Introduction

Schistosomiasis, also known as bilharzia or Katayama fever, is a parasitic disease caused by trematode helminths of the genus Schistosoma, which live and reproduce sexually in the human circulatory system [1]. This neglected tropical disease (NTD) affects at least 251.4 million in 78 countries worldwide. Approximately 800 million people were at risk, with Sub-Saharan Africa (SSA) bearing more than 90% of the global burden of the disease [2]. This is reflected in the severe impact of schistosomiasis, which leads to an estimated loss of 1.6 million Disability-Adjusted Life Years (DALYs) and causes 150–280,000 deaths annually in the region [3]. The highest prevalence and intensity of the disease is observed among school-aged children [4].

S. haematobium, S. mansoni and S. japonicum are the three main species of schistosomes that infect humans. S. haematobium and S. mansoni are found in Africa and the Middle East, while only S. mansoni occurs in America. S. japonicum is found mainly in Asia, especially in the Philippines and China. In addition, human schistosomiasis can also be due to three locally endemic species: S. mekongi in the Mekong basin, S. guineensis and S. intercalatum in West and Central Africa. The distribution of each species is determined by its host snail range, as each species has a specific range of suitable snail hosts [4].

Infection occurs when cercariae, the larval stage of the parasite shed by freshwater snails, penetrates the skin, bypasses the immune system, develop into schistosomula, gain access to the blood stream and reach the hepatic portal vein. Following sexual maturation, the female and male schistosomes pair migrates against the blood stream and reach their final destination: the mesenteric vein of the intestine (S. mansoni and S. japonicum) or the pelvic venous plexus (S. haematobium), the site of eggs deposition [1]. The intravascular eggs traverse the wall of the venule, pass through the surrounding tissue and reach the lumen of the intestine (S. mansoni and S. japonicum) or bladder (S. haematobium), where they are expelled in faeces or urine, respectively [1,4–5]. Some eggs become trapped in host tissues, causing the main pathology during schistosomiasis (i.e., liver fibrosis or genital schistosomiasis).

The immune system of infected hosts is challenged by multiple schistosome life cycle stages such as penetrating cercariae, adult worms and eggs. As a result, a multitude of humoral and cellular immune responses are stimulated leading the antibody production and T-cell proliferation targeting specific parasite stages. There are generally three stages of schistosomiasis, beginning with an initial dermatitis reaction following contamination, resulting in an allergic, inflammatory maculopapular lesion [6]. The acute symptomatic phase characterized by a T helper 1 cells (Th1) response follows this initial phase, whose most common symptoms are persistent fever (Katayama fever), weakness, vomiting, nausea, diarrhoea, malaise and rapid weight loss [1]. With the progression of the diseases, when the first eggs are produced by recently matured worms, the host immune response strongly become T helper 2 cells (Th2)-polarized. This shift results in the loss of pre-existing worm antigen specific Th1 response, leading to the onset of chronic schistosomiasis, the final phase of the disease [7]. During this immune transition, the toxic effects of trapped schistosome eggs’ secretome are neutralized through the formation of granulomas that encapsulate parasite eggs to prevent tissue damage. This process is driven by an immune-mediated CD4+ T-cell-dependent response that leads to granuloma formation [8]. However, this immune response triggers eosinophilic inflammatory reactions, which are gradually replaced by fibrotic deposition and may lead to cancer [9]. In hepatic schistosomiasis this host’s cell-mediated immune response might result in irreversible fibrosis and severe portal hypertension, if left untreated [10].

