Blastocystis: how do specific diets and human gut microbiota affect its development and pathogenicity? (original) (raw)
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Abstract
Blastocystis is an enteric parasite that inhabits the gastrointestinal tract of humans and many animals. This emerging parasite has a worldwide distribution. It is often identified as the most common eukaryotic organism reported in human fecal samples. This parasite is recognized and diagnosed more often than ever before. Furthermore, some strains develop resistance against currently recommended drugs, such as metronidazole; therefore, the use of natural remedies or special diets has many positive aspects that may address this problem. The goal of this review is to compare natural treatments and various diets against the efficacy of drugs, and describe their influence on the composition of the gut microbiota, which affects Blastocystis growth and the occurrence of symptoms. This article reviews important work in the literature, including the classification, life cycle, epidemiology, pathogenesis, pathogenicity, genetics, biology, and treatment of Blastocystis. It also includes a review of the current knowledge about human gut microbiota and various diets proposed for Blastocystis eradication. The literature has revealed that garlic, ginger, some medical plants, and many spices contain the most effective organic compounds for parasite eradication. They work by inhibiting parasitic enzymes and nucleic acids, as well as by inhibiting protein synthesis. The efficacy of any specific organic compound depends on the Blastocystis subtype, and, consequently, on its immunity to treatment. In conclusion, the article discusses the findings that human gut microbiota composition triggers important mechanisms at the molecular level, and, thus, has a crucial influence on the parasitic pathogenicity.
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Meet Blastocystis sp.: classification and life cycle
Blastocystis is a unicellular protist present throughout the world in the intestines of both healthy and symptomatic humans and animals [[1](/article/10.1007/s10096-017-2965-0#ref-CR1 "Tan KS (2008) New insights on classification, identification, and clinical relevance of Blastocystis spp. Clin Microbiol Rev 21:639–665. doi: 10.1128/CMR.00022-08
")\]. Its pathogenic potential is still controversial \[[2](/article/10.1007/s10096-017-2965-0#ref-CR2 "Moosavi A, Haghighi A, Mojarad EN, Zayeri F, Alebouyeh M, Khazan H, Kazemi B, Zali MR (2012) Genetic variability of Blastocystis sp. isolated from symptomatic and asymptomatic individuals in Iran. Parasitol Res 111:2311–2315. doi:
10.1007/s00436-012-3085-5
")–[5](/article/10.1007/s10096-017-2965-0#ref-CR5 "Lukeš J, Stensvold CR, Jirků-Pomajbíková K, Wegener Parfrey L (2015) Are human intestinal eukaryotes beneficial or commensals? PLoS Pathog 11(8), e1005039. doi:
10.1371/journal.ppat.1005039
")\]. For many years, it has been suggested that _Blastocystis_ is a commensal organism living in the human intestine. Originally, the parasite was considered to be a harmless yeast until the 1970s, when evidence showed that _Blastocystis_ was actually a protist \[[6](/article/10.1007/s10096-017-2965-0#ref-CR6 "Silberman JD, Sogin ML, Leipe DD, Clark CG (1996) Human parasite finds taxonomic home. Nature 380:398. doi:
10.1038/380398a0
")\], belonging to the Stramenopiles line of eukaryotic organisms. In 2009, Irikov et al. \[[7](/article/10.1007/s10096-017-2965-0#ref-CR7 "Irikov OA, Antokhin AI, Romanov YA (2009) Study of the dynamics of Blastocystis hominis reproduction in vitro. Bull Exp Biol Med 148:99–102. doi:
10.1007/s10517-009-0651-7
")\] proposed to place this organism in a separate sixth kingdom named “Chromista”. Until recently, the taxonomy of _Blastocystis_ was based on the host from which it was isolated (_B. hominis_ from humans, _B. ratti_ from rats, etc.). Modern phylogenic studies have identified a lack of host specificity for _B. hominis_ and _B. ratti_, and, therefore, have proposed to summarize the name as “_Blastocystis_ species”, with different ribosomal lineages classified into specific subtypes \[[8](/article/10.1007/s10096-017-2965-0#ref-CR8 "Stensvold CR, Suresh GK, Tan KS, Thompson RC, Traub RJ, Viscogliosi E, Yoshikawa H, Clark CG (2007) Terminology for Blastocystis subtypes—a consensus. Trends Parasitol 23:93–96. doi:
10.1016/j.pt.2007.01.004
"), [9](/article/10.1007/s10096-017-2965-0#ref-CR9 "Parija SC, Jeremiah S (2013) Blastocystis: taxonomy, biology and virulence. Trop Parasitol 3:17–25. doi:
10.4103/2229-5070.113894
")\].Morphologically indistinguishable phylogenetic inferences from small subunit rDNA (SSU rRNA) gene sequence analyses revealed considerable genetic divergence among Blastocystis isolated from humans and animals, with a total of 17 subtypes being identified so far [[10](/article/10.1007/s10096-017-2965-0#ref-CR10 "Alfellani MA, Taner-Mulla D, Jacob AS, Imeede CA, Yoshikawa H, Stensvold CR, Clark CG (2013) Genetic diversity of Blastocystis in livestock and zoo animals. Protist 164:497–509. doi: 10.1016/j.protis.2013.05.003
")\]. The majority of human _Blastocystis_ carriage is attributable to ST3 \[[11](/article/10.1007/s10096-017-2965-0#ref-CR11 "Forsell J, Granlund M, Stensvold CR, Clark CG, Evengård B (2012) Subtype analysis of Blastocystis isolates in Swedish patients. Eur J Clin Microbiol Infect Dis 31:1689–1696. doi:
10.1007/s10096-011-1416-6
"), [12](/article/10.1007/s10096-017-2965-0#ref-CR12 "Souppart L, Sanciu G, Cian A, Wawrzyniak I, Delbac F, Capron M, Dei-Cas E, Boorom K, Delhaes L, Viscogliosi E (2009) Molecular epidemiology of human Blastocystis isolates in France. Parasitol Res 105:413–421. doi:
10.1007/s00436-009-1398-9
")\], appearing quite rarely in non-primate hosts, suggesting that ST3 may be the only subtype (ST) of human/primate origin \[[13](/article/10.1007/s10096-017-2965-0#ref-CR13 "Noël C, Dufernez F, Gerbod D, Edgcomb VP, Delgado-Viscogliosi P, Ho LC, Singh M, Wintjens R, Sogin ML, Capron M, Pierce R, Zenner L, Viscogliosi E (2005) Molecular phylogenies of Blastocystis isolates from different hosts: implications for genetic diversity, identification of species, and zoonosis. J Clin Microbiol 43:348–355. doi:
10.1128/JCM.43.1.348-355.2005
")\]. Several STs of supposed animal origin are zoonotic, with the ability to infect humans at different frequencies. Therefore, a higher risk of _Blastocystis_ infection has been shown in people living in rural areas and/or with close animal contact \[[14](/article/10.1007/s10096-017-2965-0#ref-CR14 "Yoshikawa H, Wu Z, Pandey K, Pandey BD, Sherchand JB, Yanagi T, Kanbara H (2009) Molecular characterization of Blastocystis isolates from children and rhesus monkeys in Kathmandu, Nepal. Vet Parasitol 160:295–300. doi:
10.1016/j.vetpar.2008.11.029
")\]. Phylogenetic trees comparing _Blastocystis_ SSU rDNA sequences have been developed by many researchers in many countries \[[11](/article/10.1007/s10096-017-2965-0#ref-CR11 "Forsell J, Granlund M, Stensvold CR, Clark CG, Evengård B (2012) Subtype analysis of Blastocystis isolates in Swedish patients. Eur J Clin Microbiol Infect Dis 31:1689–1696. doi:
10.1007/s10096-011-1416-6
"), [15](/article/10.1007/s10096-017-2965-0#ref-CR15 "Abe N (2004) Molecular and phylogenetic analysis of Blastocystis isolates from various hosts. Vet Parasitol 120:235–242. doi:
10.1016/j.vetpar.2004.01.003
"), [16](/article/10.1007/s10096-017-2965-0#ref-CR16 "Rivera WL (2008) Phylogenetic analysis of Blastocystis isolates from animal and human hosts in the Philippines. Vet Parasitol 156:178–182. doi:
10.1016/j.vetpar.2008.06.001
")\]. The trees are mostly created using the neighbor-joining method (with the maximum composite likelihood model) based on either complete SSU rRNA genes or the hypervariable region at the 5′-end of the SSU rRNA gene. Relationships among _Blastocystis_ subtypes occurring in humans have been analyzed and groups of STs were named as clades. One clade consists of STs 1, 2, and 5 (the closest relation between ST1 and ST2); another clade consists of STs 3, 4, and 8 (the closest relation between ST3 and ST8). A third clade consists of STs 6, 7, and 9 (where the closest relation is between STs 6 and 9) \[[8](/article/10.1007/s10096-017-2965-0#ref-CR8 "Stensvold CR, Suresh GK, Tan KS, Thompson RC, Traub RJ, Viscogliosi E, Yoshikawa H, Clark CG (2007) Terminology for Blastocystis subtypes—a consensus. Trends Parasitol 23:93–96. doi:
10.1016/j.pt.2007.01.004
"), [11](/article/10.1007/s10096-017-2965-0#ref-CR11 "Forsell J, Granlund M, Stensvold CR, Clark CG, Evengård B (2012) Subtype analysis of Blastocystis isolates in Swedish patients. Eur J Clin Microbiol Infect Dis 31:1689–1696. doi:
10.1007/s10096-011-1416-6
")\].The parasite has been known since the early 1900s [[1](/article/10.1007/s10096-017-2965-0#ref-CR1 "Tan KS (2008) New insights on classification, identification, and clinical relevance of Blastocystis spp. Clin Microbiol Rev 21:639–665. doi: 10.1128/CMR.00022-08
")\], but only in the last decade has the biology and pathogenicity of this parasite undergone more intensive studies. However, the lack of standardization in detection techniques and methods for molecular characterization has led to confusion and misinterpretation of the data. A number of studies suggested a linkage between _Blastocystis_ and gastrointestinal disorders, skin symptoms, and many other problems. Recent epidemiological data demonstrate the association of _Blastocystis_ with a variety of disorders \[[1](/article/10.1007/s10096-017-2965-0#ref-CR1 "Tan KS (2008) New insights on classification, identification, and clinical relevance of Blastocystis spp. Clin Microbiol Rev 21:639–665. doi:
10.1128/CMR.00022-08
"), [17](/article/10.1007/s10096-017-2965-0#ref-CR17 "Roberts T, Stark D, Harkness J, Ellis J (2014) Update on the pathogenic potential and treatment options for Blastocystis sp. Gut Pathog 6:17. doi:
10.1186/1757-4749-6-17
")\], such as diarrhea, abdominal pain, fatigue, constipation, flatulence, chronic gastrointestinal illnesses (irritable bowel syndrome, IBS), and skin rash or urticaria \[[18](/article/10.1007/s10096-017-2965-0#ref-CR18 "Yakoob J, Jafri W, Beg MA, Abbas Z, Naz S, Islam M, Khan R (2010) Irritable bowel syndrome: is it associated with genotypes of Blastocystis hominis. Parasitol Res 106:1033–1038. doi:
