Getting to the guts of the matter: The status and potential of ‘omics’ research of parasitic protists of the human gastrointestinal system

Highlights

• Cryptospordium, Giardia and Entamoeba dominate ‘omics’ research of enteric protists.

• Blastocystis and Enterocytozoon genomes are complete.

• There is no information for Dientamoeba, Isospora, Balantidium and Cyclospora.

• There have been major recent advances in sequencing, analytical and functional methods in this field.

• There are numerous novel areas for potential research in this field in the coming years.

Abstract

Parasitic protists are a major cause of diarrhoeal illnesses in humans globally. Collectively, enteric pathogens exceed all other forms of infectious disease, in terms of their estimated global prevalence and socioeconomic impact. They have a disproportionately high impact on children in impoverished communities, leading to acute (diarrhoea, vomiting, dehydration and death) and chronic disease (malabsorption, malnutrition, physical and cognitive stunting and predisposition to chronic, non-communicable disease) consequences. However, historically, investment in research and disease control measures has been disproportionately poor, leading to their current classification as neglected pathogens. A sound understanding of their biology is essential in underpinning detection, treatment and control efforts. One major tool in rapidly improving our knowledge of these parasites is the use of biological systems, including ‘omic’ technologies. In recent years, these tools have shown significant success when applied to enteric protists. This review summarises much of this knowledge and highlights the significant remaining knowledge gaps. A major focus of the present review was to provide a perspective on a way forward to address these gaps using advanced biotechnologies.

Introduction

Globally, diarrhoeal pathogens (viruses, bacteria and parasites) are among the most significant causes of human morbidity and mortality, exceeding nearly all other forms of infectious disease. Each year such pathogens cause an estimated 1.7 billion cases of infectious diarrhoea in children in low to middle-income countries alone (Fischer Walker et al., 2012) and, after perinatal disorders, are the second leading cause of death in this group (∼25% of all under-5 years childhood mortality globally (Anon., 2004)). Recent estimates of the loss of disability adjusted life-years (DALYs) attributable to infectious diarrhoea exceed 300 million (Ricci et al., 2006). Although these figures place enteric pathogens amongst the commonest and most devastating causes of human morbidity and mortality worldwide (Anon., 2004), it is highly likely that they still represent a significant underestimate, as many enteric infections go unreported, undiagnosed and/or untreated in endemic regions of the world. Emerging evidence now suggests that early childhood diarrhoea has a previously unrecognised, but profound, impact on long-term physical and cognitive development (Kosek et al., 2003, Ricci et al., 2006). Particularly troubling is growing evidence that in impoverished populations recurrent diarrhoeal disease in the first 2 years of childhood contributes to an estimated (average) 10 cm growth and 10 IQ point shortfall by the time a child is 7–9 years of age (Guerrant et al., 2012). In part, this stunting is the result of pathophysiological changes in the gastrointestinal tract itself, with frequent/chronic diarrhoea leading often to permanent atrophy of the intestinal villi, and causing long-term changes to the gastrointestinal microfauna, leading to diminished nutrient/fluid absorption and pro-longed gastrointestinal dysfunction (Guerrant et al., 2012). Moreover, evidence now suggests that high burdens of disease due to gastrointestinal pathogens in early life can, paradoxically, predispose humans to increased risks of obesity and associated metabolic syndromes in adult life (Guerrant et al., 2012). The combination of (i) acute gastroenteric illness, (ii) indirect effects of chronic or recurrent disease and (iii) predisposition to chronic metabolic disease in later adult life, have been described as the “triple burden” of gastrointestinal pathogens (Guerrant et al., 2012). Taken together, their effects on human capital and the future health-care burden are likely to have profound consequences that go beyond health and impact significantly on potential for economic development in these countries.

To an overwhelmingly disproportionate extent, the long-term consequences of diarrhoeal diseases are linked to the frequency and chronicity of infections during childhood (being most significant in children experiencing ⩾3 episodes of enteritis per year, when each episode lasts ∼2–3 weeks (Guerrant et al., 2012)). In most instances, chronic cases are caused by parasitic protists, including Cryptosporodium parvum and Cryptosporidium hominis (see Jex et al., 2010), the Giardia intestinalis (syn. Giardia duodenalis and Giardia lamblia) complex (Cacciò and Ryan, 2008) and Entamoeba histolytica (see Haque et al., 2003). Indeed, G. intestinalis is considered among the commonest parasites of humans globally, irrespective of socioeconomic status, being estimated as the cause of >200 million cases of symptomatic illness and >1 billion total infections annually (Feng and Xiao, 2011). Increasingly, the contributions of other pathogenic, enteric protists to human disease are being recognised. These taxa include Enterocytozoon bieneusi (see Mathis et al., 2005), Cyclospora cayetanensis (see Helmy, 2010, Ortega and Sanchez, 2010), Blastocystis hominis (see Stensvold et al., 2009, Roberts et al., 2013) and Dientomoeba fragilis (see Stark et al., 2010). The pathogenicity of some of these (e.g., Cyclospora and Enterocytozoon), although relatively recently recognised, now appear to be well established (Mathis et al., 2005, Helmy, 2010, Ortega and Sanchez, 2010). In contrast, the pathogenic status of Blastocystis and Dientamoeba remain somewhat controversial (Stensvold et al., 2009, Stark et al., 2010, Roberts et al., 2013). However, intriguingly, these latter protists appear to favour a role in manipulating and modifying the healthy gastrointestinal microfauna, and therefore have potential for contributing to long-term health problems including autoimmune disorders such as irritable bowel disease (IBD) (Johnson et al., 2004, Stark et al., 2007). Many enteric pathogens are now considered to be seriously neglected and in urgent need of increased attention as agents of disease (Savioli et al., 2006). Although some drugs are available for some enteric protists (e.g., Giardia; seeBusatti et al., 2009), many of these pathogens (e.g., Cryptosporidium; see Jex et al., 2010) remain essentially untreatable, aside from standard supportive therapy (including rehydration and anti-inflammatory treatment).

The genomics age, heralded by the advent of next generation sequencing technologies (Mardis, 2008), has the potential to stimulate advances in our understanding of many critically important pathogens, providing insights into their epidemiology, evolution, and molecular and cellular biology. These technologies provide real prospects for making tangible impacts on global health through improved resources for developing molecular diagnostic tools and identifying novel targets for urgently needed new drugs. Indeed, an expert panel of clinicians and research scientists (Daar et al., 2002) has ranked improved tests for infectious diseases, genomics research and drug discovery as first, fourth and sixth, respectively, among a list of the top 10 biotechnologies based on their potential for improvement of public health in impoverished countries, with improved diagnostic tools for enteric pathogens alone estimated to deliver a benefit to the global health burden equivalent to 50% of that estimated for malaria (Ricci et al., 2006). Acknowledging the importance of this field, we review the current status of ‘omics’ research (with a primary focus on genomics) of parasitic protists of the human gastrointestinal tract, identify major knowledge gaps and provide a perspective on the future directions of biological research of these most important pathogens.