Introduction
Intestinal parasitic infections continue to pose a significant public health challenge, particularly in regions lacking adequate sanitation. With an estimated 3.5 billion people globally affected by various parasitic infections, the resulting diseases impact approximately 450 million individuals annually (Fauziah et al. Reference Fauziah, Aviani, Agrianfanny and Fatimah2022). Recent research has uncovered complex interactions between infectious diseases and chronic conditions, notably in the context of helminth infections and their potential link to the development of diabetes mellitus (DM), which is probably related to the hygiene hypothesis formulated by David Strachan in 1989. The association between Strongyloides stercoralis (S. stercoralis) infection and DM has garnered significant interest (Htun et al. Reference Htun, Odermatt, Paboriboune, Sayasone, Vongsakid, Phimolsarn-Nusith, Tran, Ounnavong, Andriama-Hefasoa, Senvanpan, Homsana, Lianosay, Xayavong, Robinson, Bounsavath, Prasayasith, Syphan, Lu, Thilakoun, Xaiyaphet, Vongngakesone, Eze, Imboden, Sripa, Reinharz and Probst-Hensch2018; Yingklang et al. Reference Yingklang, Chaidee, Dangtakot, Jantawong, Haonon, Sitthirach, Hai, Cha’on, Anutrakulchai, Kamsa-ard and Pinlaor2022).
As noted in the study by Amer et al. (Reference Amer, Othman, Dawood, El-Nouby, Gobert and Abou Rayia2023), various host factors, including genetic predisposition, immunological responses, and metabolic changes, can significantly influence host–parasite interactions. These factors may disrupt critical parasite functions such as oviposition, worm development, and the pathophysiology of the resulting infection. However, it is important to note that this study used mice as the experimental model (Amer et al. Reference Amer, Othman, Dawood, El-Nouby, Gobert and Abou Rayia2023). Recent studies show that helminth infection, such as that caused by Strongyloides stercoralis, might have a protective effect against the development of DM, probably concerning the hygiene hypothesis. People are assumed to become more susceptible to autoimmune and metabolic diseases in an advanced environment with less exposure to germs (Santiago and Nutman Reference Santiago and Nutman2016). While some pathophysiological mechanisms suggest that helminth infections may increase insulin sensitivity, the study by Salvador et al. (Reference Salvador, Galvis, Treviño, Sulleiro, Sánchez-Montalvá, Serre-Delcor, Goterris, Aznar, Bosch-Nicolau, Oliveira, Espinosa-Pereiro, Pou and Molina2023) found no association between S. stercoralis infection and type 2 DM or other metabolic diseases (Salvador et al. Reference Salvador, Galvis, Treviño, Sulleiro, Sánchez-Montalvá, Serre-Delcor, Goterris, Aznar, Bosch-Nicolau, Oliveira, Espinosa-Pereiro, Pou and Molina2023). The association of S. stercoralis infection with DM has remained poorly explored and quite conflicting; hence, further clinical studies are needed to better understand the potential interaction between these diseases.
The current paper presents a meta-analysis of previous studies to shed light on the association between S. stercoralis infection and the risk of developing DM. Results are expected to contribute to a general understanding of how parasitic infections may affect DM epidemiology and guide future research on areas where both DM and helminth infection prevalence is high.
Materials and Methods
Target population, controls, and outcomes of the study
Patients diagnosed with S. stercoralis infections were grouped as the case population, and those without any sign of the parasitic infection or those who were generally healthy were tagged as controls. Intervention or exposure was not applied in this study. The outcome of interest in this meta-analysis is the susceptibility to develop DM.
Literature search strategy
PROSPERO, Cochrane Library, and PubMed were initially searched to determine if an ongoing or published meta-analysis was done on the topic. After verifying the non-existence of a meta-analysis on the topic, a thorough search was done using PubMed, ScienceDirect, Google Scholar (title search only), and Web of Science. The search concluded on August 1, 2024. In doing the full search, a combination of the following key search terms was used: “Strongyloides” OR “Strongyloides stercoralis” OR “S. stercoralis” OR “helminths” AND “diabetes” OR “T2D”. All resulting studies from the various database sites were collated, sorted, and cleaned to remove duplicate studies. After removing duplicate studies, the screening was done by initially checking the title and abstract for relevance, namely if they were conducted among humans, involved patients infected with S. stercoralis, and patients diagnosed with DM. Full papers of those who passed the initial screening were retrieved and reviewed. Full papers were only included if they contained the number of patients with and without S. stercoralis infection who developed or did not develop DM. No restrictions on the year and type of publication were set. Papers such as letters to editors, clinical trials, and brief/short communications were included as long as relevant data could be extracted. Two authors (R.E.T. and M.J.D.) screened the included studies.