10.1007/s00436-010-1761-x
"), [19](/article/10.1007/s10096-017-2965-0#ref-CR19 "Bálint A, Dóczi I, Bereczki L, Gyulai R, Szűcs M, Farkas K, Urbán E, Nagy F, Szepes Z, Wittmann T, Molnár T (2014) Do not forget the stool examination!—cutaneous and gastrointestinal manifestations of Blastocystis sp. infection. Parasitol Res 113:1585–1590. doi:
10.1007/s00436-014-3805-0
")\]. _Blastocystis_ has been found in both patients with gastrointestinal symptoms and asymptomatic individuals \[[20](/article/10.1007/s10096-017-2965-0#ref-CR20 "Tan KSW, Mirza H, Teo JDW, Wu B, Macary PA (2010) Current views on the clinical relevance of Blastocystis spp. Curr Infect Dis Rep 12:28–35. doi:
10.1007/s11908-009-0073-8
"), [21](/article/10.1007/s10096-017-2965-0#ref-CR21 "Scanlan PD, Stensvold CR, Rajilić-Stojanović M, Heilig HG, De Vos WM, O’Toole PW, Cotter PD (2014) The microbial eukaryote Blastocystis is a prevalent and diverse member of the healthy human gut microbiota. FEMS Microbiol Ecol 90:326–330. doi:
10.1111/1574-6941.12396
")\]. According to a number of studies, the life cycle of _Blastocystis_ and its pathogenic aspects are still unclear.Blastocystis infects at least 5–15% of individuals in developed countries and 50–100% of individuals in developing countries [[22](/article/10.1007/s10096-017-2965-0#ref-CR22 "Alfellani MA, Stensvold CR, Vidal-Lapiedra A, Onuoha ES, Fagbenro-Beyioku AF, Clark CG (2013) Variable geographic distribution of Blastocystis subtypes and its potential implications. Acta Trop 16:11–18. doi: 10.1016/j.actatropica.2012.12.011
"), [23](/article/10.1007/s10096-017-2965-0#ref-CR23 "Stensvold CR (2013) Blastocystis: genetic diversity and molecular methods for diagnosis and epidemiology. Trop Parasitol 3:26–34. doi:
10.4103/2229-5070.113896
")\]. The difference can be partly explained by poor hygiene practices and consumption of contaminated water or food in developing countries \[[24](/article/10.1007/s10096-017-2965-0#ref-CR24 "Li LH, Zhou XN, Du ZW, Wang XZ, Wang LB, Jiang JY, Yoshikawa H, Steinmann P, Utzinger J, Wu Z, Chen JX, Chen SH, Zhang L (2007) Molecular epidemiology of human Blastocystis in a village in Yunnan province, China. Parasitol Int 56:281–286. doi:
10.1016/j.parint.2007.06.001
")\]. The fecal–oral route is considered to be the main mode of transmission. Controversy regarding the commensal or pathogenic nature of the infection has not changed for decades. Many case reports and epidemiological and microbiological studies support a pathogenic role of _Blastocystis_ in causing intestinal inflammation and urticarial symptoms \[[25](/article/10.1007/s10096-017-2965-0#ref-CR25 "Chen TL, Chan CC, Chen HP, Fung CP, Lin CP, Chan WL, Liu CY (2003) Clinical characteristics and endoscopic findings associated with Blastocystis hominis in healthy adults. Am J Trop Med Hyg 69:213–216")\], while there are many reports on asymptomatic colonization by _Blastocystis_ \[[26](/article/10.1007/s10096-017-2965-0#ref-CR26 "Raś-Noryńska M, Białkowska J, Sokół R, Piskorz-Ogórek K (2011) Parasitological stool examination from children without the typical symptoms of parasitic disease. Przegl Epidemiol 65:599–603"), [27](/article/10.1007/s10096-017-2965-0#ref-CR27 "Kaneda Y, Horiki N, Cheng X, Tachibana H, Tsutsumi Y (2000) Serologic response to Blastocystis hominis infection in asymptomatic individuals. Tokai J Exp Clin Med 25:51–56")\]. Other aspects, including mode of transmission, pathogenicity, life cycle, and molecular biology, remain largely unclear.The prevalence of Blastocystis infection is higher than that of other intestinal parasites, such as Giardia, Entamoeba, or Cryptosporidium [[4](/article/10.1007/s10096-017-2965-0#ref-CR4 "Wawrzyniak I, Poirier P, Viscogliosi E, Dionigia M, Texier C, Delbac F, Alaoui HE (2013) Blastocystis, an unrecognized parasite: an overview of pathogenesis and diagnosis. Ther Adv Infect Dis 1:167–178. doi: 10.1177/2049936113504754
")\]. In immunocompromised individuals, such as those with human immunodeficiency virus (HIV) infection, the prevalence of _Blastocystis_ is between 30 and 38% in developed countries \[[28](/article/10.1007/s10096-017-2965-0#ref-CR28 "Albrecht H, Stellbrink HJ, Koperski K, Greten H (1995) Blastocystis hominis in human immunodeficiency virus-related diarrhea. Scand J Gastroenterol 30:909–914"), [29](/article/10.1007/s10096-017-2965-0#ref-CR29 "Sanchez-Aguillon F, Lopez-Escamilla E, Velez-Perez F, Martinez-Flores WA, Rodriguez-Zulueta P, Martinez-Ocaña J, Martinez-Hernandez F, Romero-Valdovinos M, Maravilla P (2013) Parasitic infections in a Mexican HIV/AIDS cohort. J Infect Dev Ctries 7:763–766. doi:
10.3855/jidc.3512
")\]. It is suggested that _Blastocystis_ is linked with diarrhea in immunocompromised hosts, such as HIV-infected persons, and nutrition status may be one of the important risk factors associated with co-infections \[[3](/article/10.1007/s10096-017-2965-0#ref-CR3 "Basak S, Rajurkar MN, Mallick SK (2014) Detection of Blastocystis hominis: a controversial human pathogen. Parasitol Res 113:261–265. doi:
10.1007/s00436-013-3652-4
")\]. Children and the elderly appear to be highly susceptible to _Blastocystis_ infection \[[30](/article/10.1007/s10096-017-2965-0#ref-CR30 "Martín-Sánchez AM, Canut-Blasco A, Rodríguez-Hernández J, Montes-Martínez I, García-Rodríguez JA (1992) Epidemiology and clinical significance of Blastocystis hominis in different population groups in Salamanca (Spain). Eur J Epidemiol 8:553–559. doi:
10.1007/BF00146376
"), [31](/article/10.1007/s10096-017-2965-0#ref-CR31 "El Safadi D, Gaayeb L, Meloni D, Cian A, Poirier P, Wawrzyniak I, Delbac F, Dabboussi F, Delhaes L, Seck M, Hamze M, Riveau G, Viscogliosi E (2014) Children of Senegal River Basin show the highest prevalence of Blastocystis sp. ever observed worldwide. BMC Infect Dis 14:164–174. doi:
10.1186/1471-2334-14-164
")\], while other researchers have suggested that people between 30 and 50 years of age are most prone to being infected by _Blastocystis_ \[[32](/article/10.1007/s10096-017-2965-0#ref-CR32 "Doyle PW, Helgason MM, Mathias RG, Proctor EM (1990) Epidemiology and pathogenicity of Blastocystis hominis. J Clin Microbiol 28:116–121")–[34](/article/10.1007/s10096-017-2965-0#ref-CR34 "Zaglool DAM, Khodari YAW, Farooq MU (2012) Blastocystis hominis and allergic skin diseases; a single centre experience. J Health Sci 2:66–69. doi:
10.17532/jhsci.2012.66
")\].Six different morphological forms of the parasite have been reported (vacuolar, granular, amoeboid, avacuolar, multivacuolar, and cystic), with the cyst being the infective stage and the amoeboid form supposedly playing a more active role in the development of clinical manifestations [[35](/article/10.1007/s10096-017-2965-0#ref-CR35 "Tan TC, Suresh KG (2006) Predominance of amoeboid forms of Blastocystis hominis in isolates from symptomatic patients. Parasitol Res 98:189–193. doi: 10.1007/s00436-005-0033-7
")\]. The vacuolar form is most commonly observed in both laboratory culture and stool samples \[[36](/article/10.1007/s10096-017-2965-0#ref-CR36 "Elghareeb AS, Younis MS, El Fakahany AF, Nagaty IM, Nagib MM (2015) Laboratory diagnosis of Blastocystis spp. in diarrheic patients. Trop Parasitol 5(1):36–41. doi:
10.4103/2229-5070.149919
"), [37](/article/10.1007/s10096-017-2965-0#ref-CR37 "Abaza SMM (2000) Blastocystis hominis: update. Review article")\].The life cycle and transmission of the parasite are still under intensive investigation. Two types of reproduction have been described: asexual reproduction by binary fission and sexual reproduction by autogamy to form a primary cyst [[3](/article/10.1007/s10096-017-2965-0#ref-CR3 "Basak S, Rajurkar MN, Mallick SK (2014) Detection of Blastocystis hominis: a controversial human pathogen. Parasitol Res 113:261–265. doi: 10.1007/s00436-013-3652-4
"), [38](/article/10.1007/s10096-017-2965-0#ref-CR38 "Stenzel DJ, Boreham PF, McDougall R (1991) Ultrastructure of Blastocystis hominis in human stool samples. Int J Parasitol 21:807–812. doi:
10.1016/0020-7519(91)90149-2
")\], which is the only transmissible form of _Blastocystis_ \[[39](/article/10.1007/s10096-017-2965-0#ref-CR39 "Yoshikawa H, Wu Z, Kimata I, Iseki M, Ali IK, Hossain MB, Zaman V, Haque R, Takahashi Y (2004) Polymerase chain reaction-based genotype classification among human Blastocystis hominis populations isolated from different countries. Parasitol Res 92:22–29. doi:
10.1007/s00436-003-0995-2
")\]. After getting into the intestinal lumen, the cysts first develop into the vacuolar form. In humans, vacuolar forms divide by binary fission and may develop into amoeboid, multivacuolar, or granular forms, before they become pre-cyst \[[9](/article/10.1007/s10096-017-2965-0#ref-CR9 "Parija SC, Jeremiah S (2013) Blastocystis: taxonomy, biology and virulence. Trop Parasitol 3:17–25. doi:
10.4103/2229-5070.113894
")\]. Vacuolar forms undergo encystation in the host intestine, while intermediate cyst forms may be surrounded by a thick fibrillar layer that is subsequently lost during passage into the external environment to infect other individuals. The pre-cyst may also develop into the thin-wall cyst and lead to autoinfection of the host \[[9](/article/10.1007/s10096-017-2965-0#ref-CR9 "Parija SC, Jeremiah S (2013) Blastocystis: taxonomy, biology and virulence. Trop Parasitol 3:17–25. doi:
10.4103/2229-5070.113894
")\]. Information about the transformation from the amoeboid to the vacuolar form and from the vacuolar to the cyst form is lacking. _Blastocystis_ is a strict anaerobe and a common inhabitant of the human gastrointestinal tract, as well as other mammals. Many reports suggest that humans are potentially infected by five or more subtypes of _Blastocystis_ \[[40](/article/10.1007/s10096-017-2965-0#ref-CR40 "Scicluna SM, Tawari B, Clark CG (2006) DNA barcoding of Blastocystis. Protist 157(1):77–85. doi:
10.1016/j.protis.2005.12.001
")\], and that certain animals represent reservoirs for transmission to humans \[[1](/article/10.1007/s10096-017-2965-0#ref-CR1 "Tan KS (2008) New insights on classification, identification, and clinical relevance of Blastocystis spp. Clin Microbiol Rev 21:639–665. doi:
10.1128/CMR.00022-08
")\].Genetic diversity and pathogenicity of Blastocystis sp.
