The Effect of Gut Microbiome Composition on Human Immune Responses: An Exploration of Interference by Helminth Infections

Background: Soil-transmitted helminths have been shown to have the immune regulatory capacity, which they use to enhance their long term survival within their host. As these parasites reside in the gastrointestinal tract, they might modulate the immune system through altering the gut bacterial composition. Although the relationships between helminth infections or the microbiome with the immune system have been studied separately, their combined interactions are largely unknown. In this study we aim to analyze the relationship between bacterial communities with cytokine response in the presence or absence of helminth infections. Results: For 66 subjects from a randomized placebo-controlled trial, stool and blood samples were available at both baseline and 21 months after starting three-monthly albendazole treatment. The stool samples were used to identify the helminth infection status and fecal microbiota composition, while whole blood samples were cultured to obtain cytokine responses to innate and adaptive stimuli. When subjects were free of helminth infection (helminth-negative), increasing proportions of Bacteroidetes was associated with lower levels of IL-10 response to LPS {estimate [95% confidence interval (CI)] −1.96 (−3.05, −0.87)}. This association was significantly diminished when subjects were helminth-infected (helminth positive) (p-value for the difference between helminth-negative versus helminth-positive was 0.002). Higher diversity was associated with greater IFN-γ responses to PHA in helminth-negative (0.95 (0.15, 1.75); versus helminth-positive [−0.07 (−0.88, 0.73), p-value = 0.056] subjects. Albendazole treatment showed no direct effect in the association between bacterial proportion and cytokine responses, although the Bacteroidetes’ effect on IL-10 responses to LPS tended downward in the albendazole-treated group [−1.74 (−4.08, 0.59)] versus placebo [−0.11 (−0.84, 0.62); p-value = 0.193]. Conclusion: We observed differences in the relationship between gut microbiome composition and immune responses, when comparing individuals infected or uninfected with geohelminths. Although these findings are part of a preliminary exploration, the data support the hypothesis that intestinal helminths may modulate immune responses, in unison with the gut microbiota. Trial Registration: ISRCTN, ISRCTN83830814. Registered 27 February 2008 — Retrospectively registered, http://www.isrctn.com/ISRCTN83830814

Epidemiology of Plasmodium infections in Flores Island, Indonesia using real-time PCR

BACKGROUND:\ud DNA-based diagnostic methods have been shown to be highly sensitive and specific for the detection of malaria. An 18S-rRNA-based, real-time polymerase chain reaction (PCR) was used to determine the prevalence and intensity of Plasmodium infections on Flores Island, Indonesia.\ud METHODS:\ud Microscopy and real-time multiplex PCR for the detection of Plasmodium species was performed on blood samples collected in a population-based study in Nangapanda Flores Island, Indonesia.\ud RESULTS:\ud A total 1,509 blood samples were analysed. Real-time PCR revealed prevalence for Plasmodium falciparum, Plasmodium vivax, and Plasmodium malariae to be 14.5%, 13.2%, and 1.9% respectively. Sub-microscopic parasitaemia were found in more than 80% of all positive cases. The prevalence of P. falciparum and P. vivax was significantly higher in subjects younger than 20 years (p <= 0.01). In the present study, among non-symptomatic healthy individuals, anaemia was strongly correlated with the prevalence and load of P. falciparum infections (p <= 0.01; p = 0.02) and with the load of P. vivax infections (p = 0.01) as detected with real-time PCR. Subjects with AB blood group tend to have a higher risk of being infected with P. falciparum and P. vivax when compared to other blood groups.\ud CONCLUSION:\ud The present study has shown that real-time PCR provides more insight in the epidemiology of Plasmodium infections and can be used as a monitoring tool in the battle against malaria. The unsurpassed sensitivity of real-time PCR reveals that sub microscopic infections are common in this area, which are likely to play an important role in transmission and control.Trial registration: Trials number ISRCTN83830814

A longitudinal study of allergy and intestinal helminth infections in semi urban and rural areas of Flores, Indonesia (ImmunoSPIN Study)

BACKGROUND: The prevalence of asthma and atopic disease has been reported to be low in low income countries, however helminth infections are likely to be high among these communities. The question of whether helminth infections play a role in allergic diseases can best be addressed by intervention studies. None of the studies so far have been based on a large scale placebo-controlled trial. METHOD/DESIGN: This study was designed to assess how intestinal helminth infections can influence the immune response and atopic and allergic disorders in children in Indonesia. The relations between allergic outcomes and infection and lifestyle factors will be addressed. This study was set up among school-age children in semi urban and rural areas, located in Ende District of Flores Island, Indonesia. A randomized placebo-controlled anthelmintic treatment trial to elucidate the impact of helminth infections on the prevalence of skin prick test (SPT) reactivity and symptoms of allergic diseases will be performed. The children living in these semi-urban and rural areas will be assessed for SPT to allergens before and after 1 and 2 years of treatment as the primary outcome of the study; the secondary outcome is symptoms (asthma and atopic dermatitis); while the tertiary outcome is immune responses (both antibody levels to allergens and cellular immune responses). DISCUSSION: The study will provide information on the influence of helminth infections and anthelmintic treatment on immune response, atopy and allergic disorders. TRIAL REGISTRATION: Current Controlled Trials ISRCTN: ISRCTN8383081

