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The gut microbiome in the helminth infected host
TREPAR-1397; No. of Pages 2
Spotlight
The gut microbiome in the helminth infected host Francisca Mutapi Institute of Immunology and Infection Research, Centre for Immunology, Infection, and Evolution, School of Biological Sciences, University of Edinburgh, Ashworth Laboratories, King’s Buildings, Charlotte Auerbach Road, Edinburgh, EH9 3FL, UK
Two kinds of organism that affect human nutrition and health are gut bacteria and intestinal helminths. The interaction between helminths and gut bacteria is currently a subject of much research interest and speculation in terms of host health. This is unsurprising given the excitement stimulated by potential therapeutic interventions that could arise from manipulating the gut microbiome structure. Intestinal helminths affect over a quarter of the world’s population in developing countries with people often carrying multiple helminth infections and consequently suffering the co-morbidities that arise. The health impact of these infections is further compounded by malnutrition; the vast majority of the world’s hungry people live in developing countries, where 13.5% of the population is undernourished [1]. This presents a need and an opportunity for integrated interventions for co-morbidities arising from poor nutrition and helminth infection. However, before any such interventions can be entertained, it is necessary to understand the interaction between the host, gut microbiome, and parasitic helminths. These interactions are complex. The host takes up food of differing nutritional content whose metabolism and absorption is greatly influenced by the composition of the gut microbiome. Conversely, the gut microbiome structure differs significantly with diet as we reviewed in [2]. The carbohydrate diets predominating in Africa favour the Bacteroidetes which are able to degrade xylan and cellulose to utilise energy from plant-based diets. The fat and animal protein-rich diets predominating in Western countries favour the Firmicutes that are associated with the metabolism of protein and sugars (see review [2]). Intestinal and blood helminths interfere with the processing of food in the gut by causing internal bleeding which can lead to loss of iron and anaemia, malabsorption of nutrients; diarrhoea; and loss of appetite which can lead to a reduction in energy intake, significantly affecting childhood growth and development (http://www.who.int/elena/ titles/deworming/en/). There are also immunological interactions. Both helminths and gut microbes modulate the host immune system, reducing inflammatory responses directed against themselves and unrelated antigens [3,4]. However, infection with helminths, particularly schistosomes and lymphatic worms, can also cause significant immunopathology. The Corresponding author: Mutapi, F. ([email protected]). 1471-4922/ ß 2015 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.pt.2015.06.003
gut bacteria are increasingly being invoked in the development and regulation of the host’s immune system allowing for both direct and indirect effects of the gut microbiome on host-immune responses directed against helminths, whether they mediate the development of protective immunity or aetiology of the immunopathology. Given the complexity of this three-way relationship it is necessary to conduct some hypothesis driven studies not only characterising the gut microbiome structure but also establishing causation and underlying mechanism. This is particularly important for investigating nutritional intervention strategies to improve childhood health in helminth-endemic areas. Experimental studies have begun to address these questions. Recent work by Houlden and Wang [5] working on the intestinal helminth Trichuris muris demonstrated that infection of mice with this parasite significantly altered their gut microbiome, reducing the diversity and abundance of the Bacteroidetes, Prevotella and Parabacteroidetes. This dysbiosis was associated with a significant reduction in amounts of vitamin D derivatives as well as a reduction in the breakdown of dietary plant derived carbohydrates involved in amino acid synthesis and conversely, a significant increase in the number of amino acids. The readout on animal health status was a reduction in the weight of the infected animals that was attributed to changes in the digestive function. This is the first study relating differences in the gut microbiome structure to nutritional metabolism during helminth infection. It will be interesting to determine if such a metabolic readout of the helminth-related dysbiosis can be translated to the natural human and veterinary hosts. Recent studies in humans confirm the observation that there is a difference in the gut microbiome structure in helminth-infected individuals [6–8]. However, in contrast to the experimental studies, human studies in Zimbabweans exposed to Schistosoma haematobium [6] and in Malaysians exposed to Trichuris, Ascaris and hookworm showed significantly higher diversity and abundance of some taxonomic groups compared to uninfected people [7]. However, this observation is not consistent across human populations, as a study in Ecuadorians exposed to Trichuris trichuria showed no significant differences in the gut microbiome diversity in infected vs. uninfected people [8]. With only a handful of studies in different geographical areas and in populations exposed to different helminth species, it is too early to determine the sources of such heterogeneity and dissect out the factors explaining the greatest variation. Our understating of such factors and how they relate to experimental models can only improve as more studies are published. Nonetheless, an Trends in Parasitology xx (2015) 1–2
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TREPAR-1397; No. of Pages 2