Data extraction and computation
The same authors (R.E.T. and M.J.D.) who screened the included studies also extracted the needed data. A third author (E.J.C.) further verified the accuracy of the collated data. A customized spreadsheet was created as the primary data abstraction tool. For each included study, the following data were collected: (1) first author’s last name; (2) year of publication; (3) geographic location where the study was conducted; (4) method of identifying S. stercoralis infection; (5) method of identifying DM; (6) number of cases and controls; and (8) number of patients who developed and did not develop DM per case and control group.
Assessment of study quality
The Newcastle-Ottawa Scale assessment tool was used to check for the quality of the eligible studies. Studies were judged based on selection, comparability, and exposure. The rating system has scores ranging from 0 to 9 points. Studies scoring 5–6 and ≥7 points were considered moderate and high-quality, respectively.
Meta-analysis protocol
Review Manager 5.4. was used (Copenhagen: Nordic Cochrane Centre, Cochrane Collaboration, 2014) to compute the odds ratio (OR) and 95% confidence interval (CI). The data encoded in the software followed the following format:
Heterogeneity was assessed using the chi-square-based Q test and I 2 statistics. Both random-effects (significant heterogeneity) and fixed-effects (non-significant heterogeneity) models were used in the study (DerSimonian and Laird Reference DerSimonian and Laird1986; Mantel and Haenszel Reference Mantel and Haenszel1959). P values are significant if they are less than .05 for association testing and less than .10 for heterogeneity testing (DerSimonian and Laird Reference DerSimonian and Laird1986; Higgins Reference Higgins2003; Higgins and Thompson Reference Higgins and Thompson2002). Publication bias testing was no longer performed due to the limited studies included (Dalton et al. Reference Dalton, Bolen and Mascha2016; Ioannidis Reference Ioannidis2008).
Results
The summary of the literature search is highlighted in Figure 1. The full search yielded a total of 1725 studies. After removing duplicates and thorough screening, only five studies consisting of 2106 participants (536 cases and 1570 controls) were included in the meta-analysis. The characteristics of the included studies are summarised in Table 1. Most of the studies (Hays et al. Reference Hays, Thompson, Esterman and McDermott2016; McGuire et al. Reference McGuire, Welch and Melzer2019; Salvador et al. Reference Salvador, Galvis, Treviño, Sulleiro, Sánchez-Montalvá, Serre-Delcor, Goterris, Aznar, Bosch-Nicolau, Oliveira, Espinosa-Pereiro, Pou and Molina2023; Talukder et al. Reference Talukder, Pham, Woodman, Wilson, Taylor, Kaldor and Einsiedel2022) were done in non-Asian countries and identified S. stercoralis infection using an enzyme-linked immunoassay serology. The study by Yingklang et al. (Reference Yingklang, Chaidee, Dangtakot, Jantawong, Haonon, Sitthirach, Hai, Cha’on, Anutrakulchai, Kamsa-ard and Pinlaor2022) used conventional methods such as the modified agar plate culture and the formalin-ethyl acetate concentration technique to identify S. stercoralis infection (Yingklang et al. Reference Yingklang, Chaidee, Dangtakot, Jantawong, Haonon, Sitthirach, Hai, Cha’on, Anutrakulchai, Kamsa-ard and Pinlaor2022). As assessed using the Newcastle-Ottawa Scale, the overall quality of the included studies is 6.00 (±1.22) with a median of 6.00.
Figure 1. Summary of the literature search.
Table 1. Characteristics of the included studies
DM: diabetes mellitus; ELISA: enzyme-linked immunoassay; NOS: Newcastle-Ottawa scale.
The overall analysis (Figure 2) showed non-significant (P = .75) but highly heterogeneous (I 2 = 95%, P < .00001), which warranted us to determine the cause using a Funnel plot (Figure 3). The funnel plot identified two outlier studies, namely the studies of Hays et al. (Reference Hays, Thompson, Esterman and McDermott2016) and McGuire et al. (Reference McGuire, Welch and Melzer2019). Subsequent analysis was done where the outlier studies were removed. Based on the results of the post-outlier analysis (Figure 4), a significant (P = .02) and homogenous (I 2 = 0%, P = .55) outcome was achieved.
