Diet in the driving seat: natural diet-immunity-microbiome interactions in wild fish

Natural interactions between the diet, microbiome and immunity are largely unstudied. Here we employ wild three-spined sticklebacks as a model, combining field observations with complementary experimental manipulations of diet designed to mimic seasonal variation in the wild. We clearly demonstrate that season-specific diets are a powerful causal driver of major systemic immunophenotypic variation. This effect occurred largely independently of the bulk composition of the bacterial microbiome (which was also driven by season and diet) and of host condition, demonstrating neither of these, per se, constrain immune allocation in healthy individuals. Nonetheless, through observations in multiple anatomical compartments, differentially exposed to the direct effects of food and immunity, we found evidence of immune-driven control of bacterial community composition in mucus layers. This points to the interactive nature of the host-microbiome relationship, and is the first time, to our knowledge, that this causal chain (diet → immunity → microbiome) has been demonstrated in wild vertebrates. Microbiome effects on immunity were not excluded and, importantly, we identified outgrowth of potentially pathogenic bacteria (especially mycolic-acid producing corynebacteria) as a consequence of the more animal-protein-rich summertime diet. This may provide part of the ultimate explanation (and possibly a proximal cue) for the dramatic immune re-adjustments that we saw in response to diet change

Human resident liver myeloid cells protect against metabolic stress in obesity

Although multiple populations of macrophages have been described in the human liver, their function and turnover in patients with obesity at high risk of developing non-alcoholic fatty liver disease (NAFLD) and cirrhosis are currently unknown. Herein, we identify a specific human population of resident liver myeloid cells that protects against the metabolic impairment associated with obesity. By studying the turnover of liver myeloid cells in individuals undergoing liver transplantation, we find that liver myeloid cell turnover differs between humans and mice. Using single-cell techniques and flow cytometry, we determine that the proportion of the protective resident liver myeloid cells, denoted liver myeloid cells 2 (LM2), decreases during obesity. Functional validation approaches using human 2D and 3D cultures reveal that the presence of LM2 ameliorates the oxidative stress associated with obese conditions. Our study indicates that resident myeloid cells could be a therapeutic target to decrease the oxidative stress associated with NAFLD

Discovery of several thousand highly diverse circular DNA viruses.

Although millions of distinct virus species likely exist, only approximately 9000 are catalogued in GenBank's RefSeq database. We selectively enriched for the genomes of circular DNA viruses in over 70 animal samples, ranging from nematodes to human tissue specimens. A bioinformatics pipeline, Cenote-Taker, was developed to automatically annotate over 2500 complete genomes in a GenBank-compliant format. The new genomes belong to dozens of established and emerging viral families. Some appear to be the result of previously undescribed recombination events between ssDNA and ssRNA viruses. In addition, hundreds of circular DNA elements that do not encode any discernable similarities to previously characterized sequences were identified. To characterize these 'dark matter' sequences, we used an artificial neural network to identify candidate viral capsid proteins, several of which formed virus-like particles when expressed in culture. These data further the understanding of viral sequence diversity and allow for high throughput documentation of the virosphere

How can the MHC mediate social odor via the microbiota community? A deep dive into mechanisms

Genes of the major histocompatibility complex (MHC) have long been linked to odor signaling and recently researchers’ attention has focused on MHC structuring of microbial communities and how this may in turn impact odor. However, understanding of the mechanisms through which the MHC could affect the microbiota to produce a chemical signal that is both reliable and strong enough to ensure unambiguous transmission of behaviorally important information remains poor. This is largely because empirical studies are rare, predictions are unclear, and the underlying immunological mechanisms governing MHC-microbiota interactions are often neglected. Here we review the immunological processes involving MHC class II (MHC-II) that could affect the commensal community. Focusing on immunological and medical research, we provide background knowledge for non-immunologists by describing key players within the vertebrate immune system relating to MHC-II molecules (which present extracellular-derived peptides, and thus interact with extracellular commensal microbes). We then systematically review the literature investigating MHC-odor-microbiota interactions in animals and identify areas for future research. These insights will help to design studies that are able to explore the role of MHC-II and the microbiota in the behavior of wild populations in their natural environment and consequently propel this research area forward