The current strategy for controlling schistosomiasis is based on an annual campaign of mass administration of praziquantel (PZQ), as no effective vaccine has yet been developed [11]. In 2020, the WHO released its roadmap for addressing NTDs globally and sets ambitious targets to eliminate schistosomiasis as a public health problem by 2030 [12]. To achieve elimination goals, it is crucial to develop simple, reliable, and minimal invasive tools for accurately detecting Schistosoma eggs in stools or urine samples, and associated pathologies. Research into identifying and validating appropriate biomarkers, such as signature from the gut microbiome, to indicate the presence and progression of Schistosoma infection is strongly encouraged [13,14]. The human gastrointestinal (GI) tract harbours a complex and dynamic community of microorganisms known as the gut microbiota, which significantly impacts the host’s health both during homeostasis and disease [15]. Multiple factors (e.g., diet) play a role in shaping the human gut microbiota across the lifetime. The gut microbiota provides numerous benefits to the host, including enhancing gut integrity, shaping the intestinal epithelium through epithelial cell proliferation and differentiation, harvesting energy, protecting form pathogens, and regulating host immunity [16,17]. However, dysbiosis, or alteration in the composition and function of the microbial composition, has been linked to a variety of GI and systemic disorders, including obesity, colorectal cancer, cardiovascular risk, autism and Alzheimer’s disease [18,19]. In developing countries, helminth infections are a common cause of gut microbiota dysbiosis. Several studies reported alterations of gut microbial richness, diversity and modifications in metabolic signatures associated with human gastrointestinal helminth infections [20–23]. Interestingly, only thirteen studies, as retrieved in the present systematic review, have robustly shown that gut microbiota becomes altered during acute and advanced human schistosomiasis. These studies, though limited in their numbers, suggest that gut microbiota may be helpful for the diagnosis, monitoring, treatment, and prevention of schistosomiasis. This review seeks to comprehensively evaluate evidences from these studies and summarize existing findings on the relationship between the gut microbiome and schistosomiasis in humans.

Methods

This systematic review was designed and conducted using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist (S1 Table) [24]. The protocol was published in the international database PROSPERO under the identification CRD42023425371. Ethical clearance was not required as this systematic review solely reports on previously published data.

Study selection

Studies published in English or French languages were included if they contained data about the gut microbiota composition in schistosomiasis patient. After removing duplicated studies from the list, titles and abstracts of eligible findings were independently examined by two authors (MGO and SK) for the selection of relevant studies. In this review, we considered cross-sectional, case-control, and longitudinal studies, as well as community- and hospital-based studies carried out worldwide. We included studies that reported modification of gut microbiota composition and/or function in schistosomiasis-infected patients with or without pathology. Studies with inappropriate study designs, such as comments, case reports, reviews, systematic reviews, and meta-analyses, animal studies, and articles with no data about the gut microbiota composition changes in schistosomiasis patient data were excluded. Studies published in neither the English nor French languages, as well as studies whose complete text and abstract were unavailable or unretrievable, were also excluded. Details of the study selection process are presented in the PRISMA flow diagram (Fig 1).

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Fig 1. PRISMA flow diagram showing the study selection process.

https://doi.org/10.1371/journal.pntd.0012844.g001

Results

Characteristics of the included articles

As shown in Fig 1, the literature search across various databases initially yielded a total of 881 potentially relevant articles. After removing 302 duplicate articles and excluding 555 articles based on thorough screening of the titles and abstracts, 24 articles were sought for retrieval. Of the 24 articles, 3 articles could not be retrieved, leaving 21 articles to be assessed for eligibility. Following the full-text screening, 9 articles met the inclusion criteria. Additionally, 4 relevant articles were identified through manual searches of the reference lists of the included studies, resulting in a total of 13 publications included in this systematic review.

In terms of study design, of the 13 studies included in this review, more than three-quarters (10 studies: 77%) were cross-sectional studies [26–35], the remaining were: 1 (7.7%) longitudinal study [36], 01 (7.7%) clinical trial [37], and 01 (7.7%) case-control [38]. Seven (53.8%) of the studies were hospital-based [28,30,31,33,34,35,38] and 6 (46.2%) were community-based studies [26,27,29,32,36,37]. Most of the study participants were adults (n = 7; 53.8%) [27,28,30,33,34,35,38] followed by children (pre- and school-aged) (n = 6; 46.2%) [27,29,31,32,36,37], and then adolescents (n = 1; 7.7%) [26]. Studies selected in this review were conducted in two schistosomiasis-endemic areas of the world: Asia (7 studies, 53.8%) [27,28,30,33,34,35,38] and SSA (6 studies, 46.2%) studies [26,29,31,32,36,37]. In SSA, where the burden of human schistosomiasis is greatest [2], of the forty SSA countries endemic to human schistosomiasis, studies of the relationship between human schistosomiasis and gut microbiome were conducted only in 3 countries: Zimbabwe (3 studies, 23%) [29,31,32], Nigeria (2 studies, 15.4%) [26,36] and Côte d’Ivoire (1 study, 7.7%) [37]; in Asia, China was the main study site with 6 (46.2%) studies [28,30,33,34,35,38], and the Philippine with 1 (7.7%) study [27].

