © 2015 Wiley Periodicals, Inc. Am. J. Hum. Biol. 28:484-492, 2016. © 2015 Wiley Periodicals, Inc.

Magnesium Oxide Reduces Anxiety-like Behavior in Mice by Inhibiting Sulfate-Reducing Bacteria.

The gut microbiota-brain axis allows for bidirectional communication between the microbes in our gastrointestinal (GI) tract and the central nervous system. Psychological stress has been known to disrupt the gut microbiome (dysbiosis) leading to anxiety-like behavior. Pathogens administered into the gut have been reported to cause anxiety. Whether commensal bacteria affect the gut-brain axis is not well understood. In this study, we examined the impact of a commensal sulfate-reducing bacteria (SRB) and its metabolite, hydrogen sulfide (H2S), on anxiety-like behavior. We found that mice gavaged with SRB had increased anxiety-like behavior as measured by the open field test. We also tested the effects of magnesium oxide (MgO) on SRB growth both in vitro and in vivo using a water avoidance stress (WAS) model. We found that MgO inhibited SRB growth and H2S production in a dose-dependent fashion. Mice that underwent psychological stress using the WAS model were observed to have an overgrowth (bloom) of SRB (Deferribacterota) and increased anxiety-like behavior. However, WAS-induced overgrowth of SRB and anxiety-like behavioral effects were attenuated in animals fed a MgO-enriched diet. These findings supported a potential MgO-reversible relationship between WAS-induced SRB blooms and anxiety-like behavior.

Pathogen disgust is associated with interpersonal bias among healthcare professionals.

Background and objectives: Pathogen avoidance is a fundamental motive that shapes many aspects of human behavior including bias against groups stereotypically linked to disease (e.g. immigrants, outgroup members). This link has only been examined in convenience samples and it is unknown how pathogen avoidance processes operate in populations experiencing prolonged and heightened pathogen threat such as healthcare professionals. We examined whether healthcare professionals demonstrate the same link between pathogen disgust and intergroup bias as has been documented among the general population. Methodology: Participants (N = 317; 210 healthcare professionals) were recruited using snowball sampling to take an online survey. Participants completed the Three Domain Disgust Scale to assess pathogen, sexual and moral disgust. Participants then rated their perceptions of a fictitious immigrant group ('Krasneeans') and the degree to which they endorsed group-binding moral values. Results: Compared to control participants, healthcare professionals reported lower levels of pathogen disgust, but not sexual or moral disgust. However, regardless of profession, higher pathogen disgust was associated with viewing Krasneeans as less likeable and more unclean. Additionally, regardless of profession, higher pathogen disgust was associated with greater endorsement of group-binding moral values, although healthcare professionals reported greater overall endorsement of group-binding moral values than did control participants. Conclusions and implications: Although healthcare professionals demonstrated lower levels of pathogen disgust, they nevertheless exhibited largely the same relationship between pathogen disgust and interpersonal biases as did control participants. One practical implication of this association is that pathogen avoidance motives may contribute to inequitable patient treatment in healthcare settings.

Mucin and Agitation Shape Predation of Escherichia coli by Lytic Coliphage.

The ability of bacteriophage (phage), abundant within the gastrointestinal microbiome, to regulate bacterial populations within the same micro-environment offers prophylactic and therapeutic opportunities. Bacteria and phage have both been shown to interact intimately with mucin, and these interactions invariably effect the outcomes of phage predation within the intestine. To better understand the influence of the gastrointestinal micro-environment on phage predation, we employed enclosed, in vitro systems to investigate the roles of mucin concentration and agitation as a function of phage type and number on bacterial killing. Using two lytic coliphage, T4 and PhiX174, bacterial viability was quantified following exposure to phages at different multiplicities of infection (MOI) within increasing, physiological levels of mucin (0-4%) with and without agitation. Comparison of bacterial viability outcomes demonstrated that at low MOI, agitation in combination with higher mucin concentration (>2%) inhibited phage predation by both phages. However, when MOI was increased, PhiX predation was recovered regardless of mucin concentration or agitation. In contrast, only constant agitation of samples containing a high MOI of T4 demonstrated phage predation; briefly agitated samples remained hindered. Our results demonstrate that each phage-bacteria pairing is uniquely influenced by environmental factors, and these should be considered when determining the potential efficacy of phage predation under homeostatic or therapeutic circumstances.

