Soil-transmitted helminth infection and intestinal inflammation among the Shuar of Amazonian Ecuador.

OBJECTIVES: Little research exists documenting levels of intestinal inflammation among indigenous populations where exposure to macroparasites, like soil-transmitted helminths (STHs), is common. Reduced STH exposure is hypothesized to contribute to increased prevalence of elevated intestinal inflammation in wealthy nations, likely due to coevolutionary histories between STHs and human immune systems that favored anti-inflammatory pathways. Here, we document levels of intestinal inflammation and test associations with STH infection among the Shuar of Ecuador, an indigenous population undergoing socioeconomic/lifestyle changes that influence their hygienic environment. We predict that fecal calprotectin (FC; a measure of intestinal inflammation) will be lower in STH infected individuals and that FC will be negatively associated with infection intensity. METHODS: Stool samples to analyze FC levels and STH infection were collected from 69 Shuar participants (ages 5-75 years). Children (<15 years) and adults (15+ years) were analyzed separately to understand the role of exposure in immune system development and the intestinal inflammatory response. RESULTS: Two species of STH were present: Ascaris lumbricoides and Trichuris trichiura. The relationships between infection and intestinal inflammation were age- and species-specific. While no significant relationships were found among adults, children who were singly infected with T. trichiura had lower FC levels than uninfected children. Infection intensity was not significantly associated with FC in children or adults. CONCLUSIONS: These preliminary results provide limited support for our hypotheses, documenting tentative age- and species-specific associations between FC and infection status. Findings may point to the importance of species-specific STH exposure during immune system development.

Soil exposure modulates the immune response to an influenza challenge in a mouse model.

There is increasing evidence that early life microbial exposure aids in immune system maturation, more recently known as the "old friends" hypothesis. To test this hypothesis, 4-week-old mice were exposed to soils of increasing microbial diversity for four weeks followed by an intranasal challenge with either live or heat inactivated influenza A virus and monitored for 7 additional days. Perturbations of the gut and lung microbiomes were explored through 16S rRNA amplicon sequencing. RNA-sequencing was used to examine the host response in the lung tissue through differential gene expression. We determined that compared to the gut microbiome, the lung microbiome is more susceptible to changes in beta diversity following soil exposure with Lachnospiraceae ASVs accounting for most of the differences between groups. While several immune system genes were found to be significantly differentially expressed in lung tissue due to soil exposures, there were no differences in viral load or weight loss. This study shows that exposure to diverse microbial communities through soil exposure alters the gut and lung microbiomes resulting in differential expression of specific immune system related genes within the lung following an influenza challenge.

Explanatory integration and integrated explanations in Darwinian medicine and evolutionary medicine.

Recently, two research traditions that bring together evolutionary biology and medicine, that is to say, Darwinian medicine and evolutionary medicine, have been identified. In this paper, I analyse these two research traditions with respect to explanatory and interdisciplinary integration. My analysis shows that Darwinian medicine does not integrate medicine and evolutionary biology in any strong sense but does incorporate evolutionary concepts into medicine. I also show that backward-looking explanations in Darwinian medicine are not integrated proximate-and-ultimate explanations but functional explanations that include reference to evolutionary concepts. Nevertheless, explanations in Darwinian medicine have heuristic roles as they potentially contribute to conceptual change and tie pieces of knowledge from different fields of medical research together. I argue that Darwinian medicine is an "interfield" that fosters cross-disciplinary exchange between evolutionary biologists and medical researchers and practitioners based on division of labour and separation, rather than unity. Research in evolutionary medicine, on the other hand, happens at the intersection of evolutionary biology and medicine where the two disciplines are already integrated and is designed to produce entangled proximate-evolutionary explanations. My analysis thus adds another important aspect to the philosophical discussion on the distinction between Darwinian medicine and evolutionary medicine.

Helminth infection is associated with dampened cytokine responses to viral and bacterial stimulations in Tsimane forager-horticulturalists.