Figure 2. Forest plot analysis on the association of S. stercoralis infection with diabetes mellitus development.
Figure 3. Funnel plot analysis for the identification of outlier studies.
Figure 4. Forest plot analysis on the association of S. stercoralis infection with diabetes mellitus development after removal of the outlier studies.
Discussion
Summary and interpretation of findings
The post-outlier analysis summarizes the results of three studies involving 1418 participants, including 349 cases and 1069 controls. Initially, five studies were considered for inclusion. By pooling the ORs and 95% CIs from the individual articles, we demonstrated that individuals with S. stercoralis infection are less likely to develop DM. Overall, the likelihood of developing DM was diminished among individuals infected with S. stercoralis (OR: 0.71; 95% CI, 0.53–0.94). Furthermore, the results were homogeneous (I 2 = 0%) and significant (P = .02) after excluding two outlier studies, reinforcing the association between S. stercoralis infection and a reduced likelihood of developing DM.
The significant findings provide strong evidence for the possible association between S. stercoralis infection and DM. This association is supported by the homogeneity of the post-outlier results, indicating the combinability of the individual studies. Moreover, the high degree of statistical significance, the consistent precision of effects, and the robustness of the post-outlier outcomes enhance the evidence presented in this meta-analysis.
Comparison with other studies
This meta-analysis’ findings align with previous studies’ results (Salvador et al. Reference Salvador, Galvis, Treviño, Sulleiro, Sánchez-Montalvá, Serre-Delcor, Goterris, Aznar, Bosch-Nicolau, Oliveira, Espinosa-Pereiro, Pou and Molina2023; Talukder et al. Reference Talukder, Pham, Woodman, Wilson, Taylor, Kaldor and Einsiedel2022; Yingklang et al. Reference Yingklang, Chaidee, Dangtakot, Jantawong, Haonon, Sitthirach, Hai, Cha’on, Anutrakulchai, Kamsa-ard and Pinlaor2022). According to Yingklang et al. (Reference Yingklang, Chaidee, Dangtakot, Jantawong, Haonon, Sitthirach, Hai, Cha’on, Anutrakulchai, Kamsa-ard and Pinlaor2022), there is an inverse relationship between S. stercoralis infection and type 2 DM. However, individuals with this infection exhibit a low estimated glomerular filtration rate, higher alanine aminotransferase levels, and an increased urine albumin-creatinine ratio. This relationship is attributed to nutrition, gut homeostasis, and the immunoregulatory response during parasitic infection. Moreover, Yingklang et al. (Reference Yingklang, Chaidee, Dangtakot, Jantawong, Haonon, Sitthirach, Hai, Cha’on, Anutrakulchai, Kamsa-ard and Pinlaor2022) suggested that helminth infection can alter intestinal microbial diversity and physiological processes at the cellular level, leading to increased insulin sensitivity.
Similarly, Talukder et al. (Reference Talukder, Pham, Woodman, Wilson, Taylor, Kaldor and Einsiedel2022) reported that changes in the gut microbiome due to S. stercoralis and other helminths reduce the risk of developing DM by regulating glucose uptake, inflammation, and insulin sensitivity. They also noted that the reductions in insulin and glucagon levels associated with S. stercoralis infection were reversed during anti-helminthic therapy, which increases the likelihood of developing DM. Additionally, Salvador et al. (Reference Salvador, Galvis, Treviño, Sulleiro, Sánchez-Montalvá, Serre-Delcor, Goterris, Aznar, Bosch-Nicolau, Oliveira, Espinosa-Pereiro, Pou and Molina2023) confirmed that pathophysiological mechanisms reinforce the concept that helminth infections may enhance insulin sensitivity and promote the production of anti-inflammatory cytokines.