Spotlight important question raised by the human studies is whether the gut microbiome structure predisposes the host to infection or if infection causes the gut microbiome dysbiosis. The study by Houlden and Wang [5] suggests the latter, while experimental infection of humans with Necator americanus results in no significant change in the microbiome [9], suggesting the former. Houlden and Wang’s study [5] also showed immunological changes upon T. muris infection, with proportions of regulatory T cells and Th1 cells in the lamina propria and intestinal epithelium significantly decreasing. The relative contributions of the helminth infection vs. gut microbiome in determining the immunological phenotype is unclear. Clearance of the helminth infection using antihelminthic drugs restored the gut microbiome structure but did not reverse the immunological changes. In our study [6], the gut microbiome in schistosome-infected children was refractory to antihelminthic treatment, as it was in Ecuadorian school children infected with Ascaris lumbricoides [8]. Factors responsible for such differences in experimental vs. natural human infection will become clearer with more research. To harness knowledge on the role and function of the gut microbiome for human interventions, it will be crucial for the scientific community to have a clear understanding of mechanisms/pathways involved in the
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Trends in Parasitology xxx xxxx, Vol. xxx, No. x
three way interaction between the host, helminths and gut microbiome in the target species, humans. Exciting times lie ahead for scientific research and prospects for improved human health in affected populations. References 1 FAO, IFAD and WFP (2015) The State of Food Insecurity in the World 2015. Meeting the 2015 International Hunger Targets: Taking Stock of Uneven Progress, FAO 2 Glendinning, L. et al. (2014) The microbiota and helminths: sharing the same niche in the human host. Parasitology 141, 1255–1271 3 Hooper, L.V. et al. (2012) Interactions between the microbiota and the immune system. Science 336, 1268–1273 4 Mcsorley, H.J. and Maizels, R.M. (2012) Helminth infections and host immune regulation. Clin. Microbiol. Rev. 25, 585–608 5 Houlden, A. and Wang, P. (2015) Chronic Trichuris muris infection in C57BL/6 mice causes significant changes in host microbiota and metabolome: effects reversed by pathogen clearance. PLoS ONE 10, e0125945 6 Kay, G.L. et al. (2015) Differences in the faecal microbiome in Schistosoma haematobium infected children vs. uninfected children. PLoS Negl. Trop. Dis. 9, e0003861 7 Lee, S.C. and Loke, P. (2014) Helminth colonization is associated with increased diversity of the gut microbiota. PLoS Negl. Trop. Dis. 8, e2880 8 Cooper, P. and Vaca, M. (2013) Patent human infections with the whipworm, Trichuris trichiura, are not associated with alterations in the faecal microbiota. PLoS ONE 8, e76573 9 Cantacessi, C. et al. (2014) Impact of experimental hookworm infection on the human gut microbiota. J. Infect. Dis. 210, 1431–1434
Spotlight
The gut microbiome in the helminth infected host Francisca Mutapi Institute of Immunology and Infection Research, Centre for Immunology, Infection, and Evolution, School of Biological Sciences, University of Edinburgh, Ashworth Laboratories, King’s Buildings, Charlotte Auerbach Road, Edinburgh, EH9 3FL, UK
Two kinds of organism that affect human nutrition and health are gut bacteria and intestinal helminths. The interaction between helminths and gut bacteria is currently a subject of much research interest and speculation in terms of host health. This is unsurprising given the excitement stimulated by potential therapeutic interventions that could arise from manipulating the gut microbiome structure. Intestinal helminths affect over a quarter of the world’s population in developing countries with people often carrying multiple helminth infections and consequently suffering the co-morbidities that arise. The health impact of these infections is further compounded by malnutrition; the vast majority of the world’s hungry people live in developing countries, where 13.5% of the population is undernourished [1]. This presents a need and an opportunity for integrated interventions for co-morbidities arising from poor nutrition and helminth infection. However, before any such interventions can be entertained, it is necessary to understand the interaction between the host, gut microbiome, and parasitic helminths. These interactions are complex. The host takes up food of differing nutritional content whose metabolism and absorption is greatly influenced by the composition of the gut microbiome. Conversely, the gut microbiome structure differs significantly with diet as we reviewed in [2]. The carbohydrate diets predominating in Africa favour the Bacteroidetes which are able to degrade xylan and cellulose to utilise energy from plant-based diets. The fat and animal protein-rich diets predominating in Western countries favour the Firmicutes that are associated with the metabolism of protein and sugars (see review [2]). Intestinal and blood helminths interfere with the processing of food in the gut by causing internal bleeding which can lead to loss of iron and anaemia, malabsorption of nutrients; diarrhoea; and loss of appetite which can lead to a reduction in energy intake, significantly affecting childhood growth and development (http://www.who.int/elena/ titles/deworming/en/). There are also immunological interactions. Both helminths and gut microbes modulate the host immune system, reducing inflammatory responses directed against themselves and unrelated antigens [3,4]. However, infection with helminths, particularly schistosomes and lymphatic worms, can also cause significant immunopathology. The Corresponding author: Mutapi, F. ([email protected]). 1471-4922/ ß 2015 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.pt.2015.06.003