In addition, the included studies focus on the three main species of human Schistosoma including S. japonicum, the most reported species (7 studies, 53.8%) [27,28,30,33,34,35,38], followed by S. haematobium (5 studies, 38.5%) [26,39,31,32,36] and S. mansoni (1 study, 7.7%) [37]. Traditional tools were used for the detection of Schistosoma eggs in samples collected: Kato Katz (KK) technique for the detection of S. japonicum and S. mansoni eggs in the stool sample, and urine filtration for the detection of S. haematobium eggs in urine sample. Next generation sequencing methods were used to characterise the gut microbiota signature of the study participants as follows: amplicon (16S rRNA) sequencing (11 studies, 84.6%) [26–30,33–37] and shotgun metagenomics sequencing (2 studies, 15.4%) [31,32]. All the characteristics of the 13 studies included in this systematic review are summarized in The Table 1 below.

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Table 1. Characteristics of all included studies.

https://doi.org/10.1371/journal.pntd.0012844.t001

Alteration in gut microbiome of patients with schistosomiasis infection

Among the 13 articles included in this systematic review, 9 (69.2%) of them reported modifications of gut microbiome structure and composition among patients infected with S. haematobium [26,29,31,32,36], S. japonicum [27,28,30] and S. mansoni [37]. Overall, 4 bacterial genus appeared as potential biomarkers for S. haematobium and S. japonicum infection namely Faecalibacterium, Bacteroides, Blautia and Megasphaera (Fig 2A). Details are shown in Table 2.

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Fig 2. Flow diagram describing all current human-based studies on the host gut microbiome and schistosomiasis.

A. Intersects of microbes revealed in studies comparing the differential gut microbiomes between non-infected and infected individuals. B. Intersects of microbes revealed in studies unveiling the differential gut microbiomes of schistosomiasis patients with liver fibrosis. C. Intersects of microbes revealed in studies unveiling the differential gut microbiomes of schistosomiasis patients following praziquantel administration. Cartoon illustrations were retrieved from Biorender.com and used in the present figure.

https://doi.org/10.1371/journal.pntd.0012844.g002

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Table 2. Main findings reported in the included studies.

https://doi.org/10.1371/journal.pntd.0012844.t002

Discussion

During the last decade, human gut microbiome studies have garnered increasing attention in order to determine their diagnostic, prognostic and therapeutic potential. In recent decade, several studies were undertaken in order to characterise the gut microbiome signature of schistosomiasis-infected patients with or without associated liver pathology [26–38]. This systematic review aimed to assess the current evidence on the interaction between the gut microbiome and the human schistosomiasis.

Generally, the human gut microbiota is mainly composed of 6 phyla of bacteria including Firmicutes, Bacteroidetes, Actinobacteria, Proteobacteria, Fusobacteria and Verrucomicrobia, which account for over >95% of the gut microbiota [39]. Among the fungi, the most studied are Candida, Saccharomyces, Malassezia, and Cladosporium [40]. In addition to bacteria and fungi, the human gut microbiota also contains viruses, phages, and archaea, mainly Methanobrevibacter smithii [41]. Data collected from studies included in this systematic review reveal infection with schistosomes lead to a change in diversity of the gut microbiome of schistosomiasis-infected patients, consistent with known influence factors such as age, gender, ethnicity, genetics, and pathology [42]. It was observed that both S. haematobium [27] and S. japonicum [36–38] infection significantly reduced the alpha and beta-diversity of infected patients compared to healthy individuals. The reduction of the diversity of the intestinal microbiota leads to intestinal dysbiosis and a decrease in both metabolic and immune function, which can lead to more serious complications [43].