Test-retest reliability of multidimensional dyspnea profile recall ratings in the emergency department: a prospective, longitudinal study.

BACKGROUND: Dyspnea is among the most common reasons for emergency department (ED) visits by patients with cardiopulmonary disease who are commonly asked to recall the symptoms that prompted them to come to the ED. The reliability of recalled dyspnea has not been systematically investigated in ED patients. METHODS: Patients with chronic or acute cardiopulmonary conditions who came to the ED with dyspnea (N = 154) completed the Multidimensional Dyspnea Profile (MDP) several times during the visit and in a follow-up visit 4 to 6 weeks later (n = 68). The MDP has 12 items with numerical ratings of intensity, unpleasantness, sensory qualities, and emotions associated with how breathing felt when participants decided to come to the ED (recall MDP) or at the time of administration ("now" MDP). The recall MDP was administered twice in the ED and once during the follow-up visit. Principal components analysis (PCA) with varimax rotation was used to assess domain structure of the recall MDP. Internal consistency reliability was assessed with Cronbach's alpha. Test-retest reliability was assessed with intraclass correlation coefficients (ICCs) for absolute agreement for individual items and domains. RESULTS: PCA of the recall MDP was consistent with two domains (Immediate Perception, 7 items, Cronbach's alpha = .89 to .94; Emotional Response, 5 items; Cronbach's alpha = .81 to .85). Test-retest ICCs for the recall MDP during the ED visit ranged from .70 to .87 for individual items and were .93 and .94 for the Immediate Perception and Emotional Response domains. ICCs were much lower for the interval between the ED visit and follow-up, both for individual items (.28 to .66) and for the Immediate Perception and Emotional Response domains (.72 and .78, respectively). CONCLUSIONS: During an ED visit, recall MDP ratings of dyspnea at the time participants decided to seek care in the ED are reliable and sufficiently stable, both for individual items and the two domains, that a time lag between arrival and questionnaire administration does not critically affect recall of perceptual and emotional characteristics immediately prior to the visit. However, test-retest reliability of recall over a 4- to 6-week interval is poor for individual items and significantly attenuated for the two domains.

Time Domains of Hypoxia Responses and -Omics Insights.

The ability to respond rapidly to changes in oxygen tension is critical for many forms of life. Challenges to oxygen homeostasis, specifically in the contexts of evolutionary biology and biomedicine, provide important insights into mechanisms of hypoxia adaptation and tolerance. Here we synthesize findings across varying time domains of hypoxia in terms of oxygen delivery, ranging from early animal to modern human evolution and examine the potential impacts of environmental and clinical challenges through emerging multi-omics approaches. We discuss how diverse animal species have adapted to hypoxic environments, how humans vary in their responses to hypoxia (i.e., in the context of high-altitude exposure, cardiopulmonary disease, and sleep apnea), and how findings from each of these fields inform the other and lead to promising new directions in basic and clinical hypoxia research.

Cytokine storms, evolution and COVID-19.

Since the identification of severe illness caused by the novel coronavirus SARS-CoV-2, the role of the host immune system in causing disease has attracted widespread attention, along with intense interest in medical interventions that target the host immune response. A wide variety of agents have been proposed to treat a cytokine storm in coronavirus disease 2019 (COVID-19), but so far, only one class of medications, corticosteroids, has proved useful. In recent decades, experimental therapies for cytokine storms have been tried and mostly failed to help patients with severe sepsis and other infections. We summarize this history in order to frame expectations for novel interventions in COVID-19 and to bring an evolutionary medicine perspective to the concept of cytokine storms and their treatment.

High-altitude pulmonary edema.

Lay summary: High Altitude Pulmonary Edema (HAPE) is a potentially fatal disease of altitude, in which the lungs can become filled with fluid. In this article we explore the mechanisms causing this condition and how it can be viewed as a condition of a mismatch between current environment and evolutionary experience.

Conflicts over calcium and the treatment of COVID-19.