Community deworming alleviates geohelminth-induced immune hyporesponsiveness

In cross-sectional studies, chronic helminth infections have been associated with immunological hyporesponsiveness that can affect responses to unrelated antigens. To study the immunological effects of deworming, we conducted a cluster-randomized, double-blind, placebo-controlled trial in Indonesia and assigned 954 households to receive albendazole or placebo once every 3 mo for 2 y. Helminth-specific and nonspecific whole-blood cytokine responses were assessed in 1,059 subjects of all ages, whereas phenotyping of regulatory molecules was undertaken in 121 school-aged children. All measurements were performed before and at 9 and 21 mo after initiation of treatment. Anthelmintic treatment resulted in significant increases in proinflammatory cytokine responses to Plasmodium falciparum-infected red blood cells (PfRBCs) and mitogen, with the largest effect on TNF responses to PfRBCs at 9 mo—estimate [95% confidence interval], 0.37 [0.21–0.53], P value over time (Ptime) < 0.0001. Although the frequency of regulatory T cells did not change after treatment, there was a significant decline in the expression of the inhibitory molecule cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) on CD4+ T cells of albendazole-treated individuals, –0.060 [–0.107 to –0.013] and –0.057 [–0.105 to –0.008] at 9 and 21 mo, respectively; Ptime = 0.017. This trial shows the capacity of helminths to up-regulate inhibitory molecules and to suppress proinflammatory immune responses in humans. This could help to explain the inferior immunological responses to vaccines and lower prevalence of inflammatory diseases in low- compared with high-income countries

Dynamic changes in human-gut microbiome in relation to a placebo-controlled anthelminthic trial in Indonesia

Background: Microbiome studies suggest the presence of an interaction between the human gut microbiome and soil-transmitted helminth. Upon deworming, a complex interaction between the anthelminthic drug, helminths and microbiome composition might occur. To dissect this, we analyse the changes that take place in the gut bacteria profiles in samples from a double blind placebo controlled trial conducted in an area endemic for soil transmitted helminths in Indonesia. Methods: Either placebo or albendazole were given every three months for a period of one and a half years. Helminth infection was assessed before and at 3 months after the last treatment round. In 150 subjects, the bacteria were profiled using the 454 pyrosequencing. Statistical analysis was performed cross-sectionally at pre-treatment to assess the effect of infection, and at post-treatment to determine the effect of infection and treatment on microbiome composition using the Dirichlet-multinomial regression model. Results: At a phylum level, at pre-treatment, no difference was seen in microbiome composition in terms of relative abundance between helminth-infected and uninfected subjects and at post-treatment, no differences were found in microbiome composition between albendazole and placebo group. However, in subjects who remained infected, there was a significant difference in the microbiome composition of those who had received albendazole and placebo. This difference was largely attributed to alteration of Bacteroidetes. Albendazole was more effective against Ascaris lumbricoides and hookworms but not against Trichuris trichiura, thus in those who remained infected after receiving albendazole, the helminth composition was dominated by T. trichiura. Discussion: We found that overall, albendazole does not affect the microbiome composition. However, there is an interaction between treatment and helminths as in subjects who received albendazole and remained infected there was a significant alteration in Bacteroidetes. This helminth-albendazole interaction needs to be studied further to fully grasp the complexity of the effect of deworming on the microbiome. Trial registration: ISRCTN Registy, ISRCTN83830814

Infection with Soil-Transmitted Helminths Is Associated with Increased Insulin Sensitivity

Contains fulltext : 153163.PDF (publisher's version ) (Open Access)OBJECTIVE: Given that helminth infections have been shown to improve insulin sensitivity in animal studies, which may be explained by beneficial effects on energy balance or by a shift in the immune system to an anti-inflammatory profile, we investigated whether soil-transmitted helminth (STH)-infected subjects are more insulin sensitive than STH-uninfected subjects. DESIGN: We performed a cross-sectional study on Flores island, Indonesia, an area with high prevalence of STH infections. METHODS: From 646 adults, stool samples were screened for Trichuris trichiura by microscopy and for Ascaris lumbricoides, Necator americanus, Ancylostoma duodenale, and Strongyloides stercoralis by qPCR. No other helminth was found. We collected data on body mass index (BMI, kg/m2), waist-to-hip ratio (WHR), fasting blood glucose (FBG, mmol/L), insulin (pmol/L), high sensitive C-reactive protein (ng/ml) and Immunoglobulin E (IU/ml). The homeostatic model assessment for insulin resistance (HOMAIR) was calculated and regression models were used to assess the association between STH infection status and insulin resistance. RESULTS: 424 (66%) participants had at least one STH infection. STH infected participants had lower BMI (23.2 vs 22.5 kg/m2, p value = 0.03) and lower HOMAIR (0.97 vs 0.81, p value = 0.05). In an age-, sex- and BMI-adjusted model a significant association was seen between the number of infections and HOMAIR: for every additional infection with STH species, the HOMAIR decreased by 0.10 (p for linear trend 0.01). This effect was mainly accounted for by a decrease in insulin of 4.9 pmol/L for every infection (p for trend = 0.07). CONCLUSION: STH infections are associated with a modest improvement of insulin sensitivity, which is not accounted for by STH effects on BMI alone

Epidemiology and monitoring of the effect of treatment of soil-transmitted helminth using multiplex real-time PCR

Host-parasite interactio

Risk factors for the development of allergic disorders in Indonesia

Host-parasite interactio