Firmicutes and Proteobacteria are the most affected gut microbiota phyla following schistosomiasis-infection and associated pathology. Studies reported decreased abundance of Firmicutes and increased abundance of Proteobacteria. Several studies have linked these gut microbiome changes with the inflammatory environment [44–47]. Indeed, members of phylum Firmicutes are known for their ability in metabolizing complex carbohydrates, which can promote the induction of colonic regulatory T (Treg) cells. These Treg cells are crucial for suppressing inflammatory and allergic responses [48]. A reduction in Firmicutes abundance could thus contribute to a pro-inflammatory environment in the gut. Moreover, elevated levels of Proteobacteria-derived lipopolysaccharides (LPS) can trigger immune responses in the gut, leading to inflammation [49]. This inflammation environment in the gut can exacerbate the pathology associated with the schistosomiasis infection. Jiang et al. [32] reported an increase in relative abundance of TM7 phylum in acute S. japonicum infected patients, which is commonly associated with inflammatory diseases, and the TM7 phylotype is recognize for its potential immunosuppressive capacity through the inhibition of the production of tumour necrosis factor alpha (TNF-α) [50].

Many bacteria genera are considered as biomarkers to distinguish between infected and uninfected humans, mainly Bacteroides, Faecalibacterium, Blautia and Megasphaera. Members of the genus Bacteroides such as Bacteroides vulgatus and Bacteroides fragilis have been reported to be the two main isolates from patients suffering from Crohn’s disease, while the latter has been associated with intra-abdominal abscesses, appendicitis, and inflammatory bowel disease [49]. Data suggest that Enterotoxigenic Bacteroides fragilis secretes a toxin termed B. fragilis toxin (BFT) which induces IL-8 secretion from intestinal epithelial cell lines including HT29, T84, and Caco-2. IL-8 is a major chemotactic and activating peptide for neutrophils, and increased IL-8 expression is found in both acute and chronic inflammation [50]. Many studies have shown that Faecalibacterium abundance is reduced in different intestinal disorders and may be useful potential biomarker to assist in the diagnostic of gut diseases such as ulcerative colitis and Crohn’s disease [51]. Indeed, anti-inflammatory properties have been attributed to F. prausnitzii, through its capability to induce a tolerogenic cytokine profile with very low secretion of pro-inflammatory cytokines like IL-12 and IFN-γ, and an elevated secretion of the anti-inflammatory cytokine IL-10 [52]. Benítez-Páez et al. [53] reported that decreased abundance of Blautia species, especially Blautia luti and B. wexlerae, in the gut microbiota of obese children, are correlated with increase in pro-inflammatory cytokines and chemokines (gamma interferon [IFN-γ], tumour necrosis factor alpha [TNF-α], and monocyte chemoattractant protein 1 [MCP-1]).