Protective role of Strongyloidiasis against DM
An inverse relationship between allergic diseases and bacterial infections was proposed during early childhood, aligning with the hygiene hypothesis (Rajamanickam et al. Reference Rajamanickam, Munisankar, Bhootra, Dolla, Thiruvengadam, Nutman and Babu2019). Over time, this hypothesis was expanded to encompass helminthic infections, as immunomodulation observed during chronic helminthic infections protects against allergic and autoimmune diseases (Pineda and Ramos Reference Pineda and Ramos2012a, Reference Pineda and Ramos2012b). As studied by other researchers, this association has expanded to include metabolic diseases such as DM. The incidence of type 2 DM and the mechanisms involved in its development show an inverse relationship with the prevalence of helminthic infections, particularly those caused by S. stercoralis. This suggests that helminths may be protective against type 2 DM, as supported by the hygiene hypothesis (Talukder et al. Reference Talukder, Pham, Woodman, Wilson, Taylor, Kaldor and Einsiedel2022; Yingklang et al. Reference Yingklang, Chaidee, Dangtakot, Jantawong, Haonon, Sitthirach, Hai, Cha’on, Anutrakulchai, Kamsa-ard and Pinlaor2022). Several factors and pathophysiological changes influence the protective mechanism of S. stercoralis infection against DM (Rajamanickam et al. Reference Rajamanickam, Munisankar, Bhootra, Dolla, Thiruvengadam, Nutman and Babu2019). Other factors that may explain the protective mechanism of strongyloidiasis against DM are explained below.
Alteration of gut microbiota
The gut microbiota comprises various microbial communities that inhabit the gastrointestinal tract (Nguyen et al. Reference Nguyen, Hongsrichan, Intuyod, Pinlaor, Yingklang, Chaidee, Sengthong, Pongking, Dangtakot, Banjong, Anutrakulchai, Cha’On and Pinlaor2022). These microorganisms exert beneficial and harmful effects on the human host. However, they predominantly confer benefits, including protection against infections, the development of immunity, the absorption of nutrients, and the synthesis of vitamins (D’Argenio and Salvatore Reference D’Argenio and Salvatore2015).
In line with this, Strongyloides spp., which inhabit the gastrointestinal tract, interact with the host’s gut microbiota, leading to substantial changes in its composition. Notably, Strongyloides spp. increase the abundance of certain microorganisms, including Lactobacillus spp., Blautia, and the Ruminococcus torques group (Pace et al. Reference Pace, Carvalho, Zanotto, Santos, Guadagnini, Silva, Mendes, Rocha, Alegretti, Santos, Catharino, Paroni, Folli and Saad2018; Tran et al. Reference Tran, Chaidee, Surapinit, Yingklang, Roytrakul, Charoenlappanit, Pinlaor, Hongsrichan, Anutrakulchai, Cha’on and Pinlaor2023). These microbes are known for their ability to produce short-chain fatty acids (SCFAs), with acetic acid, propionic acid, and butyric acid being the principal SCFAs. Remarkably, the presence of SCFAs in the bloodstream influences glucose storage in the muscle, liver, and fat by stimulating the secretion of glucagon-like peptide-1, which indirectly increases insulin secretion and decreases pancreatic glucagon secretion (He et al. Reference He, Zhang, Shen, Niu, Tan, Chen, Zhao, Bai, Hao, Li, Zhang and Zhu2020; Kim Reference Kim2018). This process helps regulate blood glucose levels and may contribute to a reduction in the risk of type 2 DM. Additionally, high levels of these metabolites enhance energy harvest capacity, promote an anti-inflammatory status, and increase satiety, leading to better overall health (Nguyen et al. Reference Nguyen, Hongsrichan, Intuyod, Pinlaor, Yingklang, Chaidee, Sengthong, Pongking, Dangtakot, Banjong, Anutrakulchai, Cha’On and Pinlaor2022).
The alteration of the gut microbiome favors the production of beneficial metabolites such as SCFAs, suggesting that Strongyloides spp. may contribute to improved glucose regulation and a reduced risk of type 2 DM. This highlights the potential of Strongyloides infection to induce protective mechanisms, aiding in managing type 2 DM.
Immunomodulation
Strongyloidiasis significantly impacts the immunomodulation of glycemic, hormonal, and cytokine parameters, potentially leading to reduced blood glucose levels in the body (Talukder et al. Reference Talukder, Pham, Woodman, Wilson, Taylor, Kaldor and Einsiedel2022). Type 2 DM is a chronic low-grade inflammatory disease characterized by elevated levels of pro-inflammatory cytokines and chemokines, contributing to increased insulin resistance (He et al. Reference He, Dai, Liu, Yang, Liu, Li and Liao2022; Salvador et al. Reference Salvador, Galvis, Treviño, Sulleiro, Sánchez-Montalvá, Serre-Delcor, Goterris, Aznar, Bosch-Nicolau, Oliveira, Espinosa-Pereiro, Pou and Molina2023). Reduced levels of pro-inflammatory cytokines have been shown to improve the management of type 2 DM (Velikova et al. Reference Velikova, Kabakchieva, Assyov and Georgiev2021).