Several recent studies have provided evidence that use of calcium channel blockers (CCBs), especially amlodipine and nifedipine, can reduce mortality from coronavirus disease 2019 (COVID-19). Moreover, hypocalcemia (a reduced level of serum ionized calcium) has been shown to be strongly positively associated with COVID-19 severity. Both effectiveness of CCBs as antiviral therapy, and positive associations of hypocalcemia with mortality, have been demonstrated for many other viruses as well. We evaluate these findings in the contexts of virus-host evolutionary conflicts over calcium metabolism, and hypocalcemia as either pathology, viral manipulation or host defence against pathogens. Considerable evidence supports the hypothesis that hypocalcemia represents a host defence. Indeed, hypocalcemia may exert antiviral effects in a similar manner as do CCBs, through interference with calcium metabolism in virus-infected cells. Prospective clinical studies that address the efficacy of CCBs and hypocalcemia should provide novel insights into the pathogenicity and treatment of COVID-19 and other viruses.

Let fever do its job: The meaning of fever in the pandemic era.

Although fever is one of the main presenting symptoms of COVID-19 infection, little public attention has been given to fever as an evolved defense. Fever, the regulated increase in the body temperature, is part of the evolved systemic reaction to infection known as the acute phase response. The heat of fever augments the performance of immune cells, induces stress on pathogens and infected cells directly, and combines with other stressors to provide a nonspecific immune defense. Observational trials in humans suggest a survival benefit from fever, and randomized trials published before COVID-19 do not support fever reduction in patients with infection. Like public health measures that seem burdensome and excessive, fevers involve costly trade-offs but they can prevent infection from getting out of control. For infections with novel SARS-CoV-2, the precautionary principle applies: unless evidence suggests otherwise, we advise that fever should be allowed to run its course. Lay summary: For COVID-19, many public health organizations have advised treating fever with medicines such as acetaminophen or ibuprofen. Even though this is a common practice, lowering body temperature has not improved survival in laboratory animals or in patients with infections. Blocking fever can be harmful because fever, along with other sickness symptoms, evolved as a defense against infection. Fever works by causing more damage to pathogens and infected cells than it does to healthy cells in the body. During pandemic COVID-19, the benefits of allowing fever to occur probably outweigh its harms, for individuals and for the public at large.

Associations Between Change Over Time in Pandemic-Related Stress and Change in Physical Activity.

BACKGROUND: Physical activity (PA) mitigated psychological distress during the initial weeks of the COVID-19 pandemic, yet not much is known about whether PA had effects on stress in subsequent months. We examined the relationship between change over time in COVID-related stress and self-reported change in PA between March and July 2020. METHODS: Latent growth modeling was used to examine trajectories of change in pandemic-related stress and test their association with self-reported changes in PA in an international sample (n = 679). RESULTS: The participants reported a reduction in pandemic-related stress between April and July of 2020. Significant linear (factor mean = -0.22) and quadratic (factor mean = 0.02) changes (Ps < .001) were observed, indicating a deceleration in stress reduction over time. Linear change was related to change in PA such that individuals who became less active during the pandemic reported less stress reduction over time compared with those who maintained or increased their PA during the pandemic. CONCLUSIONS: Individuals who experienced the greatest reduction in stress over time during the pandemic were those who maintained their activity levels or became more active. Our study cannot establish a causal relationship between these variables, but the findings are consistent with other work showing that PA reduces stress.

Standard Bacteriophage Purification Procedures Cause Loss in Numbers and Activity.

For decades, bacteriophage purification has followed structured protocols focused on generating high concentrations of phage in manageable volumes. As research moves toward understanding complex phage populations, purification needs have shifted to maximize the amount of phage while maintaining diversity and activity. The effects of standard phage purification procedures such as polyethylene glycol (PEG) precipitation and cesium chloride (CsCl) density gradients on both diversity and activity of a phage population are not known. We have examined the effects of PEG precipitation and CsCl density gradients on a number of known phage (M13, T4, and ΦX 174) of varying structure and size, individually and as mixed sample. Measurement of phage numbers and activity throughout the purification process was performed. We demonstrate that these methods, used routinely to generate "pure" phage samples, are in fact detrimental to retention of phage number and activity; even more so in mixed phage samples. As such, minimal amounts of processing are recommended to introduce less bias and maintain more of a phage population.

A comparison of bacterial colony-forming units in water bottles and hydration bags among outdoor enthusiasts.