BACKGROUND: Soil-transmitted helminths (STHs) and humans share long co-evolutionary histories over which STHs have evolved strategies to permit their persistence by downregulating host immunity. Understanding the interactions between STHs and other pathogens can inform our understanding of human evolution and contemporary disease patterns. METHODOLOGY: We worked with Tsimane forager-horticulturalists in the Bolivian Amazon, where STHs are prevalent. We tested whether STHs and eosinophil levels-likely indicative of infection in this population-are associated with dampened immune responses to in vitro stimulation with H1N1 and lipopolysaccharide (LPS) antigens. Whole blood samples (n = 179) were treated with H1N1 vaccine and LPS and assayed for 13 cytokines (INF-γ, IL-1ß, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12p70, IL-13, GM-CSF and TNF-ɑ). We evaluated how STHs and eosinophil levels affected cytokine responses and T helper (Th) 1 and Th2-cytokine suite responses to stimulation. RESULTS: Infection with Ascaris lumbricoides was significantly (P ≤ 0.05) associated with lower response of some cytokines to H1N1 and LPS in women. Eosinophils were significantly negatively associated with some cytokine responses to H1N1 and LPS, with the strongest effects in women, and associated with a reduced Th1- and Th2-cytokine response to H1N1 and LPS in women and men. CONCLUSIONS AND IMPLICATIONS: Consistent with the 'old friends' and hygiene hypotheses, we find that STHs were associated with dampened cytokine responses to certain viral and bacterial antigens. This suggests that STH infections may play an essential role in immune response regulation and that the lack of STH immune priming in industrialized populations may increase the risk of over-reactive immunity. Lay Summary: Indicators of helminth infection were associated with dampened cytokine immune responses to in vitro stimulation with viral and bacterial antigens in Tsimane forager-horticulturalists in the Bolivian Amazon, consistent with the 'old friends' and hygiene hypotheses.

Old friends meet a new foe: A potential role for immune-priming parasites in mitigating COVID-19 morbidity and mortality.

The novel virus, Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), and the associated Coronavirus Disease 2019 (COVID-19) represent a pathogen to which human beings have limited to no evolved immune response. The most severe symptoms are associated with overactive inflammatory immune responses, leading to a cytokine storm, tissue damage, and death, if not balanced and controlled. Hypotheses within Evolutionary Medicine, including the Hygiene/Old Friends Hypothesis, provide an important lens through which to understand and possibly control this overactive immune response. In this article, we explore the role that infection with soil-transmitted helminths (STHs; i.e. intestinal parasitic worms) may play in dampening SARS-CoV-2 symptoms and mitigating the worst COVID-19 outcomes. Specifically, STHs stimulate the immunosuppressive and regulatory T-helper 2 (TH2) branch of the immune system, which decreases ACE2-receptor expression (i.e. receptors SARS-CoV-2 uses to infect host cells), balances the inflammatory TH1/TH17 branches of the immune system triggered by SARS-CoV-2 infection, and reduces inflammation through the release of anti-inflammatory/regulatory cytokines. Because STHs are common and affect the most vulnerable and marginalized members of society, it is especially important to consider how these parasites may impact COVID-19 outcomes. Areas experiencing endemic STH infections are often characterized by a lack of preventative infrastructure and medical care, which may further exacerbate risk of SARS-CoV-2 infection and COVID-19 development. For this reason, we also explore biocultural factors that contribute to disease outcomes for both SARS-CoV-2 and STH infections. Biocultural and Evolutionary Medicine perspectives on COVID-19 are crucial for understanding the global impact of the disease. Lay summary: An evolutionary perspective is required to understand the global impact and various presentations of COVID-19. We consider how coinfection with soil-transmitted helminths (common parasitic worms that coevolved with humans) may suppress inflammatory immune activity, thereby potentially reducing COVID-19 disease severity. Structural and lifestyle factors shaping coinfection patterns are also discussed.

Development and validation of an ELISA for a biomarker of thyroid dysfunction, thyroid peroxidase autoantibodies (TPO-Ab), in dried blood spots.

BACKGROUND: The prevalence of allergic and autoimmune conditions has been steadily increasing in wealthy nations over the past century. One hypothesis put forward to explain this is the Old Friends Hypothesis, which posits that increased hygiene, urbanization, and lifestyle changes have reduced our exposure to parasites and microbes that we co-evolved with, resulting in immune dysregulation. However, research in traditionally living populations, who are exposed to greater parasite and pathogen loads such as those encountered during our evolution, is limited, in part due to a lack of minimally invasive, field-friendly biomarkers of autoimmune disorders. We therefore developed an ELISA to assess positivity for thyroid peroxidase autoantibody (TPO-Ab), an indicator of autoimmune thyroid disease, based on dried blood spot (DBS) samples. RESULTS: We used the Accubind anti-thyroid peroxidase test system to screen our validation samples comprising matched fingerprick DBS, venous DBS, and plasma samples from 182 adults. After confirming that we had TPO-Ab-positive individuals in our validation sample (n = 12), we developed an indirect ELISA to measure TPO-Ab levels from one 3-mm DBS punch. The sensitivity and specificity of our assay for DBS samples ranged from 91.7-100% and 98.2-98.8%, respectively, using a cut-off value of ≥ 26 IU/mL. Intra-assay reliability for duplicate quality control DBS punches was 5.2%, while inter-assay reliability ranged from 11.5-24.4% for high, medium, and low DBS controls. Dilutional linearity ranged from 80 to 120%, and spike and recovery experiments indicated that the DBS matrix does not interfere with the detection of TPO-Ab. TPO-Ab levels remained stable in DBS samples stored at - 28 °C or - 80 °C, but decreased over time in DBS samples kept at 22 °C or at 37 °C. CONCLUSIONS: We developed an in-house, kit-independent indirect ELISA assay to determine individuals' TPO-Ab positivity based on dried blood spots, representing a cost-effective method with potential applications in a range of research settings.