Individuals with Strongyloides infection have been shown to have significantly reduced circulating levels of pro-inflammatory cytokines and increased levels of Th2-associated and regulatory cytokines (Anuradha et al. Reference Anuradha, Munisankar, Bhootra, Jagannathan, Dolla, Kumaran, Shen, Nutman and Babu2016). Pro-inflammatory cytokines, such as Th1 cytokines (interferon-γ, tumour necrosis factor-α, and interleukin [IL]-2), Th17 cytokines (IL-17A, IL-17F, IL-22, and IL-23), and other pro-inflammatory cytokines (IL-1β and IL-1), are known to induce harmful host inflammation and contribute to the development of inflammatory disorders. During Strongyloides infection, the levels of these pro-inflammatory cytokines decrease, providing evidence that strongyloidiasis may help control harmful inflammation. Further studies revealed that Th1 and Th17 cytokines were significantly lower in type 2 DM patients infected with Strongyloides, which tends to improve insulin sensitivity and barrier function (Rajamanickam et al. Reference Rajamanickam, Munisankar, Bhootra, Dolla, Thiruvengadam, Nutman and Babu2019). On the other hand, helminthic infections stimulate the production of Th2 cytokines (IL-4, IL-5, IL-9, and IL-13) and regulatory cytokines (IL-10 and transforming growth factor-β), which are believed to modulate pro-inflammatory cytokines (Anuradha et al. Reference Anuradha, Munisankar, Bhootra, Jagannathan, Dolla, Kumaran, Shen, Nutman and Babu2016; Rajamanickam et al. Reference Rajamanickam, Munisankar, Thiruvengadam, Menon, Dolla, Nutman and Babu2020). Additionally, Th2 and regulatory cytokines enhance insulin sensitivity by promoting the development of alternatively activated macrophages, encouraging eosinophilic infiltration of adipose tissue, and activating innate lymphoid cells (Rajamanickam et al. Reference Rajamanickam, Munisankar, Bhootra, Dolla, Thiruvengadam, Nutman and Babu2019). Interestingly, following anti-helminthic therapy, the levels of pro-inflammatory cytokines have been observed to increase, while the Th2-associated and regulatory cytokines diminish, suggesting that post-treatment of Strongyloides infection may increase the risk of type 2 DM (Anuradha et al. Reference Anuradha, Munisankar, Bhootra, Jagannathan, Dolla, Kumaran, Shen, Nutman and Babu2016; Rajamanickam et al. Reference Rajamanickam, Munisankar, Thiruvengadam, Menon, Dolla, Nutman and Babu2020). Strongyloidiasis significantly affects the host’s immune system, demonstrating a potentially beneficial role in managing type 2 DM. The reduction of pro-inflammatory cytokines and the increase in Th2-associated and regulatory cytokines are key effects of Strongyloides.
The meta-analysis provided more precise estimates on the association of S. stercoralis infection with DM development. Overall, results suggest that the infection may decrease the likelihood of developing DM. However, even with the significant findings of this review, care should be taken in applying these results clinically given the study’s limitations such as (1) only one of the three post-outlier studies showed significant associations – which may obscure the overall effect of the results, (2) inconsistencies in the method of S. stercoralis infection and DM determination as well as the diversity of the ethnicity of the participants leads to significant clinical heterogeneity, and (3) limited studies done in tropics and subtropic areas where strongyloidiasis is endemic. Further longitudinal studies may be done in various ethnic groups and geographic locations may be done to verify these claims.
Author contribution
R.E.T. and M.R.P.C. conceptualized the study; R.E.T., J.A.F., and S.A.D. designed the study protocol; R.E.T., E.J.C., and M.J.D. performed data extraction; R.E.T. and E.M. analyzed the data and interpreted the results. All authors were involved in the drafting and critically revising of the manuscript. All authors read and approved the version of the manuscript to be sent for publication.
Ethical approval
Not required
Funding
None
Competing interest
None