Based on SSU rDNA analysis, at least 17 different STs of Blastocystis were detected, which colonize a wide range of hosts, including humans and animals, both mammalian and non-mammalian. Some STs exhibit host specificity with variable geographic distribution. There is a high prevalence of ST1 and ST2 in America, ST1 and ST3 in Australia, Europe, and South Eastern Asia, and ST4 in Europe [[8](/article/10.1007/s10096-017-2965-0#ref-CR8 "Stensvold CR, Suresh GK, Tan KS, Thompson RC, Traub RJ, Viscogliosi E, Yoshikawa H, Clark CG (2007) Terminology for Blastocystis subtypes—a consensus. Trends Parasitol 23:93–96. doi: 10.1016/j.pt.2007.01.004
")\]. Humans are colonized mainly by ST1 through ST4, comprising over 90% of reports; however, depending on the regions and countries, infection by ST5 through ST9 is also observed \[[8](/article/10.1007/s10096-017-2965-0#ref-CR8 "Stensvold CR, Suresh GK, Tan KS, Thompson RC, Traub RJ, Viscogliosi E, Yoshikawa H, Clark CG (2007) Terminology for Blastocystis subtypes—a consensus. Trends Parasitol 23:93–96. doi:
10.1016/j.pt.2007.01.004
"), [41](/article/10.1007/s10096-017-2965-0#ref-CR41 "Parkar U, Traub RJ, Vitali S, Elliot A, Levecke B, Robertson I, Geurden T, Steele J, Drake B, Thompson RC (2010) Molecular characterization of Blastocystis isolates from zoo animals and their animal-keepers. Vet Parasitol 169:8–17. doi:
10.1016/j.vetpar.2009.12.032
")\]. To date, ST10 through ST17 have not been found in humans \[[11](/article/10.1007/s10096-017-2965-0#ref-CR11 "Forsell J, Granlund M, Stensvold CR, Clark CG, Evengård B (2012) Subtype analysis of Blastocystis isolates in Swedish patients. Eur J Clin Microbiol Infect Dis 31:1689–1696. doi:
10.1007/s10096-011-1416-6
"), [41](/article/10.1007/s10096-017-2965-0#ref-CR41 "Parkar U, Traub RJ, Vitali S, Elliot A, Levecke B, Robertson I, Geurden T, Steele J, Drake B, Thompson RC (2010) Molecular characterization of Blastocystis isolates from zoo animals and their animal-keepers. Vet Parasitol 169:8–17. doi:
10.1016/j.vetpar.2009.12.032
")\], with the exception of research by Ramírez et al. \[[42](/article/10.1007/s10096-017-2965-0#ref-CR42 "Ramírez JD, Sánchez A, Hernández C, Flórez C, Bernal MC, Giraldo JC, Reyes P, López MC, García L, Cooper PJ, Vicuña Y, Mongi F, Casero RD (2016) Geographic distribution of human Blastocystis subtypes in South America. Infect Genet Evol 41:32–35. doi:
10.1016/j.meegid.2016.03.017
")\] in 2016, who reported, for the first time, human infection with ST12\. Gender differences in the prevalence of _Blastocystis_ STs have been reported. In Sweden, for instance, ST3 was found to be more common in males than in females, while in females, ST4 was almost as common as ST3\. However, the difference in the relative frequency of ST4 between men and women was statistically insignificant \[[43](/article/10.1007/s10096-017-2965-0#ref-CR43 "Clark CG (1997) Extensive genetic diversity in Blastocystis hominis. Mol Biochem Parasitol 87:79–83. doi:
10.1016/S0166-6851(97)00046-7
")\].In the recent literature, researchers have been debating over the correlation between distinct Blastocystis subtypes and their pathogenic potential. Clark was the first to suggest that different subtypes with different pathological potentials may exist [[43](/article/10.1007/s10096-017-2965-0#ref-CR43 "Clark CG (1997) Extensive genetic diversity in Blastocystis hominis. Mol Biochem Parasitol 87:79–83. doi: 10.1016/S0166-6851(97)00046-7
")\]. With respect to that fact, in 2000, Kaneda et al. \[[27](/article/10.1007/s10096-017-2965-0#ref-CR27 "Kaneda Y, Horiki N, Cheng X, Tachibana H, Tsutsumi Y (2000) Serologic response to Blastocystis hominis infection in asymptomatic individuals. Tokai J Exp Clin Med 25:51–56")\] suggested that STs 1, 2, and 4 might be responsible for gastrointestinal symptoms. In 2012, Poirier et al. \[[44](/article/10.1007/s10096-017-2965-0#ref-CR44 "Poirier P, Wawrzyniak I, Vivarès CP, Delbac F, El Alaoui H (2012) New insights into Blastocystis spp.: a potential link with irritable bowel syndrome. PLoS Pathog 8, e1002545. doi:
10.1371/journal.ppat.1002545
")\] indicated that ST7 is correlated with IBS. Puthia et al. \[[45](/article/10.1007/s10096-017-2965-0#ref-CR45 "Puthia MK, Lu J, Tan KSW (2008) Blastocystis ratti contains cysteine proteases that mediate interleukin-8 response from human intestinal epithelial cells In an NF-kappaB-dependent manner. Eukaryot Cell 7:435–443. doi:
10.1128/EC.00371-07
")\] have shown that, in rat epithelial cells, ST4 can induce apoptosis in a contact-independent manner to increase epithelial permeability. ST7 likely uses hydrolases to attack host tissues for its nutrient supply \[[44](/article/10.1007/s10096-017-2965-0#ref-CR44 "Poirier P, Wawrzyniak I, Vivarès CP, Delbac F, El Alaoui H (2012) New insights into Blastocystis spp.: a potential link with irritable bowel syndrome. PLoS Pathog 8, e1002545. doi:
10.1371/journal.ppat.1002545
")\]. In 2006, Yan et al. \[[46](/article/10.1007/s10096-017-2965-0#ref-CR46 "Yan Y, Su S, Lai R, Liao H, Ye J, Li X, Luo X, Chen G (2006) Genetic variability of Blastocystis hominis isolates in China. Parasitol Res 99:597–601. doi:
10.1007/s00436-006-0186-z
")\] demonstrated only ST1 in a group of symptomatic patients, which was later confirmed by El Safadi et al. \[[47](/article/10.1007/s10096-017-2965-0#ref-CR47 "El Safadi D, Meloni D, Poirier P, Osman M, Cian A, Gaayeb L, Wawrzyniak I, Delbac F, El Alaoui H, Delhaes L, Dei-Cas E, Mallat H, Dabboussi F, Hamze M, Viscogliosi E (2013) Molecular epidemiology of Blastocystis in Lebanon and correlation between subtype 1 and gastrointestinal symptoms. Am J Trop Med Hyg 88:1203–1206. doi:
10.4269/ajtmh.12-0777
")\] in 2013, demonstrating that ST1 was associated with an elevated pathogenicity. The pathogenicity of ST4 was also hypothesized by Stensvold et al. \[[48](/article/10.1007/s10096-017-2965-0#ref-CR48 "Stensvold CR, Christiansen DB, Olsen KE, Nielsen HV (2011) Blastocystis sp. subtype 4 is common in Danish Blastocystis-positive patients presenting with acute diarrhea. Am J Trop Med Hyg 84:883–885. doi:
10.4269/ajtmh.2011.11-0005
")\] in a short report in 2011\. The explanations for pathogenicity may include intra-subtype differences in _Blastocystis_ protease activity, variations in intestinal microbiota of the individual host, and a symbiotic role for viruses associated with _Blastocystis_, which can interact to mediate host colonization and _Blastocystis_ virulence \[[49](/article/10.1007/s10096-017-2965-0#ref-CR49 "Abdel-Hameed DM, Hassanin OM (2011) Proteaese activity of Blastocystis hominis subtype3 in symptomatic and asymptomatic patients. Parasitol Res 109:321–327. doi:
10.1007/s00436-011-2259-x
"), [50](/article/10.1007/s10096-017-2965-0#ref-CR50 "Teow WL, Ho LC, Ng GC, Chan YC, Yap EH, Chan PP, Howe J, Zaman V, Singh M (1992) Virus-like particles in a Blastocystis species from the sea-snake, Lapemis hardwickii. Int J Parasitol 22:1029–1032. doi:
10.1016/0020-7519(92)90065-S
")\]. Also, the presence of gut microbiota seems to be essential for the pathogenic expression of enteric protozoan such as _Blastocystis_. The hypothesis of protozoa axenization by some bacteria has been proposed \[[51](/article/10.1007/s10096-017-2965-0#ref-CR51 "Berrilli F, Di Cave D, Cavallero S, D’Amelio S (2012) Interactions between parasites and microbial communities in the human gut. Front Cell Infect Microbiol 2:141. doi:
10.3389/fcimb.2012.00141
")\]. The cysteine proteases produced by ST4 and ST7 were revealed to be able to cleave human IgA in vitro \[[52](/article/10.1007/s10096-017-2965-0#ref-CR52 "Mirza H, Tan KSW (2009) Blastocystis exhibits inter- and intra-subtype variation in cysteine protease activity. Parasitol Res 104:355–361. doi:
10.1007/s00436-008-1203-1
"), [53](/article/10.1007/s10096-017-2965-0#ref-CR53 "Puthia MK, Vaithilingam A, Lu J, Tan KSW (2005) Degradation of human secretory immunoglobulin A by Blastocystis. Parasitol Res 97:386–389. doi:
10.1007/s00436-005-1461-0
")\], as a mechanism for parasite survival and colonization in the gut, immune evasion, virulence, and cell cycle regulation \[[53](/article/10.1007/s10096-017-2965-0#ref-CR53 "Puthia MK, Vaithilingam A, Lu J, Tan KSW (2005) Degradation of human secretory immunoglobulin A by Blastocystis. Parasitol Res 97:386–389. doi:
10.1007/s00436-005-1461-0
")\]. Enzymes can also modulate inflammatory IL-8 production, as well as cathepsin B activation \[[54](/article/10.1007/s10096-017-2965-0#ref-CR54 "Nourrisson C, Wawrzyniak I, Cian A, Livrelli V, Viscogliosi E, Delbac F, Poirier P (2016) On Blastocystis secreted cysteine proteases: a legumain-activated cathepsin B increases paracellular permeability of intestinal Caco-2 cell monolayers. Parasitology 146(13):1713–1722. doi:
10.1017/S0031182016001396
