The human gut microbiome and health inequities.

Individuals who are minoritized as a result of race, sexual identity, gender, or socioeconomic status experience a higher prevalence of many diseases. Understanding the biological processes that cause and maintain these socially driven health inequities is essential for addressing them. The gut microbiome is strongly shaped by host environments and affects host metabolic, immune, and neuroendocrine functions, making it an important pathway by which differences in experiences caused by social, political, and economic forces could contribute to health inequities. Nevertheless, few studies have directly integrated the gut microbiome into investigations of health inequities. Here, we argue that accounting for host-gut microbe interactions will improve understanding and management of health inequities, and that health policy must begin to consider the microbiome as an important pathway linking environments to population health.

Identifying key questions in the ecology and evolution of cancer.

The application of evolutionary and ecological principles to cancer prevention and treatment, as well as recognizing cancer as a selection force in nature, has gained impetus over the last 50 years. Following the initial theoretical approaches that combined knowledge from interdisciplinary fields, it became clear that using the eco-evolutionary framework is of key importance to understand cancer. We are now at a pivotal point where accumulating evidence starts to steer the future directions of the discipline and allows us to underpin the key challenges that remain to be addressed. Here, we aim to assess current advancements in the field and to suggest future directions for research. First, we summarize cancer research areas that, so far, have assimilated ecological and evolutionary principles into their approaches and illustrate their key importance. Then, we assembled 33 experts and identified 84 key questions, organized around nine major themes, to pave the foundations for research to come. We highlight the urgent need for broadening the portfolio of research directions to stimulate novel approaches at the interface of oncology and ecological and evolutionary sciences. We conclude that progressive and efficient cross-disciplinary collaborations that draw on the expertise of the fields of ecology, evolution and cancer are essential in order to efficiently address current and future questions about cancer.

The scope of viral causation of human cancers: interpreting virus density from an evolutionary perspective.

Most known oncogenic viruses of humans use DNA as their genomic material. Research over the past quarter century has revealed that their oncogenicity results largely from direct interference with barriers to oncogenesis. In contrast to viruses that have been accepted causes of particular cancers, candidate viral causes tend to have fewer viral than cellular genomes in the tumours. These low viral loads have caused researchers to conclude that the associated viruses are not primary causes of the associated cancers. Consideration of differential survival, reproduction and infiltration of cells in a tumour suggest, however, that viral loads could be low even when viruses are primary causes of cancer. Resolution of this issue has important implications for human health because medical research tends to be effective at preventing and controlling infectious diseases. Mathematical models may clarify the problem and help guide future research by assessing whether low viral loads are likely outcomes of the differential survival, reproduction, and infiltration of cells in a tumour and, more generally, the extent to which viruses contribute to cancer. This article is part of the theme issue 'Silent cancer agents: multi-disciplinary modelling of human DNA oncoviruses'.

Inflammation, infection and depression: an evolutionary perspective.

The evolutionary basis for clinical depression is not well understood. A growing body of literature that is not based on evolutionary logic links inflammation to depression. Integration of these findings with an evolutionary framework for depression, however, needs to address the reasons why the body's inflammatory response would be regulated so poorly that it would result in incapacitating depression. Pathogen induction of inflammation offers an explanation, but the extent to which the association between inflammation and depression can be attributed to general inflammation as opposed to particular effects of pro-inflammatory pathogens remains unclear. This paper reports a study of sexually transmitted pathogens, which addresses this issue. Although several sexually transmitted pathogens were associated with depression according to bivariate tests, only Chlamydia trachomatis and Trichomonas vaginalis were significantly associated with depression by a multivariate analysis that accounted for correlations among the pathogens. This finding is consistent with the hypothesis that infection may contribute to depression through induction of tryptophan restriction, and a consequent depletion of serotonin. It reinforces the idea that some depression may be caused by specific pathogens in specific evolutionary arms races with their human host.

Natural Selection, The Microbiome, and Public Health.

The microbiome is composed of hundreds of interacting species that have co-evolved with the host and alterations in microbiome composition have been associated with health and disease. Insights from evolutionary ecology may aid efforts to ameliorate microbiome-associated diseases. One step toward this goal involves recognition that the idea of commensalism has been applied too broadly to human/microbe symbioses. Commensalism is most accurately viewed on a symbiosis continuum as a dividing line that separates a spectrum of mutualisms of decreasing positive interdependence from parasitisms of increasing severity. Insights into the evolution of the gut microbial symbiosis continuum will help distinguish between human actions that will advance or hinder health. Theory and research indicate that a major benefit of mutualistic microbes will be protection against pathogens. Mismatches between current and ancestral diets may disfavor mutualists, resulting in microbiome effects on health problems, including obesity, diabetes, autism, and childhood allergy. Evolutionary theory indicates that mutualisms will be favored when symbionts depend on resources that are not used by the host. These resources, which are referred to as human-inaccessible microbiota-accessible carbohydrates (HIMACs), can be supplied naturally through diet. Public health interventions need to consider the position of gut microbes on the mutualist-parasite continuum and the specific associations between prebiotics, such as HIMACs, and the mutualists they support. Otherwise interventions may fail to restore the match between human adaptations, diet, and microbiome function and may thereby fail to improve health and even inadvertently promote illness.