OBJECTIVE: Transporting clean drinking water in an easily accessible container is a priority for many outdoor enthusiasts. Two basic hydration systems are commonly used to provide water: the water bottle and the hydration bladder. The authors tested the hypothesis that there were different levels of microbiologic contamination between these 2 systems. METHODS: Sixty-seven water samples were collected using sterile techniques from outdoor enthusiasts at several outdoor recreational locations. These users were then asked to complete a brief survey that reported demographic information and details of water container use. Water samples were then plated on sheep blood agar, and the colony-forming units were counted after 24 hours of growth. The 2 groups were compared using Student's t test. RESULTS: The 2 groups using water bottles or hydration bladders did not show significant differences in container age, duration of outdoor activity, or duration since last cleaning. The groups differed slightly in their composition of hikers/walkers/runners vs cyclists. The water bottle group had a mean colony-forming unit count per 100 mL of 37 (95% CI 26-48), and the hydration bladder had a mean of 27 (95% CI 17-35). CONCLUSIONS: There was no statistically significant difference between hydration bladders and water bottles in microbial contamination or colonization. Judging from the available data, outdoor enthusiasts should select their water container based on criteria other than the relative exposure to microbes. Additional study is required to replicate this finding in other locations and with improved sample methodology.

Kombucha: a novel model system for cooperation and conflict in a complex multi-species microbial ecosystem.

Kombucha, a fermented tea beverage with an acidic and effervescent taste, is composed of a multispecies microbial ecosystem with complex interactions that are characterized by both cooperation and conflict. In kombucha, a complex community of bacteria and yeast initiates the fermentation of a starter tea (usually black or green tea with sugar), producing a biofilm that covers the liquid over several weeks. This happens through several fermentative phases that are characterized by cooperation and competition among the microbes within the kombucha solution. Yeast produce invertase as a public good that enables both yeast and bacteria to metabolize sugars. Bacteria produce a surface biofilm which may act as a public good providing protection from invaders, storage for resources, and greater access to oxygen for microbes embedded within it. The ethanol and acid produced during the fermentative process (by yeast and bacteria, respectively) may also help to protect the system from invasion by microbial competitors from the environment. Thus, kombucha can serve as a model system for addressing important questions about the evolution of cooperation and conflict in diverse multispecies systems. Further, it has the potential to be artificially selected to specialize it for particular human uses, including the development of antimicrobial ecosystems and novel materials. Finally, kombucha is easily-propagated, non-toxic, and inexpensive, making it an excellent system for scientific inquiry and citizen science.

Hemostatic containment - an evolutionary hypothesis of injury by innate immune cells.

Tissue damage mediated by innate immune cells in reperfusion injury may have a survival benefit in infections, preventing sepsis. Tissue damage by leukocytes - plugging of small vessels, endothelial cell damage, tissue edema around vessels, and stimulation of platelet aggregation - occurs in both reperfusion injury and infection-prone wounds. These events create a physical barrier that may sequester bacteria, preventing bacterial invasion of the blood. This antisepsis effect, termed "hemostatic containment," is triggered by signals that convey susceptibility to infection, such as poor blood flow and oxygenation. In active and incipient infections, the host accepts some sacrifice of body tissues while preventing pathogens from gaining access into sterile sites. This tradeoff prevents bacteremia and promotes survival in diseases such as abscesses. Other diseases mimic infection-prone states and elicit costly host injury that exceeds antibacterial benefits. Mimic diseases include cocaine-induced heart attacks and decompression illness. Mimics produce signals that active innate immune cells despite the absence of pathogens. Atherosclerotic cardiovascular diseases comprise an intermediate, or pseudo-mimic, state characterized by indolent pathogens that rarely cause sepsis. Treatment of innate immune cell injury is likely to be more effective for mimic and pseudo-mimic states than for infectious diseases. Interventions against reperfusion injury might be most effective when they improve host immune defenses while eliminating signals of infection risk.

The Emperor Has No Clothes? Searching for Dysregulation in Sepsis.

The core conception of sepsis-that it is a dysregulated state-is a powerful and durable idea that has inspired decades of research. But is it true that the body's response to sepsis is dysregulated? To answer that question, this review surveyed the history of trials of experimental sepsis treatments targeting the host response. Sepsis survival is not improved by blocking one or many immune pathways. Similarly, sepsis is resistant to treatment by normalizing one or many physiologic parameters simultaneously. The vast majority of interventions are either ineffective or harmful. With this track record of failure, it is time to consider the alternative hypothesis-regulation instead of dysregulation-and the possibility that sepsis traits are often functional, and that some physiologic alterations in sepsis do more good than harm, while others are neutral. This review discusses the implications of this perspective for the future of sepsis research.