For a global metabolomics profile, the altered metabolic pathways were divided into seven different categories namely energy, gut microbial, amino acids, nucleic acids, immune proteins, structural proteins/lipids and hormone related metabolites. From the studies included in this scoping review, a total of 127 altered metabolites were extracted in response to S. haematobium and S. mansoni infections in which 90 were unique non repeated metabolites. Furthermore, 44 repeats (frequency in which the metabolite is determined to be a biomarker in a study) of 17 different metabolites were identified in these seven metabolic pathway categories. With respect to energy metabolism, a total of 44 energy related metabolites with 12 repeats of 7 different metabolites were identified while 14 gut microbial related metabolites containing 11 repeats of 3 different metabolites and 8 different nucleic acid related metabolites were identified. With respect to amino acid metabolism, 32 metabolites were found to be altered with 17 repeats of 7 different metabolites. Finally, a total of 11 metabolites, 15 metabolites and 3 metabolites were identified for immune proteins, structural lipids or protein and hormone metabolism respectively. Comparison of all extracted metabolites revealed that the energy metabolism was significantly affected as their metabolites deviate from normal concentrations in schistosomiasis infected individuals as compared to healthy controls, followed by amino acid, structural lipids or protein, gut microbial, immune proteins, nucleic acid and hormones metabolism. Adult schistosome worms utilise glucose ranging from one-sixth to one-fifth of its dry weight leading to energy related metabolites, enzyme and intermediate deviations from their homeostatic level which may explain the reason for a high number in energy related metabolism related biomarkers in schistosomiasis (40). Table 2 provides an overview of key altered metabolites from the studies pathway enrichment analysis on the extracted metabolites and manual assignment of the metabolites to pathway.

Energy metabolic pathways are critical to all living organisms through production of ATP to effectuate the bioenergetic need of cellular functions and processes contributing to net biomass formation and homeostasis (41). In the current review, schistosome infection was reported to upregulate glycolysis which was indicated by an increase in intermediates (glucose-6-phosphate and 3-phosphoglyceric acid) and their end product pyruvate whilst the main substrate glucose and its stores declined (29, 31, 32, 37). Furthermore, glucose-6-phoshate and 3-phosphoglyceric acid were found to be major metabolite biomarkers in discriminating human S. haematobium infection in paediatrics below the age of five (37). A study conducted by Tielens and colleagues highlighted that during the helminth complex life cycle in mammalian hosts, paired adult schistosomes utilise glucose and glycogen for their maturation and to compensate for their substantial needs for the energy required to produce the large numbers of eggs laid continuously by the female worm (42). Consequently, enhanced activation of glycolysis was reported to directly stimulate the tricarboxylic acid cycle as exhibited by high levels of pathway intermediates such as alpha ketoglutarate (39). However, tricarboxylic acid intermediates, succinate and fumerate were considered poor diagnostic markers as they may be inconclusively lower or higher in concentration during schistosome infection (34, 39). Aconitate levels were reported to be significantly decreased during S. mansoni infection, thus may be a potent oxidative biomarker (34, 35). The findings of Yarian and colleagues suggest that perturbations of aconitase is associated with aging and disturbances in the tricarboxylic acid cycle activities leading to reduction in overall capability of mitochondrial bioenergetics (43).

Helminth infections contribute to the structure and composition of the gut microbiome which play a major role in the development of the immune system (44). The studies in this review showed that hippurate is a major candidate microbiome biomarker during intestinal and urogenital schistosomiasis and the reduction in the metabolite concentration in biofluids is associated with infection (29, 30, 33, 34). Furthermore, one study reported that hippurate concentration is elevated during light schistosome infection while the concentration is decreased in chronic schistosome infection hence the metabolite may be used as a marker to determine the intensity of infection (39). Elevated levels of triethylamine and p-cresol glucuronide were significantly associated with schistosome infection despite other microbiome metabolites such as trimethylamine N-oxide and aminovalerate detection being elevated in urine and plasma (29, 33, 34). The presence of microbial based metabolites such as hippurate, p-cresol glucuronide and trimethylamine derivatives in biofluids suggest a cross-talk between helminth worms in mammalian host and its gut microbiota therefore such unique biomarkers may be utilised in the development of new diagnostic tools for schistosomiasis (33). However, propionate had indeterminate pertubations as the metabolite may either be decreased or increased during schistosome infections, hindering its predictor value as a gut microbiota biomarker (29, 33).

Urogenital schistosomiasis alters nucleic acid metabolism by increasing the synthesis of purines mainly inosine, AMP and ADP (37). Two studies supported the findings as purine derived metabolites namely guanidino acetate, methylguanidine cyclic adenosine monophosphate response element binding protein were elevated during schistosomiasis (21, 34). A possible explanation for the upregulation of purine metabolism is an increase in demand for energy in the form of ATP by schistosome worms, which consequently increase ADP and AMP as products of hydrolysis (21). Additionally, the concentrations of the high energy phosphates, AMP and ADP in the blood are key regulators of energy homeostasis as they determine the initiation of alternative metabolic pathways such as fatty acid degradation and glycogenolysis to restore energy balance (37).