Helminth Therapy - From the Parasite Perspective.

Studies in animal models and humans suggest that intentional exposure to helminths or helminth-derived products may hold promise for treating chronic inflammatory-associated diseases (CIADs). Although the mechanisms underlying 'helminth therapy' are being evaluated, little attention has been paid to the actual organisms in use. Here we examine the notion that, because of the complexity of biological symbiosis, intact helminths rather than helminth-derived products are likely to prove more useful for clinical purposes. Further, weighing potential cost/benefit ratios of various helminths along with other factors, such as feasibility of production, we argue that the four helminths currently in use for CIAD treatments in humans were selected more by happenstance than by design, and that other candidates not yet tested may prove superior.

Hygiene Hypothesis in Asthma Development: Is Hygiene to Blame?

Industrialized countries have registered epidemic rates on allergic diseases, such as hay fever, asthma, eczema, and food allergies. The Hygiene Hypothesis was born from work made by Dr. David Strachan, who observed that younger siblings were less susceptible to eczema and asthma, and proposed that this was a result of increased transmission of infectious agents via unhygienic practices within a household. This initial hypothesis was then reframed as the old friends/microbiota hypothesis, implicating non-pathogenic commensal microorganisms as the source of immunomodulatory signals necessary to prevent immune-mediated chronic disorders. Although the hygiene hypothesis is supported by epidemiological research of allergic diseases in certain industrialized settings, it often fails to explain the incidence of asthma in less affluent regions of the world. In this review, we summarize up-to-date information on genetic and environmental factors associated with asthma in different human populations, and present evidence that calls for caution when associating hygiene with the pathogenesis of asthma and other allergic conditions.

The Soil Bacterium Methylococcus capsulatus Bath Interacts with Human Dendritic Cells to Modulate Immune Function.

The prevalence of inflammatory bowel disease (IBD) has increased in Western countries during the course of the twentieth century, and is evolving to be a global disease. Recently we showed that a bacterial meal of a non-commensal, non-pathogenic methanotrophic soil bacterium, Methylococcus capsulatus Bath prevents experimentally induced colitis in a murine model of IBD. The mechanism behind the effect has this far not been identified. Here, for the first time we show that M. capsulatus, a soil bacterium adheres specifically to human dendritic cells, influencing DC maturation, cytokine production, and subsequent T cell activation, proliferation and differentiation. We characterize the immune modulatory properties of M. capsulatus and compare its immunological properties to those of another Gram-negative gammaproteobacterium, the commensal Escherichia coli K12, and the immune modulatory Gram-positive probiotic bacterium, Lactobacillus rhamnosus GG in vitro. M. capsulatus induces intermediate phenotypic and functional DC maturation. In a mixed lymphocyte reaction M. capsulatus-primed monocyte-derived dendritic cells (MoDCs) enhance T cell expression of CD25, the γ-chain of the high affinity IL-2 receptor, supports cell proliferation, and induce a T cell cytokine profile different from both E. coli K12 and Lactobacillus rhamnosus GG. M. capsulatus Bath thus interacts specifically with MoDC, affecting MoDC maturation, cytokine profile, and subsequent MoDC directed T cell polarization.

Cardiovascular disease and type 2 diabetes in evolutionary perspective: a critical role for helminths?

Heart disease and type 2 diabetes are commonly believed to be rare among contemporary subsistence-level human populations, and by extension prehistoric populations. Although some caveats remain, evidence shows these diseases to be unusual among well-studied hunter-gatherers and other subsistence populations with minimal access to healthcare. Here we expand on a relatively new proposal for why these and other populations may not show major signs of these diseases. Chronic infections, especially helminths, may offer protection against heart disease and diabetes through direct and indirect pathways. As part of a strategy to insure their own survival and reproduction, helminths exert multiple cardio-protective effects on their host through their effects on immune function and blood lipid metabolism. Helminths consume blood lipids and glucose, alter lipid metabolism, and modulate immune function towards Th-2 polarization - which combined can lower blood cholesterol, reduce obesity, increase insulin sensitivity, decrease atheroma progression, and reduce likelihood of atherosclerotic plaque rupture. Traditional cardiometabolic risk factors, coupled with the mismatch between our evolved immune systems and modern, hygienic environments may interact in complex ways. In this review, we survey existing studies in the non-human animal and human literature, highlight unresolved questions and suggest future directions to explore the role of helminths in the etiology of cardio-metabolic disease.