The gut microbiome has been extensively investigated for the understanding of the physiopathology of many diseases. Changes in the composition and function of gut microbiota are correlated with the development and progression of multiple kinds of liver diseases [54–57]. To date, the role of the gut microbiome in the schistosomiasis-induced pathology is understudied; available data are limited to liver injuries induced by S. japonicum [35–38]. In this review, studies reported mainly Prevotella, genus as potential non-invasive biomarkers for differentiation of different stages of S. japonicum pathology. This genus is a common feature of the human gut microbiome and have been repeatedly implicated in health and disease. The genus Prevotella is a common component of the human gut microbiome and frequently linked to various health conditions. Within this genus, there are two main lineages: one includes P. copri, while the other comprises P. stercorea. The latter lineage produces sialidases, which are involved in immune cell interactions, pathogen binding, and gut inflammation [58,59]. Furthermore, the exposure of the liver to whole bacteria and/or their products such as LPS, peptidoglycan, viral or bacterial DNA, or fungal beta-glucan, due to compositional change of gut microbiome, leads to the induction of proinflammatory changes in the liver. These components, collectively labelled microbe-associated molecular patterns (MAMPs), are then recognised by liver innate immune cells (Kupffer cells, dendritic cells, NK and NKT cells, and hepatic stellate cells). Antigens derived from the microbiota induce inflammation by binding to pattern recognition receptors (PRRs) on liver macrophages, including Kupffer cells and stellate cells. Signalling via PRRs, mostly TLRs, leads to increased production of inflammatory (TNF, IL-1, IL-6) and fibro-genic cytokines/chemokines (TGF, MCP-1) as well as oxidative and endoplasmic reticulum (ER) stress. Microbial antigens can also induce type I interferon responses in the liver, leading to proliferation and activation of CD8+ cytotoxic T cells. Other immunological mechanisms, such as various effects of short-chain fatty acids on adaptive immune responses, are discussed separately. All these immunological mechanisms may contribute to the development of inflammation-mediated liver injury, which may progress to fibrosis, cirrhosis [60].

Few studies have investigated the effect of PZQ treatment on the gut microbiome, and some of them fail to find any relationship between schistosomiasis treatment and changes in the gut microbiome composition. In the only study that found that PZQ does in fact have a slight short-term effect on the gut microbe, authors reported that members of the class Fusobacteriales were significantly more abundant in the successfully treated group at baseline [34]. This genus is particularly interesting as it includes species known to have inflammatory properties and species that have been linked to chronic disease, such as Fusobacterium nucleatum, that could be closely associated with the worm-triggered inflammatory response. The high abundance of Fusobacterium spp. before treatment and their high decrease over the first 24 hours post-treatment is correlated with a better outcome of praziquantel treatment. This could indicate that the abundance of the genus Fusobacterium and the S. mansoni infection are dynamically linked and that preliminary presence of Fusobacterium correlated positively with the treatment efficacy following PZQ administration but were not simply altered as a general result of PZQ administration [34].

Conclusion

At the end of this systematic review, the existing data on the relationship between the gut microbiome and schistosomiasis in humans clearly showed that human schistosomiasis altered significantly the structure and composition of the human gut microbiome leading to dysbiosis state. The observation of shared gut microbial features across Schistosoma spp. infestations suggest the potential of gut microbiome to provide consensus non-invasive biomarker(s) for detecting schistosomiasis, related pathological conditions and predicting PZQ efficacy.

Outlook

Our present review, considering the depth of the available data, although confirming a clear diagnostic, prognostic and therapeutic biomarking potential of the human gut microbiome during schistosomiasis, cannot yet present some conclusive profiles of gut microbiome inherent to this biomarking. Indeed, this would require our analytical models aimed at identifying such robust biomarkers to be fed further data

from large-scale, longitudinal, diet-controlled and poly- versus mono-infected studies of more gut microbial profiles in schistosomiasis-infested individuals. Such research could pave the way for new management strategies rooted into the identification of unique and pathognomonic gut microbial features of schistosomiasis at both the infection as well as the pathological levels.

Notably somehow in terms of limitation of the currently available data sets, the view offered by most studies, reported in this review, have made use of 16S rRNA gene sequencing on highly heterogenous and superficially categorized individuals that targets at a limited depth only bacteria and archaea. Future comprehensive studies would benefit from the use of more in-depth, comprehensive and untargeted sequencing approaches such as whole genome shotgun metagenomics to include a more refined level of appraisal of gut microbe profiles, including non-bacterial microbes, in achieving the biomarking of schistosomiasis infections and associated morbidities. This will necessitate the use of robustly clinically categorized hosts from endemic areas i.e. with strictly defined clusters of infection statuses and burden and controlled for sources of bias such as age, gender, exposure experience, nutrition and, where feasible, genetic make-up.

Supporting information

Acknowledgments

The authors are grateful to Merck KGaA Global Health Institute i.e. Drs Thomas Spangenberg and Claudia Demarta-Gatsi for critically revising the present review and assisting in defining the manuscript plan.