")\], and are able to increase the permeability of intestinal epithelial cells \[[45](/article/10.1007/s10096-017-2965-0#ref-CR45 "Puthia MK, Lu J, Tan KSW (2008) Blastocystis ratti contains cysteine proteases that mediate interleukin-8 response from human intestinal epithelial cells In an NF-kappaB-dependent manner. Eukaryot Cell 7:435–443. doi:
10.1128/EC.00371-07
"), [55](/article/10.1007/s10096-017-2965-0#ref-CR55 "Wawrzyniak I, Texier C, Poirier P, Viscogliosi E, Tan KS, Delbac F, El Alaoui H (2012) Characterization of two cysteine proteases secreted by Blastocystis ST7, a human intestinal parasite. Parasitol Int 61:437–442. doi:
10.1016/j.parint.2012.02.007
")\].In contrast, several studies showed no distinct differences in STs between isolates from symptomatic and asymptomatic groups of individuals with gastrointestinal disorders [[39](/article/10.1007/s10096-017-2965-0#ref-CR39 "Yoshikawa H, Wu Z, Kimata I, Iseki M, Ali IK, Hossain MB, Zaman V, Haque R, Takahashi Y (2004) Polymerase chain reaction-based genotype classification among human Blastocystis hominis populations isolated from different countries. Parasitol Res 92:22–29. doi: 10.1007/s00436-003-0995-2
")\]. In addition to unspecific gastrointestinal symptoms, an association between the parasite subtypes and certain cutaneous disorders have been observed \[[56](/article/10.1007/s10096-017-2965-0#ref-CR56 "Hameed DM, Hassanin OM, Zuel-Fakkar NM (2011) Association of Blastocystis hominis genetic subtypes with urticaria. Parasitol Res 108:553–560. doi:
10.1007/s00436-010-2097-2
")–[59](/article/10.1007/s10096-017-2965-0#ref-CR59 "Verma R, Delfanian K (2013) Blastocystis hominis associated acute urticaria. Am J Med Sci 346:80–81. doi:
10.1097/MAJ.0b013e3182801478
")\], such as the presence of _Blastocystis_ ST2 \[[57](/article/10.1007/s10096-017-2965-0#ref-CR57 "Vogelberg C, Stensvold CR, Monecke S, Ditzen A, Stopsack K, Heinrich-Gräfe U, Pöhlmann C (2010) Blastocystis sp. subtype 2 detection during recurrence of gastrointestinal and urticarial symptoms. Parasitol Int 59:469–471. doi:
10.1016/j.parint.2010.03.009
")\], ST3 especially the amoeboid form, or ST4 in patients with acute or chronic urticaria (CU) \[[56](/article/10.1007/s10096-017-2965-0#ref-CR56 "Hameed DM, Hassanin OM, Zuel-Fakkar NM (2011) Association of Blastocystis hominis genetic subtypes with urticaria. Parasitol Res 108:553–560. doi:
10.1007/s00436-010-2097-2
"), [58](/article/10.1007/s10096-017-2965-0#ref-CR58 "Zuel-Fakkar NM, Abdel Hameed DM, Hassanin OM (2011) Study of Blastocystis hominis isolates in urticaria: a case–control study. Clin Exp Dermatol 38:908–910. doi:
10.1111/j.1365-2230.2011.04127.x
"), [60](/article/10.1007/s10096-017-2965-0#ref-CR60 "Katsarou-Katsari A, Vassalos CM, Tzanetou K, Spanakos G, Papadopoulou C, Vakalis N (2008) Acute urticaria associated with amoeboid forms of Blastocystis sp. subtype 3. Acta Derm Venereol 88:80–81. doi:
10.2340/00015555-0338
")–[62](/article/10.1007/s10096-017-2965-0#ref-CR62 "Vassalos CM, Spanakos G, Vassalou E, Papadopoulou C, Vakalis N (2010) Differences in clinical significance and morphologic features of Blastocystis sp subtype 3. Am J Clin Pathol 133:251–258. doi:
10.1309/AJCPDOWQSL6E8DMN
")\]. Oxidative stress is probably is another reason why certain _Blastocystis_ subtypes are more virulent. It is reported that _Blastocystis_ infection correlates with a significant oxidative burst, leading to oxidative stress \[[63](/article/10.1007/s10096-017-2965-0#ref-CR63 "Chandramathi S, Suresh K, Shuba S, Mahmood A, Kuppusamy UR (2010) High levels of oxidative stress in rats infected with Blastocystis hominis. Parasitology 137:605–611. doi:
10.1017/S0031182009991351
")\]. Some subtypes may induce higher concentrations of oxidative stress and precipitate skin reactions such as urticaria. A recent study showed that live _Blastocystis_ parasites and whole cell lysate alone did not activate toll-like receptors in the human TLR reporter monocytic cell line, while live ST4-WR1 parasites inhibited the LPS-mediated NF-κB activation. In contrast, whole cell lysates of ST7-B and ST4-WR1 induced pleiotropic modulation of ligand-specific TLR-2 and TLR-4 activation, with a compounding effect of ST7-B on LPS-mediated NF-κB activation \[[63](/article/10.1007/s10096-017-2965-0#ref-CR63 "Chandramathi S, Suresh K, Shuba S, Mahmood A, Kuppusamy UR (2010) High levels of oxidative stress in rats infected with Blastocystis hominis. Parasitology 137:605–611. doi:
10.1017/S0031182009991351
")\]. A higher caspase-like activity of _Blastocystis_ spp. ST3 was found in isolates from individuals who had gastrointestinal symptoms \[[65](/article/10.1007/s10096-017-2965-0#ref-CR65 "Balakrishnan DD, Kumar SG (2014) Higher Caspase-like activity in symptomatic isolates of Blastocystis spp. Parasit Vectors 7:219. doi:
10.1186/1756-3305-7-219
")\].The human gut microbiota: current knowledge
The human microbiota is made up of different microbial communities present in different parts of the human body, such as the skin, vagina, oro-nasal cavity, esophagus, and gastrointestinal (GI) tract [[66](/article/10.1007/s10096-017-2965-0#ref-CR66 "Dave M, Higgins PD, Middha S, Rioux KP (2012) The human gut microbiome: current knowledge, challenges, and future directions. Transl Res 160(4):246–257. doi: 10.1016/j.trsl.2012.05.003
")\]. The human body is composed of about 1013 cells \[[67](/article/10.1007/s10096-017-2965-0#ref-CR67 "Savage DC (1977) Microbial ecology of the gastrointestinal tract. Annu Rev Microbiol 31:107–133. doi:
10.1146/annurev.mi.31.100177.000543
")\]. There are about ten times this number of microbial cells associated with the healthy human body \[[67](/article/10.1007/s10096-017-2965-0#ref-CR67 "Savage DC (1977) Microbial ecology of the gastrointestinal tract. Annu Rev Microbiol 31:107–133. doi:
10.1146/annurev.mi.31.100177.000543
")\]. These microbes interact with their host and have an impact on human health. The human GI microbiota is mostly concentrated in the colon and is made up of a majority of bacteria, a few archaea, known as the microbiome, viruses (the virome), fungi, and other uni- and multicellular eukaryotes, called protists and helminths, respectively \[[5](/article/10.1007/s10096-017-2965-0#ref-CR5 "Lukeš J, Stensvold CR, Jirků-Pomajbíková K, Wegener Parfrey L (2015) Are human intestinal eukaryotes beneficial or commensals? PLoS Pathog 11(8), e1005039. doi:
10.1371/journal.ppat.1005039
"), [68](/article/10.1007/s10096-017-2965-0#ref-CR68 "Rajilić-Stojanović M, de Vos WM (2014) The first 1000 cultured species of the human gastrointestinal microbiota. FEMS Microbiol Rev 38:996–1047. doi:
10.1111/1574-6976.12075
")\]. Only 30% of the human GI microbiota have been characterized \[[69](/article/10.1007/s10096-017-2965-0#ref-CR69 "Lagier JC, Armougom F, Million M, Hugon P, Pagnier I, Robert C, Bittar F, Fournous G, Gimenez G, Maraninchi M, Trape JF, Koonin EV, La Scola B, Raoult D (2012) Microbial culturomics: paradigm shift in the human gut microbiome study. Clin Microbiol Infect 18(12):1185–1193. doi:
10.1111/1469-0691.12023
")\]. It is difficult to describe the actual meaning of “normal” or “healthy” human GI microbiota. A “core microbiota” has been established \[[70](/article/10.1007/s10096-017-2965-0#ref-CR70 "Turnbaugh PJ, Ridaura VK, Faith JJ, Rey FE, Knight R, Gordon JI (2009) The effect of diet on the human gut microbiome: a metagenomic analysis in humanized gnotobiotic mice. Sci Transl Med 1(6):6ra14. doi:
10.1126/scitranslmed.3000322
")\], but it remains unclear what the essential constituents are. A number of studies have emphasized that the distribution of specific microbial communities among individuals could be influenced by several factors, including the geographical origin, age, diet of the studied individual, gender \[[71](/article/10.1007/s10096-017-2965-0#ref-CR71 "Mueller S, Saunier K, Hanisch C, Norin E, Alm L, Midtvedt T, Cresci A, Silvi S, Orpianesi C, Verdenelli MC, Clavel T, Koebnick C, Zunft HJ, Doré J, Blaut M (2006) Differences in fecal microbiota in different European study populations in relation to age, gender, and country: a cross-sectional study. Appl Environ Microbiol 72(2):1027–1033. doi:
10.1128/AEM.72.2.1027-1033.2006
")\], stress, smoking, GI infections, as well as antibiotic or probiotic uptake \[[70](/article/10.1007/s10096-017-2965-0#ref-CR70 "Turnbaugh PJ, Ridaura VK, Faith JJ, Rey FE, Knight R, Gordon JI (2009) The effect of diet on the human gut microbiome: a metagenomic analysis in humanized gnotobiotic mice. Sci Transl Med 1(6):6ra14. doi:
10.1126/scitranslmed.3000322
"), [72](/article/10.1007/s10096-017-2965-0#ref-CR72 "Eckburg PB, Bik EM, Bernstein CN, Purdom E, Dethlefsen L, Sargent M, Gill SR, Nelson KE, Relman DA (2005) Diversity of the human intestinal microbial flora. Science 308(5728):1635–1638. doi:
10.1126/science.1110591