Infection and cancer in multicellular organisms.

Evolutionary considerations suggest that oncogenic infections should be pervasive among animal species. Infection-associated cancers are well documented in humans and domestic animals, less commonly reported in undomesticated captive animals, and rarely documented in nature. In this paper, we review the literature associating infectious agents with cancer to evaluate the reasons for this pattern. Non-malignant infectious neoplasms occur pervasively in multicellular life, but oncogenic progression to malignancy is often uncertain. Evidence from humans and domestic animals shows that non-malignant infectious neoplasms can develop into cancer, although generally with low frequency. Malignant neoplasms could be difficult to find in nature because of a low frequency of oncogenic transformation, short survival after malignancy and reduced survival prior to malignancy. Moreover, the evaluation of malignancy can be ambiguous in nature, because criteria for malignancy may be difficult to apply consistently across species. The information available in the literature therefore does not allow for a definitive assessment of the pervasiveness of infectious cancers in nature, but the presence of infectious neoplasias and knowledge about the progression of benign neoplasias to cancer is consistent with a widespread but largely undetected occurrence.

Joint infectious causation of human cancers.

Joint infectious causation of cancer has been accepted in a few well-studied instances, including Burkitt's lymphoma and liver cancer. In general, evidence for the involvement of parasitic agents in oncogenesis has expanded, and recent advances in the application of molecular techniques have revealed specific mechanisms by which host cells are transformed. Many parasites evolve to circumvent immune-mediated detection and destruction and to control critical aspects of host cell reproduction and survival: cell proliferation, apoptosis, adhesion, and immortalization. The host has evolved tight regulation of these cellular processes-the control of each represents a barrier to cancer. These barriers need to be compromised for oncogenesis to occur. The abrogation of a barrier is therefore referred to as an essential cause of cancer. Alternatively, some aspects of cellular regulation restrain but do not block oncogenesis. Relaxation of a restraint is therefore referred to as an exacerbating cause of cancer. In this chapter, we explore past and current evidence for joint infectious causation of cancer in the context of essential and exacerbating causes. We stress that discovery of joint infectious causation may provide great improvements in controlling cancer, particularly through the identification of many additional nonhuman targets for synergistic interventions for prevention and treatment.

An evolutionary perspective on the causes and treatment of inflammatory bowel disease.

PURPOSE OF REVIEW: To use insights from evolutionary biology to assess the current evidence for the causes, treatment, and prevention of inflammatory bowel disease (IBD). RECENT FINDINGS: When analyzed in the context of evolutionary adaptation, recent assessments of genetic, microbial, and environmental associations with IBD implicate infectious causation. SUMMARY: An evolutionary perspective provides insight into the causes of IBD, interpretation of its manifestations, and assessment of interventions. The evidence implicating infectious causation suggests that future studies of IBD would benefit from increased focus on infectious causes and interventions that prevent or inhibit them.

Toward a general evolutionary theory of oncogenesis.

We propose an evolutionary framework, the barrier theory of cancer, which is based on the distinction between barriers to oncogenesis and restraints. Barriers are defined as mechanisms that prevent oncogenesis. Restraints, which are more numerous, inhibit but do not prevent oncogenesis. Processes that compromise barriers are essential causes of cancer; those that interfere with restraints are exacerbating causes. The barrier theory is built upon the three evolutionary processes involved in oncogenesis: natural selection acting on multicellular organisms to mold barriers and restraints, natural selection acting on infectious organisms to abrogate these protective mechanisms, and oncogenic selection which is responsible for the evolution of normal cells into cancerous cells. The barrier theory is presented as a first step toward the development of a general evolutionary theory of cancer. Its attributes and implications for intervention are compared with those of other major conceptual frameworks for understanding cancer: the clonal diversification model, the stem cell theory and the hallmarks of cancer. The barrier theory emphasizes the practical value of distinguishing between essential and exacerbating causes. It also stresses the importance of determining the scope of infectious causation of cancer, because individual pathogens can be responsible for multiple essential causes in infected cells.

Infection, mutation, and cancer evolution.

An understanding of oncogenesis can be fostered by an integration of mechanistic studies with evolutionary considerations, which help explain why these mechanisms occur. This integration emphasizes infections and mutations as joint essential causes for many cancers. It suggests that infections may play a broader causal role in oncogenesis than has been generally appreciated. An evolutionary perspective also suggests that oncogenic viruses will tend to be transmitted by routes that provide infrequent opportunities for transmission, such as transmission by sexual and salivary contact. Such routes increase the intensity of natural selection for persistence within hosts, and molecular mechanisms for persistence often compromise critical barriers to oncogenesis, particularly cell cycle arrest, apoptosis, and a cap on the total number of divisions that a cell can undergo.