gut bacteria are increasingly being invoked in the development and regulation of the host’s immune system allowing for both direct and indirect effects of the gut microbiome on host-immune responses directed against helminths, whether they mediate the development of protective immunity or aetiology of the immunopathology. Given the complexity of this three-way relationship it is necessary to conduct some hypothesis driven studies not only characterising the gut microbiome structure but also establishing causation and underlying mechanism. This is particularly important for investigating nutritional intervention strategies to improve childhood health in helminth-endemic areas. Experimental studies have begun to address these questions. Recent work by Houlden and Wang [5] working on the intestinal helminth Trichuris muris demonstrated that infection of mice with this parasite significantly altered their gut microbiome, reducing the diversity and abundance of the Bacteroidetes, Prevotella and Parabacteroidetes. This dysbiosis was associated with a significant reduction in amounts of vitamin D derivatives as well as a reduction in the breakdown of dietary plant derived carbohydrates involved in amino acid synthesis and conversely, a significant increase in the number of amino acids. The readout on animal health status was a reduction in the weight of the infected animals that was attributed to changes in the digestive function. This is the first study relating differences in the gut microbiome structure to nutritional metabolism during helminth infection. It will be interesting to determine if such a metabolic readout of the helminth-related dysbiosis can be translated to the natural human and veterinary hosts. Recent studies in humans confirm the observation that there is a difference in the gut microbiome structure in helminth-infected individuals [6–8]. However, in contrast to the experimental studies, human studies in Zimbabweans exposed to Schistosoma haematobium [6] and in Malaysians exposed to Trichuris, Ascaris and hookworm showed significantly higher diversity and abundance of some taxonomic groups compared to uninfected people [7]. However, this observation is not consistent across human populations, as a study in Ecuadorians exposed to Trichuris trichuria showed no significant differences in the gut microbiome diversity in infected vs. uninfected people [8]. With only a handful of studies in different geographical areas and in populations exposed to different helminth species, it is too early to determine the sources of such heterogeneity and dissect out the factors explaining the greatest variation. Our understating of such factors and how they relate to experimental models can only improve as more studies are published. Nonetheless, an Trends in Parasitology xx (2015) 1–2
1
TREPAR-1397; No. of Pages 2
Spotlight important question raised by the human studies is whether the gut microbiome structure predisposes the host to infection or if infection causes the gut microbiome dysbiosis. The study by Houlden and Wang [5] suggests the latter, while experimental infection of humans with Necator americanus results in no significant change in the microbiome [9], suggesting the former. Houlden and Wang’s study [5] also showed immunological changes upon T. muris infection, with proportions of regulatory T cells and Th1 cells in the lamina propria and intestinal epithelium significantly decreasing. The relative contributions of the helminth infection vs. gut microbiome in determining the immunological phenotype is unclear. Clearance of the helminth infection using antihelminthic drugs restored the gut microbiome structure but did not reverse the immunological changes. In our study [6], the gut microbiome in schistosome-infected children was refractory to antihelminthic treatment, as it was in Ecuadorian school children infected with Ascaris lumbricoides [8]. Factors responsible for such differences in experimental vs. natural human infection will become clearer with more research. To harness knowledge on the role and function of the gut microbiome for human interventions, it will be crucial for the scientific community to have a clear understanding of mechanisms/pathways involved in the
2
Trends in Parasitology xxx xxxx, Vol. xxx, No. x
three way interaction between the host, helminths and gut microbiome in the target species, humans. Exciting times lie ahead for scientific research and prospects for improved human health in affected populations. References 1 FAO, IFAD and WFP (2015) The State of Food Insecurity in the World 2015. Meeting the 2015 International Hunger Targets: Taking Stock of Uneven Progress, FAO 2 Glendinning, L. et al. (2014) The microbiota and helminths: sharing the same niche in the human host. Parasitology 141, 1255–1271 3 Hooper, L.V. et al. (2012) Interactions between the microbiota and the immune system. Science 336, 1268–1273 4 Mcsorley, H.J. and Maizels, R.M. (2012) Helminth infections and host immune regulation. Clin. Microbiol. Rev. 25, 585–608 5 Houlden, A. and Wang, P. (2015) Chronic Trichuris muris infection in C57BL/6 mice causes significant changes in host microbiota and metabolome: effects reversed by pathogen clearance. PLoS ONE 10, e0125945 6 Kay, G.L. et al. (2015) Differences in the faecal microbiome in Schistosoma haematobium infected children vs. uninfected children. PLoS Negl. Trop. Dis. 9, e0003861 7 Lee, S.C. and Loke, P. (2014) Helminth colonization is associated with increased diversity of the gut microbiota. PLoS Negl. Trop. Dis. 8, e2880 8 Cooper, P. and Vaca, M. (2013) Patent human infections with the whipworm, Trichuris trichiura, are not associated with alterations in the faecal microbiota. PLoS ONE 8, e76573 9 Cantacessi, C. et al. (2014) Impact of experimental hookworm infection on the human gut microbiota. J. Infect. Dis. 210, 1431–1434