")–[78](/article/10.1007/s10096-017-2965-0#ref-CR78 "Ukhanova M, Culpepper T, Baer D, Gordon D, Kanahori S, Valentine J, Neu J, Sun Y, Wang X, Mai V (2012) Gut microbiota correlates with energy gain from dietary fibre and appears to be associated with acute and chronic intestinal diseases. Clin Microbiol Infect 18(Suppl 4):62–66. doi:
10.1111/j.1469-0691.2012.03859.x
")\]. It is believed that the highly evolved biofilm communities that are closely associated with the intestinal epithelium are biologically more relevant than planktonic microbes that exist in the lumen of the gut or associated with food residue \[[79](/article/10.1007/s10096-017-2965-0#ref-CR79 "Walker AW, Duncan SH, Harmsen HJ, Holtrop G, Welling GW, Flint HJ (2008) The species composition of the human intestinal microbiota differs between particle-associated and liquid phase communities. Environ Microbiol 10(2):3275–3283. doi:
10.1111/j.1462-2920.2008.01717.x
")\]. Furthermore, fecal specimens may not accurately portray the mucosal microbiota \[[72](/article/10.1007/s10096-017-2965-0#ref-CR72 "Eckburg PB, Bik EM, Bernstein CN, Purdom E, Dethlefsen L, Sargent M, Gill SR, Nelson KE, Relman DA (2005) Diversity of the human intestinal microbial flora. Science 308(5728):1635–1638. doi:
10.1126/science.1110591
"), [80](/article/10.1007/s10096-017-2965-0#ref-CR80 "Gillevet P, Sikaroodi M, Keshavarzian A, Mutlu EA (2010) Quantitative assessment of the human gut microbiome using multitag pyrosequencing. Chem Biodivers 7(5):1065–1075. doi:
10.1002/cbdv.200900322
")\]. And, also, there are significant differences between the microbiota of the liquid fraction compared with that associated with the solid phase \[[79](/article/10.1007/s10096-017-2965-0#ref-CR79 "Walker AW, Duncan SH, Harmsen HJ, Holtrop G, Welling GW, Flint HJ (2008) The species composition of the human intestinal microbiota differs between particle-associated and liquid phase communities. Environ Microbiol 10(2):3275–3283. doi:
10.1111/j.1462-2920.2008.01717.x
")\].The gut microbiota is typically dominated by bacteria and specifically by members of the divisions Bacteroidetes and Firmicutes [[81](/article/10.1007/s10096-017-2965-0#ref-CR81 "Turnbaugh PJ, Ley RE, Mahowald MA, Magrini V, Mardis ER, Gordon JI (2006) An obesity-associated gut microbiome with increased capacity for energy harvest. Nature 444(7122):1027–1031. doi: 10.1038/nature05414
")\]. From stomach to colon, the bacterial biomass ranges from 102–3 to 1011–12 cells/mL \[[82](/article/10.1007/s10096-017-2965-0#ref-CR82 "Walter J, Ley R (2011) The human gut microbiome: ecology and recent evolutionary changes. Ann Rev Microbiol 65:411–429. doi:
10.1146/annurev-micro-090110-102830
")\]. Ninety-five percent of them are anaerobic bacteria and at least 1000 different species have been listed to date \[[83](/article/10.1007/s10096-017-2965-0#ref-CR83 "Sankar SA, Lagier JC, Pontarotti P, Raoult D, Fournier PE (2015) The human gut microbiome, a taxonomic conundrum. Syst Appl Microbiol 38(4):276–286. doi:
10.1016/j.syapm.2015.03.004
")\]. The most frequently detected in the human gut are the phyla of the Firmicutes, Bacteroidetes, Actinobacteria, Cyanobacteria, Fusobacteria, Proteobacteria, and Verrucomicrobia \[[84](/article/10.1007/s10096-017-2965-0#ref-CR84 "Prakash S, Rodes L, Coussa-Charley M, Tomaro-Duchesneau C (2011) Gut microbiota: next frontier in understanding human health and development of biotherapeutics. Biologics 5:71–86. doi:
10.2147/BTT.S19099
")\]. Knowledge concerning bacterial communities far outpaces that of the viral and eukaryotic communities \[[85](/article/10.1007/s10096-017-2965-0#ref-CR85 "Clemente JC, Ursell LK, Parfrey LW, Knight R (2012) The impact of the gut microbiota on human health: an integrative view. Cell 148:1258–1270. doi:
10.1016/j.cell.2012.01.035
")\]. The observed ratio of 7–10 viral-like particles per microbial cell in environmental \[[86](/article/10.1007/s10096-017-2965-0#ref-CR86 "Rohwer F (2003) Global phage diversity. Cell 113(2):141. doi:
10.1016/S0092-8674(03)00276-9
")\] human samples \[[87](/article/10.1007/s10096-017-2965-0#ref-CR87 "Furlan M (2009) Viral and microbial dynamics in the human respiratory tract. Biology. San Diego State University")\] means that we could expect to find as many as 1015 phages in the body, with the gut having the highest abundance of viruses, 3 × 1012 \[[88](/article/10.1007/s10096-017-2965-0#ref-CR88 "Haynes M, Rohwer F (2011) The human virome. In: Nelson KE (ed) Metagenomics of the human body. Springer, New York, pp 63–77")\]. The diversity of the human virome is low. It is estimated that there are 1500 viral genotypes in a typical healthy, human virome \[[88](/article/10.1007/s10096-017-2965-0#ref-CR88 "Haynes M, Rohwer F (2011) The human virome. In: Nelson KE (ed) Metagenomics of the human body. Springer, New York, pp 63–77")\]. Studies of the viral community in the human gut showed Caudovirales to be prevalent \[[89](/article/10.1007/s10096-017-2965-0#ref-CR89 "Letarov A, Kulikov E (2009) The bacteriophages in human- and animal body-associated microbial communities. J Appl Microbiol 107:1–13. doi:
10.1111/j.1365-2672.2009.04143.x
")\]: Siphoviridae, Myoviridae, Podoviridae, Microviridae \[[90](/article/10.1007/s10096-017-2965-0#ref-CR90 "Reyes A, Haynes M, Hanson N, Angly FE, Heath AC, Rohwer F, Gordon JI (2010) Viruses in the faecal microbiota of monozygotic twins and their mothers. Nature 466:334–338. doi:
10.1038/nature09199
"), [91](/article/10.1007/s10096-017-2965-0#ref-CR91 "Kim MS, Park EJ, Roh SW, Bae JW (2011) Diversity and abundance of single-stranded DNA viruses in human feces. Appl Environ Microbiol 77:8062–8070. doi:
10.1128/AEM.06331-11
")\]. Eukaryotes that reside in the human gut are distributed across the eukaryotic tree and their relationship with the human host varies from parasitic to opportunistic to commensal to mutualistic \[[92](/article/10.1007/s10096-017-2965-0#ref-CR92 "Parfrey LW, Walters WA, Knight R (2011) Microbial eukaryotes in the human microbiome: ecology, evolution, and future directions. Front Microbiol 2:153. doi:
10.3389/fmicb.2011.00153
")\]. It has been known that yeasts constitute part of the intestinal flora: _Candida_ spp. (_C. parapsilosis_, _C. albicans_, _C. glabrata_, _C. krusei_, _C. tropicalis_) or _Saccharomyces boulardii_ \[[92](/article/10.1007/s10096-017-2965-0#ref-CR92 "Parfrey LW, Walters WA, Knight R (2011) Microbial eukaryotes in the human microbiome: ecology, evolution, and future directions. Front Microbiol 2:153. doi:
10.3389/fmicb.2011.00153
"), [93](/article/10.1007/s10096-017-2965-0#ref-CR93 "Andersen LO, Vedel Nielsen H, Stensvold CR (2013) Waiting for the human intestinal eukaryotome. ISME J 7:1253–1255. doi:
10.1038/ismej.2013.21
")\]. Diverse eukaryotes inhabit the human gut, including protists and helminths \[[92](/article/10.1007/s10096-017-2965-0#ref-CR92 "Parfrey LW, Walters WA, Knight R (2011) Microbial eukaryotes in the human microbiome: ecology, evolution, and future directions. Front Microbiol 2:153. doi:
10.3389/fmicb.2011.00153
")\]. Many species of protists are commensals and harmless, including _Pentatrichomonas_ and _Entamoeba dispar_ \[[94](/article/10.1007/s10096-017-2965-0#ref-CR94 "Bogitsh BJ, Carter CE, Oeltmann TN (2005) Human parasitology. Elsevier, Amsterdam")\]. Interestingly, available data suggest that many common eukaryotic residents are commensals, but are, in some cases, associated with gastrointestinal disorders \[[5](/article/10.1007/s10096-017-2965-0#ref-CR5 "Lukeš J, Stensvold CR, Jirků-Pomajbíková K, Wegener Parfrey L (2015) Are human intestinal eukaryotes beneficial or commensals? PLoS Pathog 11(8), e1005039. doi:
10.1371/journal.ppat.1005039
")\]. Good examples are _Blastocystis_ sp. or _Dientamoeba fragilis_ \[[5](/article/10.1007/s10096-017-2965-0#ref-CR5 "Lukeš J, Stensvold CR, Jirků-Pomajbíková K, Wegener Parfrey L (2015) Are human intestinal eukaryotes beneficial or commensals? PLoS Pathog 11(8), e1005039. doi:
10.1371/journal.ppat.1005039
"), [95](/article/10.1007/s10096-017-2965-0#ref-CR95 "Barratt JL, Harkness J, Marriott D, Ellis JT, Stark D (2011) A review of Dientamoeba fragilis carriage in humans: Several reasons why this organism should be considered in the diagnosis of gastrointestinal illness. Gut Microbes 2:3–12. doi:
10.4161/gmic.2.1.14755
")\]. Other representative protists that are part of the human gut eukaryome include: _Enteromonas hominis_, _Retortamonas intestinalis_, _Chilomastix mesnili_, _Entamoeba hartmanni_, _Entamoeba nana_, _Entamoeba coli_, _Isospora belli_, _Iodamoeba buetschi_ and _Encephalitozoon cuniculi_ \[[5](/article/10.1007/s10096-017-2965-0#ref-CR5 "Lukeš J, Stensvold CR, Jirků-Pomajbíková K, Wegener Parfrey L (2015) Are human intestinal eukaryotes beneficial or commensals? PLoS Pathog 11(8), e1005039. doi:
10.1371/journal.ppat.1005039