Melanoma Models for the Next Generation of Therapies

There is a lack of appropriate melanoma models that can be used to evaluate the efficacy of novel therapeutic modalities. Here, we discuss the current state of the art of melanoma models including genetically engineered mouse, patient-derived xenograft, zebrafish, and ex vivo and in vitro models. We also identify five major challenges that can be addressed using such models, including metastasis and tumor dormancy, drug resistance, the melanoma immune response, and the impact of aging and environmental exposures on melanoma progression and drug resistance. Additionally, we discuss the opportunity for building models for rare subtypes of melanomas, which represent an unmet critical need. Finally, we identify key recommendations for melanoma models that may improve accuracy of preclinical testing and predict efficacy in clinical trials, to help usher in the next generation of melanoma therapies

Interpopulation Variation in the Atlantic Salmon Microbiome Reflects Environmental and Genetic Diversity

The microbiome has a crucial influence on host phenotype, and is of broad interest to ecological and evolutionary research. Yet, the extent of variation that occurs in the microbiome within and between populations is unclear. We characterised the skin and gut microbiome of seven populations of juvenile Atlantic salmon (Salmo salar) inhabiting a diverse range of environments, including hatchery-reared and wild populations. We found shared skin OTUs across all populations and core gut microbiota for all wild fish, but the diversity and structure of both skin and gut microbial communities were distinct between populations. There was a marked difference between the gut microbiome of wild and captive fish. Hatchery-reared fish had lower intestinal microbial diversity, lacked core microbiota found in wild fish, and showed altered community structure and function. Captive fish skin and gut microbiomes were also less variable within populations, reflecting more uniform artificial rearing conditions. Surrounding water influenced the microbiome of the gut and, especially, the skin, but could not explain the degree of variation observed between populations. For both the gut and skin, we found that there was greater difference in microbial community structure between more genetically distinct fish populations, and also that population genetic diversity was positively correlated with microbiome diversity. However, diet is likely to be the major factor contributing to the large differences in gut microbiota between wild and captive fish. Our results highlight the scope of inter-population variation in the Atlantic salmon microbiome, and offer insights into the deterministic factors contributing to this

Perinatal development of innate immune topology

At the transition from intrauterine to postnatal life, drastic alterations are mirrored by changes in cellular immunity. These changes are in part immune cell intrinsic, originate in the replacement of fetal cells, or result from global regulatory mechanisms and adaptation to changes in the tissue microenvironment. Overall, longer developmental trajectories are intersected by events related to mother-infant separation, birth cues, acquisition of microbiota and metabolic factors. Perinatal alterations particularly affect immune niches, where structures with discrete functions meet, the intestinal mucosa, epidermis and lung. Accordingly, the following questions will be addressed in this review: How does the preprogrammed development supported by endogenous cues, steer innate immune cell differentiation, adaptation to tissue structures, and immunity to infection? How does the transition at birth impact on tissue immune make-up including its topology? How do postnatal cues guide innate immune cell differentiation and function at immunological niches

The gut microbiome in hypertension: recent advances and future perspectives

The pathogenesis of hypertension is known to involve a diverse range of contributing factors including genetic, environmental, hormonal, hemodynamic and inflammatory forces, to name a few. There is mounting evidence to suggest that the gut microbiome plays an important role in the development and pathogenesis of hypertension. The gastrointestinal tract, which houses the largest compartment of immune cells in the body, represents the intersection of the environment and the host. Accordingly, lifestyle factors shape and are modulated by the microbiome, modifying the risk for hypertensive disease. One well-studied example is the consumption of dietary fibers, which leads to the production of short-chain fatty acids and can contribute to the expansion of anti-inflammatory immune cells, consequently protecting against the progression of hypertension. Dietary interventions such as fasting have also been shown to impact hypertension via the microbiome. Studying the microbiome in hypertensive disease presents a variety of unique challenges to the use of traditional model systems. Integrating microbiome considerations into preclinical research is crucial, and novel strategies to account for reciprocal host-microbiome interactions, such as the wildling mouse model, may provide new opportunities for translation. The intricacies of the role of the microbiome in hypertensive disease is a matter of ongoing research, and there are several technical considerations which should be accounted for moving forward. In this review we provide insights into the host-microbiome interaction and summarize the evidence of its importance in the regulation of blood pressure. Additionally, we provide recommendations for ongoing and future research, such that important insights from the microbiome field at large can be readily integrated in the context of hypertension