Amino acid functions are not only limited as structural building blocks of proteins or nutritional elements but are also involved in a myriad of biological processes which include acting as regulatory signals for gene expression, cell signalling pathways and being precursor molecules for hormone synthesis (21). Schistosome infection resulted in elevated levels of phenylacetylglycine and alanine (29, 33, 34, 39). Phenylacetylglycine is an alpha amino acid which bears an acyl group at its terminal nitrogen atom that signals a lysosomal disorder called phospholipidosis where there is an over accumulation of phospholipids in either the liver, kidney or lungs (45). The disorder can be linked to hepatosplenomegaly due to entrapment of schistosome eggs in the liver and spleen (46). An increase in glucogenic amino acids (alanine, glutamine and asparagine) was observed in both S. mansoni and S. haematobium infections (29, 34, 39). Elevated levels in glucogenic amino acids may be attributed to upregulation of gluconeogenesis due to depletion of energy substrates and elevated liver aminotransferases (47, 48). Free proline, which is a precursor of hydroxyproline, glycine, alanine and their derivatives, were elevated in S. mansoni infections in mouse models which might imply stimulated collagen synthesis activity (49).

A disturbance of amino acid metabolic pathways was also associated with an S. mansoni infection, as indicated by the depletion of taurine, 2-oxoisocaproate and 2-oxoisovalerate. Taurine is an amino sulfonic acid that has been reported to alleviate liver fibrosis by suppressing the activation of downstream inflammatory mediators and subsequent pyroptosis (50). A decrease in 2-oxoisocaproate and 2-oxoisovalerate that originates from valine and leucine respectively was reported to be associated with increase in amino acid metabolism to synthesise precursor molecules (29). Notably, one study indicated a decrease in urea which may be due to expression of arginase induced by schistosome worms during their development in the human host, which is responsible for the hydrolysis of urea (51).

S. mansoni phosphoenolpyruvate carboxykinase (SmPEPCK) is an egg antigen for schistosome infection and studies suggested its potential as a disease specific protein marker due to its immunological properties (52). SmPEPCK was detected and elevated in the liver during intestinal schistosomiasis (32, 35), therefore this protein-based antigen may be utilised as an immunological marker of infection adding to serum cytokines, chemokines and receptors (53). Lymphocyte cytosolic protein 1 (LCP1) and prohibitin 2 were significantly increased in schistosome chronic infections (32). LCP1 has been reported to be utilised as a marker in cancers such as leukaemia whilst the latter controls the growth, development and apoptosis of cells thus it can be concluded that they are not useful markers for schistosomiasis (54, 55). Major histocompatibility complex (MHC) precursors and interleukin-2 (IL-2) were found to be increased during the infection. The MHC plays an important role in adaptive immunity through presentation of both endogenous and exogenous antigens during helminths infections (56). A surge in cytokine IL-2 have been reported in both S. haematobium and S. mansoni infections to promote the growth and development of peripheral immune cells in the initiation of the immune response (57). One study reported elevated levels of venom allergen-like (VAL) 3 proteins during schistosomiasis which is a common feature of helminths species cocktail of proteins to aid invasion, initiate feeding, facilitate adaptation and mediate modulation of the host immune responses (58).

Lipids play a major role in the formation or maintenance of the integrity of the cellular membrane bilayer and act as receptors for a variety of cell signalling processes (59). Membrane associated lipids namely glycerophosphoryl choline, phosphoryl choline and phosphatidylethanolamine are elevated in the blood during schistosomiasis infections (21, 38). However, two studies were contradicting with respect to phosphatidylcholine; one study (21) indicated that the levels were elevated whilst the other showed that the levels were decreased in during schistosomiasis (33). Disturbance in phosphocholine concentration in tissues is associated with cell proliferation which additionally explains elevated heat shock proteins (HSP) as oncogene signalling molecules (60). Due to oxidative stress in a tumour microenvironment, phosphatidylethanolamine is usually expressed on endothelial cells and has been reported that alterations in both phosphatidylethanolamine and phosphatidylcholine is one of the mechanisms for carcinogenesis in chronic infections (61, 62). Secondary structure proteins; actins, collagen, cytokeratins, hydroxyproline and connective tissue growth factor were elevated during schistosomiasis infections with a possibility in playing a role in liver fibrosis in chronic schistosome infections (32, 36).

Low levels of human estrogen-related hormones were associated with urogenital schistosomiasis infection (21). There is existing evidence for the role of estrogen metabolism in host-parasite relationship where S. haematobium adult worm utilise or inhibit production of host steroids resulting in decreased sex steroid hormones (63, 64). On the other hand, adrenochrome-O-quinone, a toxic quinone metabolite of epinephrine, was elevated in plasma during schistosomiasis infection. Adrenocromes with quinone groups are capable of forming reactive oxygen species with severe pathological effects such as bladder cancer in chronic schistosomiasis (65).