")\]. Pathogenicity is certainly the role for some intestinal protists, such as _Cryptosporidium_ spp., _Entamoeba histolytica_ or _Giardia intestinalis_ \[[92](/article/10.1007/s10096-017-2965-0#ref-CR92 "Parfrey LW, Walters WA, Knight R (2011) Microbial eukaryotes in the human microbiome: ecology, evolution, and future directions. Front Microbiol 2:153. doi:
10.3389/fmicb.2011.00153
")\], as well as for some helminths, such as _Ascaris lumbricoides_ and _Strongyloides stercoralis_ \[[5](/article/10.1007/s10096-017-2965-0#ref-CR5 "Lukeš J, Stensvold CR, Jirků-Pomajbíková K, Wegener Parfrey L (2015) Are human intestinal eukaryotes beneficial or commensals? PLoS Pathog 11(8), e1005039. doi:
10.1371/journal.ppat.1005039
")\].The role of Blastocystis in the human gut: bad and good sites
Blastocystis was first described more than 100 years ago, but there are still many obscurities about its clinical significance. It may colonize the bowels and is commonly isolated in individuals with neither gastrointestinal complaints nor symptoms [[19](/article/10.1007/s10096-017-2965-0#ref-CR19 "Bálint A, Dóczi I, Bereczki L, Gyulai R, Szűcs M, Farkas K, Urbán E, Nagy F, Szepes Z, Wittmann T, Molnár T (2014) Do not forget the stool examination!—cutaneous and gastrointestinal manifestations of Blastocystis sp. infection. Parasitol Res 113:1585–1590. doi: 10.1007/s00436-014-3805-0
"), [47](/article/10.1007/s10096-017-2965-0#ref-CR47 "El Safadi D, Meloni D, Poirier P, Osman M, Cian A, Gaayeb L, Wawrzyniak I, Delbac F, El Alaoui H, Delhaes L, Dei-Cas E, Mallat H, Dabboussi F, Hamze M, Viscogliosi E (2013) Molecular epidemiology of Blastocystis in Lebanon and correlation between subtype 1 and gastrointestinal symptoms. Am J Trop Med Hyg 88:1203–1206. doi:
10.4269/ajtmh.12-0777
")\]. However, _Blastocystis_ was also identified as the only causative agent of gastrointestinal or dermatological symptoms, such as abdominal pain, diarrhea, nausea, vomiting, bloating, anorexia, or, less commonly, urticaria, intense itching \[[56](/article/10.1007/s10096-017-2965-0#ref-CR56 "Hameed DM, Hassanin OM, Zuel-Fakkar NM (2011) Association of Blastocystis hominis genetic subtypes with urticaria. Parasitol Res 108:553–560. doi:
10.1007/s00436-010-2097-2
"), [57](/article/10.1007/s10096-017-2965-0#ref-CR57 "Vogelberg C, Stensvold CR, Monecke S, Ditzen A, Stopsack K, Heinrich-Gräfe U, Pöhlmann C (2010) Blastocystis sp. subtype 2 detection during recurrence of gastrointestinal and urticarial symptoms. Parasitol Int 59:469–471. doi:
10.1016/j.parint.2010.03.009
")\], or iron deficiency anemia \[[96](/article/10.1007/s10096-017-2965-0#ref-CR96 "Yavasoglu I, Kadikoylu G, Uysal H, Ertug S, Bolaman Z (2008) Is Blastocystis hominis a new etiologic factor or a coincidence in iron deficiency anemia? Eur J Haematol 8(1):47–50. doi:
10.1111/j.1600-0609.2008.01080.x
")–[98](/article/10.1007/s10096-017-2965-0#ref-CR98 "El Deeb HK, Khodeer S (2013) Blastocystis spp.: frequency and subtype distribution in iron deficiency anemic versus non-anemic subjects from Egypt. J Parasitol 99(4):599–602. doi:
10.1645/12-80.1
")\].As mentioned above, there can be several explanations for Blastocystis pathogenicity. It may depend on the Blastocystis subtype: different subtypes can excrete protease enzymes which are able to take part in the induction of virulence [[49](/article/10.1007/s10096-017-2965-0#ref-CR49 "Abdel-Hameed DM, Hassanin OM (2011) Proteaese activity of Blastocystis hominis subtype3 in symptomatic and asymptomatic patients. Parasitol Res 109:321–327. doi: 10.1007/s00436-011-2259-x
"), [99](/article/10.1007/s10096-017-2965-0#ref-CR99 "Scanlan PD, Stensvold CR (2013) Blastocystis: getting to grips with our guileful guest. Trends Parasitol 29(11):523–529. doi:
10.1016/j.pt.2013.08.006
"), [100](/article/10.1007/s10096-017-2965-0#ref-CR100 "Kurt Ö, Doğruman Al F, Tanyüksel M (2016) Eradication of Blastocystis in humans: Really necessary for all? Parasitol Int 65:797–801. doi:
10.1016/j.parint.2016.01.010
")\]. Most _Blastocystis_ isolates found in stool samples are in cyst or vacuolar forms. The amoeboid form is rarely seen, but is mostly associated with symptoms \[[3](/article/10.1007/s10096-017-2965-0#ref-CR3 "Basak S, Rajurkar MN, Mallick SK (2014) Detection of Blastocystis hominis: a controversial human pathogen. Parasitol Res 113:261–265. doi:
10.1007/s00436-013-3652-4
")\]. Therefore, amoeboid forms of _Blastocystis_ are probably pathogenic. A large number of the parasites in the intestine (>5 parasites per high-power field) are also connected with gastrointestinal symptoms \[[1](/article/10.1007/s10096-017-2965-0#ref-CR1 "Tan KS (2008) New insights on classification, identification, and clinical relevance of Blastocystis spp. Clin Microbiol Rev 21:639–665. doi:
10.1128/CMR.00022-08
")\]. Human gut microbiota composition and the immune system are also deciding agents in the pathogenicity and occurrence of the parasite. In immunocompromised individuals, such as those with HIV infection, the prevalence reaches 38% in developed countries \[[28](/article/10.1007/s10096-017-2965-0#ref-CR28 "Albrecht H, Stellbrink HJ, Koperski K, Greten H (1995) Blastocystis hominis in human immunodeficiency virus-related diarrhea. Scand J Gastroenterol 30:909–914")\], and an association with diarrhea is suggested. The nutritional status of an individual may be one of the most important risk factors for co-infection \[[3](/article/10.1007/s10096-017-2965-0#ref-CR3 "Basak S, Rajurkar MN, Mallick SK (2014) Detection of Blastocystis hominis: a controversial human pathogen. Parasitol Res 113:261–265. doi:
10.1007/s00436-013-3652-4
")\]. Children and the elderly are highly susceptible to _Blastocystis_ infection \[[20](/article/10.1007/s10096-017-2965-0#ref-CR20 "Tan KSW, Mirza H, Teo JDW, Wu B, Macary PA (2010) Current views on the clinical relevance of Blastocystis spp. Curr Infect Dis Rep 12:28–35. doi:
10.1007/s11908-009-0073-8
"), [31](/article/10.1007/s10096-017-2965-0#ref-CR31 "El Safadi D, Gaayeb L, Meloni D, Cian A, Poirier P, Wawrzyniak I, Delbac F, Dabboussi F, Delhaes L, Seck M, Hamze M, Riveau G, Viscogliosi E (2014) Children of Senegal River Basin show the highest prevalence of Blastocystis sp. ever observed worldwide. BMC Infect Dis 14:164–174. doi:
10.1186/1471-2334-14-164
")\], whereas research interestingly showed that people aged 30–50 years old are mostly infected \[[33](/article/10.1007/s10096-017-2965-0#ref-CR33 "Lu CT, Sung YJ (2009) Epidemiology of Blastocystis hominis and other intestinal parasites among the immigrant population in northeastern Taiwan by routine physical examination for residence approval. J Microbiol Immunol Infect 42:505–509")\]. _Blastocystis_ can also have beneficial effects stemming from its ability to modulate the host immune system. One mechanism of action is the stimulation of mucus production, via the cytokine IL-22, which alleviates symptoms of colitis, improving gut health \[[101](/article/10.1007/s10096-017-2965-0#ref-CR101 "Leung JM, Davenport M, Wolff MJ, Wiens KE, Abidi WM, Poles MA, Cho I, Ullman T, Mayer L, Loke P (2014) IL-22-producing C4+ cells are depleted in actively inflamed colitis tissue. Mucosal Immunol 7:124–133. doi:
10.1038/mi.2013.31
")\]. Perhaps _Blastocystis_ is more common in healthy people because it helps maintain a healthy mucus layer in the intestine, either directly or through interactions with beneficial bacteria or the immune system \[[5](/article/10.1007/s10096-017-2965-0#ref-CR5 "Lukeš J, Stensvold CR, Jirků-Pomajbíková K, Wegener Parfrey L (2015) Are human intestinal eukaryotes beneficial or commensals? PLoS Pathog 11(8), e1005039. doi:
10.1371/journal.ppat.1005039
")\]. _Blastocystis_ have been shown to be more prevalent in patients suffering from IBS \[[18](/article/10.1007/s10096-017-2965-0#ref-CR18 "Yakoob J, Jafri W, Beg MA, Abbas Z, Naz S, Islam M, Khan R (2010) Irritable bowel syndrome: is it associated with genotypes of Blastocystis hominis. Parasitol Res 106:1033–1038. doi:
10.1007/s00436-010-1761-x
"), [102](/article/10.1007/s10096-017-2965-0#ref-CR102 "Giacometti A, Cirioni O, Fiorentini A, Fortuna M, Scalise G (1999) Irritable bowel syndrome in patients with Blastocystis hominis infection. Eur J Clin Microbiol Infect Dis 18:436–439")–[106](/article/10.1007/s10096-017-2965-0#ref-CR106 "Jimenez-Gonzalez DE, Martinez-Flores WA, Reyes-Gordillo J, Ramirez-Miranda ME, Arroyo-Escalante S, Romero-Valdovinos M, Stark D, Souza-Saldivar V, Martinez-Hernandez F, Flisser A, Olivo-Diaz A, Maravilla P (2012) Blastocystis infection is associated with irritable bowel syndrome in a Mexican patient population. Parasitol Res 110:1269–1275. doi:
10.1007/s00436-011-2626-7
")\]. A 2014 study by Nourrisson et al. \[[107](/article/10.1007/s10096-017-2965-0#ref-CR107 "Nourrisson C, Scanzi J, Pereira B, NkoudMongo C, Wawrzyniak I, Cian A, Viscogliosi E, Livrelli V, Delbac F, Dapoigny M, Poirier P (2014) Blastocystis is associated with decrease of fecal microbiota protective bacteria: comparative analysis between patients with irritable bowel syndrome and control subjects. PLoS One 9(11), e111868. doi:
10.1371/journal.pone.0111868
")\] suggests that _Blastocystis_ may be used as an indicator of microbiota changes; a lower abundance of _Bifidobacterium_ spp. and _Faecalibacterium prausnitzii_ were reported to have protective and anti-inflammatory effects, which could lead to intestinal dysbiosis and IBS. Nagel et al. \[[108](/article/10.1007/s10096-017-2965-0#ref-CR108 "Nagel R, Traub RJ, Allcock RJN, Kwan MMS, Bielefeldt-Ohmann H (2016) Comparison of faecal microbiota in Blastocystis-positive and Blastocystis-negative irritable bowel syndrome patients. Microbiome 4(1):47. doi:
10.1186/s40168-016-0191-0
")\] confirmed these results in 2016\. On the other hand, in 2016, Audebert et al. \[[109](/article/10.1007/s10096-017-2965-0#ref-CR109 "Audebert C, Even G, Cian A, Blastocystis Investigation Group, Loywick A, Merlin S, Viscogliosi E, Chabé M (2016) Colonization with the enteric protozoa Blastocystis is associated with increased diversity of human gut bacterial microbiota. Sci Rep 6, 25255. doi:
10.1038/srep25255
")\] suggested that colonization by _Blastocystis_ could be associated with a healthy gut microbiota. Their study showed a higher bacterial diversity in _Blastocystis_\-colonized patients compared to that identified in _Blastocystis_\-free individuals. In _Blastocystis_\-colonized patients, there was a higher abundance of the Clostridia class and Ruminococcaceae and Prevotellaceae families, while Enterobacteriaceae were enriched in _Blastocystis_\-free patients. The most recent results of the latest studies leave the pathogenicity of _Blastocystis_ still unclear and this is similar to the chicken and egg question: which came first? It is still a mystery. Is _Blastocystis_ an agent of the gut dysbiosis and changing the microbiotic diversity, or are the metabolic dysfunctions and changes in the content of microbiota the reason for the higher colonization by _Blastocystis_? There is a possibility that some species of bacteria are triggering the protease activity of _Blastocystis_, which causes the gastrointestinal symptoms. It may also depend on parasitic subtype. To address this, further studies in humans are required \[[109](/article/10.1007/s10096-017-2965-0#ref-CR109 "Audebert C, Even G, Cian A, Blastocystis Investigation Group, Loywick A, Merlin S, Viscogliosi E, Chabé M (2016) Colonization with the enteric protozoa Blastocystis is associated with increased diversity of human gut bacterial microbiota. Sci Rep 6, 25255. doi:
10.1038/srep25255
")\].The influence of different diets on Blastocystis as compared to antibiotic treatment
Although many Blastocystis infections remain asymptomatic, recent data suggest that it is a frequent cause of gastrointestinal symptoms in children and adults [[110](/article/10.1007/s10096-017-2965-0#ref-CR110 "Tan KS, Singh M, Yap EH (2002) Recent advances in Blastocystis hominis research: hot spots in terra incognita. Int J Parasitol 32:789–804. doi: 10.1016/S0020-7519(02)00005-X
")\]. Many parasitologists insist that, when _Blastocystis_ organisms are present in large numbers in stool examination, even without the presence of any other known bacterial, viral, or parasitic infection, treatment should be proposed \[[110](/article/10.1007/s10096-017-2965-0#ref-CR110 "Tan KS, Singh M, Yap EH (2002) Recent advances in Blastocystis hominis research: hot spots in terra incognita. Int J Parasitol 32:789–804. doi:
10.1016/S0020-7519(02)00005-X
"), [111](/article/10.1007/s10096-017-2965-0#ref-CR111 "Dinleyici EC, Eren M, Dogan N, Reyhanioglu S, Yargic ZA, Vandenplas Y (2011) Clinical efficacy of Saccharomyces boulardii or metronidazole in symptomatic children with Blastocystis hominis infection. Parasitol Res 108:541–545. doi:
10.1007/s00436-010-2095-4
")\]. Therapy should be limited to patients with relentless symptoms and a complete negative workup for alternative etiologies. Several drugs have been used against _Blastocystis_ infection, the most common still being metronidazole (MTZ), as the first-line treatment, followed by nitazoxanide (NTZ), trimethoprim–sulfamethoxazole (TMP-SMX), ketoconazole, and tinidazole as secondary treatments. Studies have shown that, while MTZ demonstrates effectiveness in some individuals \[[112](/article/10.1007/s10096-017-2965-0#ref-CR112 "Lucía JF, Aguilar C, Betran A (2007) Blastocystis hominis colitis in a haemophilic patient as a cause of lower gastrointestinal bleeding. Haemophilia 13(2):224–225. doi:
10.1111/j.1365-2516.2006.01434.x
"), [113](/article/10.1007/s10096-017-2965-0#ref-CR113 "Moghaddam DD, Ghadirian E, Azami M (2005) Blastocystis hominis and the evaluation of efficacy of metronidazole and trimethoprim/sulfamethoxazole. Parasitol Res 96(4):273–275. doi:
10.1007/s00436-005-1363-1
")\], it has also been shown to exhibit side effects and resistance in others \[[114](/article/10.1007/s10096-017-2965-0#ref-CR114 "Johnson PJ (1993) Metronidazole and drug resistance. Parasitol Today 9:183–186. doi:
10.1016/0169-4758(93)90143-4
"), [115](/article/10.1007/s10096-017-2965-0#ref-CR115 "Voolmann T, Boreham PFL (1993) Metronidazole resistant Trichomonas vaginalis in Brisbane. Med J Aust 159:490")\]. Most probably, it depends on the _Blastocystis_ subtypes. Girish et al. \[[116](/article/10.1007/s10096-017-2965-0#ref-CR116 "Girish S, Kumar S, Aminudin N (2015) Tongkat Ali (Eurycoma longifolia): a possible therapeutic candidate against Blastocystis sp. Parasit Vectors 8:332. doi:
10.1186/s13071-015-0942-y
")\], in 2015, reported that STs 1, 3, and 5 are susceptible to MTZ, but resistant to ketoconazole, even when high doses were administrated. ST1 is also resistant to TMP-SMX in lower doses, and ST3 to NTZ in lower doses \[[116](/article/10.1007/s10096-017-2965-0#ref-CR116 "Girish S, Kumar S, Aminudin N (2015) Tongkat Ali (Eurycoma longifolia): a possible therapeutic candidate against Blastocystis sp. Parasit Vectors 8:332. doi:
10.1186/s13071-015-0942-y
")\]. Studies have shown STs 4 and 7 to be resistant to MTZ \[[117](/article/10.1007/s10096-017-2965-0#ref-CR117 "Mirza H, Wu Z, Kidwai F, Tan KSW (2011) A metronidazole-resistant isolate of Blastocystis spp. is susceptible to nitric oxide and downregulates intestinal epithelial inducible nitric oxide synthase by a novel parasite survival mechanism. Infect Immun 79(12):5019–5026. doi:
10.1128/IAI.05632-11
")\]. This drug can cause undesirable side effects and changes in the gut microbiota. Moreover, failures in treatment are frequently reported \[[117](/article/10.1007/s10096-017-2965-0#ref-CR117 "Mirza H, Wu Z, Kidwai F, Tan KSW (2011) A metronidazole-resistant isolate of Blastocystis spp. is susceptible to nitric oxide and downregulates intestinal epithelial inducible nitric oxide synthase by a novel parasite survival mechanism. Infect Immun 79(12):5019–5026. doi:
10.1128/IAI.05632-11
")–[122](/article/10.1007/s10096-017-2965-0#ref-CR122 "Sekar U, Shanthi M (2013) Blastocystis: consensus of treatment and controversies. Trop Parasitol 3:35–39. doi:
10.4103/2229-5070.113901
")\]. Additionally, potential carcinogenic, teratogenic, and embryotoxic effects of metronidazole have been reported \[[123](/article/10.1007/s10096-017-2965-0#ref-CR123 "Roe FJ (1983) Toxicologic evaluation of metronidazole with particular reference to carcinogenic, mutagenic, and teratogenic potential. Surgery 93:158–164")\]. Therefore, there is a need to develop safe and alternative antimicrobial agents, such as the use of medicinal plants, spices, specific vegetables, or yeasts.The number of trials, in vitro and in vivo, in which the anti-Blastocystis efficacies of some local plants are assessed have been on the rise lately [[124](/article/10.1007/s10096-017-2965-0#ref-CR124 "Rokaya MB, Uprety Y, Poudel RC, Timsina B, Münzbergová Z, Asselin H, Tiwari A, Shrestha SS, Sigdel SR (2014) Traditional uses of medicinal plants in gastrointestinal disorders in Nepal. J Ethnopharmacol 158:221–229. doi: 10.1016/j.jep.2014.10.014
")\]. Plants were chosen for their antimicrobial activity and chemical composition. Garlic (_Allium sativum_) contains a wide range of the thiosulfinates (e.g., allicin), which are responsible for the antibacterial activity \[[125](/article/10.1007/s10096-017-2965-0#ref-CR125 "Iimuro M, Shibata H, Kawamori T, Matsumoto T, Arakawa T, Sugimura T, Wakabayashi K (2002) Suppressive effects of garlic extract on Helicobacter pylori-induced gastritis in Mongolian gerbils. Cancer Lett 187:61–68. doi:
10.1016/S0304-3835(02)00401-9
")\] related to the inhibition of enzymes, including thiol in microorganisms \[[126](/article/10.1007/s10096-017-2965-0#ref-CR126 "Goncagul G, Ayaz E (2010) Antimicrobial effect of garlic (Allium sativum) and traditional medicine. J Anim Vet Adv 9:1–4. doi:
10.3923/javaa.2010.1.4
"), [127](/article/10.1007/s10096-017-2965-0#ref-CR127 "Majewski M (2014) Allium sativum: facts and myths regarding human health. Rocz Panstw Zakl Hig 65(1):1–8")\]. Moreover, allicin in the garlic acts by totally inhibiting RNA synthesis and partially inhibiting DNA and protein synthesis of the parasites \[[128](/article/10.1007/s10096-017-2965-0#ref-CR128 "Feldberg RS, Chang SC, Kotik AN, Nadler M, Neuwirth Z, Sundstrom DC, Thompson NH (1988) In vitro mechanism of inhibition of bacterial cell growth by allicin. Antimicrob Agents Chemother 32:1763–1768")\]. Additionally, hexahydrocurcumin, a constituent isolated from ginger (_Zingiber officinale_), might be effective in killing the parasites \[[129](/article/10.1007/s10096-017-2965-0#ref-CR129 "Lin RJ, Chen CY, Chung LY, Yen CM (2010) Larvicidal activities of ginger (Zingiber officinale) against Angiostrongylus cantonensis. Acta Trop 115:69–76. doi:
10.1016/j.actatropica.2009.12.007
")\]. Yakoob et al. \[[130](/article/10.1007/s10096-017-2965-0#ref-CR130 "Yakoob J, Abbas Z, Beg MA, Naz S, Awan S, Hamid S, Jafri W (2011) In vitro sensitivity of Blastocystis hominis to garlic, ginger, white cumin, and black pepper used in diet. Parasitol Res 109:379–385. doi:
10.1007/s00436-011-2265-z
")\] in 2011 and Abdel-Hafeez et al. \[[131](/article/10.1007/s10096-017-2965-0#ref-CR131 "Abdel-Hafeez EH, Ahmad AK, Kamal AM, Abdellatif MZM, Abdelgelil NH (2015) In vivo antiprotozoan effects of garlic (Allium sativum) and ginger (Zingiber officinale) extracts on experimentally infected mice with Blastocystis spp. Parasitol Res 114(9):3439–3444. doi:
10.1007/s00436-015-4569-x
")\] in 2015 proved activity against _Blastocystis_ with garlic extract in vitro as compared to the antimicrobial drugs MTZ and NTZ, respectively. Interestingly, they also tested the antiparasitic activity of ginger and had differing results. As Yakoobs and colleagues \[[130](/article/10.1007/s10096-017-2965-0#ref-CR130 "Yakoob J, Abbas Z, Beg MA, Naz S, Awan S, Hamid S, Jafri W (2011) In vitro sensitivity of Blastocystis hominis to garlic, ginger, white cumin, and black pepper used in diet. Parasitol Res 109:379–385. doi:
10.1007/s00436-011-2265-z
")\] showed in their study, _Blastocystis_ STs 1 and 3 were not sensitive to ginger, black pepper, or cumin when compared to garlic and MTZ. According to the study of Abdel-Hafeez et al. \[[131](/article/10.1007/s10096-017-2965-0#ref-CR131 "Abdel-Hafeez EH, Ahmad AK, Kamal AM, Abdellatif MZM, Abdelgelil NH (2015) In vivo antiprotozoan effects of garlic (Allium sativum) and ginger (Zingiber officinale) extracts on experimentally infected mice with Blastocystis spp. Parasitol Res 114(9):3439–3444. doi:
10.1007/s00436-015-4569-x
")\], ginger has the greatest effect on _Blastocystis_ clinical isolates, but onion (_Allium cepa_) or turmeric (_Curcuma longa_) do not \[[131](/article/10.1007/s10096-017-2965-0#ref-CR131 "Abdel-Hafeez EH, Ahmad AK, Kamal AM, Abdellatif MZM, Abdelgelil NH (2015) In vivo antiprotozoan effects of garlic (Allium sativum) and ginger (Zingiber officinale) extracts on experimentally infected mice with Blastocystis spp. Parasitol Res 114(9):3439–3444. doi:
10.1007/s00436-015-4569-x
"), [132](/article/10.1007/s10096-017-2965-0#ref-CR132 "Abdel-Hafeez EH, Ahmad AK, Andelgelil NH, Abdellatif MZM, Kamal AM, Mohamed RM (2015) In vitro effect of some Egyptian herbal extracts against Blastocystis hominis. J Egypt Soc Parasitol 45(1):93–100. doi:
10.12816/0010854
")\]. Moreover, garlic and ginger decrease malondialdehyde (MDA) production significantly. The allicin contained in garlic acts as an antioxidant by retrieving reactive oxygen species (ROS), preventing lipid oxidation and production of pro-inflammatory messengers \[[133](/article/10.1007/s10096-017-2965-0#ref-CR133 "Banerjee SK, Mukherjee PK, Maulik SK (2003) Garlic as an antioxidant: the good, the bad and the ugly. Phytother Res 17:97–106. doi:
10.1002/ptr.1281
")\]. Additionally, gingerol contained in ginger inhibits the ascorbate/ferrous complex-induced lipid peroxidation \[[134](/article/10.1007/s10096-017-2965-0#ref-CR134 "Ahmed RS, Seth V, Banerjee BD (2000) Influence of dietary ginger (Zingiber officinales Rosc) on antioxidant defense system in rat: comparison with ascorbic acid. Indian J Exp Biol 38:604–606")\]. Dugasani et al. \[[135](/article/10.1007/s10096-017-2965-0#ref-CR135 "Dugasani S, Pichika MR, Nadarajah VD, Balijepalli MK, Tandra S, Korlakunta JN (2010) Comparative antioxidant and anti-inflammatory effects of [6]-gingerol, [8]-gingerol, [10]-gingerol and [6]-shogaol. J Ethnopharmacol 127:515–520. doi:
10.1016/j.jep.2009.10.004
")\], in 2010, reported that gingerols and shogaols are the most bioactive compounds of ginger. Both garlic and ginger seem to be strong antioxidants inhibiting nitric oxide (NO) production \[[131](/article/10.1007/s10096-017-2965-0#ref-CR131 "Abdel-Hafeez EH, Ahmad AK, Kamal AM, Abdellatif MZM, Abdelgelil NH (2015) In vivo antiprotozoan effects of garlic (Allium sativum) and ginger (Zingiber officinale) extracts on experimentally infected mice with Blastocystis spp. Parasitol Res 114(9):3439–3444. doi:
10.1007/s00436-015-4569-x
"), [135](/article/10.1007/s10096-017-2965-0#ref-CR135 "Dugasani S, Pichika MR, Nadarajah VD, Balijepalli MK, Tandra S, Korlakunta JN (2010) Comparative antioxidant and anti-inflammatory effects of [6]-gingerol, [8]-gingerol, [10]-gingerol and [6]-shogaol. J Ethnopharmacol 127:515–520. doi:
10.1016/j.jep.2009.10.004
")\]. Intestinal NO increases upon _Blastocystis_ infection as a host defense mechanism of epithelial cells against parasites \[[117](/article/10.1007/s10096-017-2965-0#ref-CR117 "Mirza H, Wu Z, Kidwai F, Tan KSW (2011) A metronidazole-resistant isolate of Blastocystis spp. is susceptible to nitric oxide and downregulates intestinal epithelial inducible nitric oxide synthase by a novel parasite survival mechanism. Infect Immun 79(12):5019–5026. doi:
10.1128/IAI.05632-11
"), [131](/article/10.1007/s10096-017-2965-0#ref-CR131 "Abdel-Hafeez EH, Ahmad AK, Kamal AM, Abdellatif MZM, Abdelgelil NH (2015) In vivo antiprotozoan effects of garlic (Allium sativum) and ginger (Zingiber officinale) extracts on experimentally infected mice with Blastocystis spp. Parasitol Res 114(9):3439–3444. doi:
10.1007/s00436-015-4569-x
")\]. Mirza et al. \[[117](/article/10.1007/s10096-017-2965-0#ref-CR117 "Mirza H, Wu Z, Kidwai F, Tan KSW (2011) A metronidazole-resistant isolate of Blastocystis spp. is susceptible to nitric oxide and downregulates intestinal epithelial inducible nitric oxide synthase by a novel parasite survival mechanism. Infect Immun 79(12):5019–5026. doi:
10.1128/IAI.05632-11
")\], in 2011, suggested that _Blastocystis_ is susceptible to NO. Nitric oxide is important in homeostasis and host defense; however, it may also lead to cellular damage and gut barrier failure, as well as having been involved in the pathogenesis of many inflammatory and autoimmune diseases \[[136](/article/10.1007/s10096-017-2965-0#ref-CR136 "Potoka DA, Nadler EP, Upperman JS, Ford HR (2002) Role of nitric oxide and peroxynitrite in gut barrier failure. World J Surg 26:806–811. doi:
10.1007/s00268-002-4056-2
"), [137](/article/10.1007/s10096-017-2965-0#ref-CR137 "Lanas A (2008) Role of nitric oxide in the gastrointestinal tract. Arthritis Res Ther 10(Suppl 2):S4. doi:
10.1186/ar2465
")\]. Garlic and ginger treatments significantly downregulated NO intestinal release \[[131](/article/10.1007/s10096-017-2965-0#ref-CR131 "Abdel-Hafeez EH, Ahmad AK, Kamal AM, Abdellatif MZM, Abdelgelil NH (2015) In vivo antiprotozoan effects of garlic (Allium sativum) and ginger (Zingiber officinale) extracts on experimentally infected mice with Blastocystis spp. Parasitol Res 114(9):3439–3444. doi:
10.1007/s00436-015-4569-x
")\]. This may be caused by a decrease in _Blastocystis_ loads in the intestine. Downregulation of MDA and NO are important mechanisms of garlic- and ginger-induced antiparasitic effects.El Deeb et al. [[138](/article/10.1007/s10096-017-2965-0#ref-CR138 "El Deeb HK, Al Khadrawy FM, Abd El-Hameid AK (2012) Inhibitory effect of Ferula asafoetida L. (Umbelliferae) on Blastocystis sp. subtype 3 growth in vitro. Parasitol Res 111:1213–1221. doi: 10.1007/s00436-012-2955-1
")\], in 2012, proved an inhibitory effect of _Ferula asafoetida_ (in both powder and oil form) on _Blastocystis_ ST3\. Furthermore, asafetida exerted a detrimental effect on _Blastocystis_ morphology, which was especially obvious at higher concentrations. The viable vacuolar forms which were typically seen before incubation with either powder or oil were replaced by more granular forms, which lost viability over time and showed a shriveled appearance \[[138](/article/10.1007/s10096-017-2965-0#ref-CR138 "El Deeb HK, Al Khadrawy FM, Abd El-Hameid AK (2012) Inhibitory effect of Ferula asafoetida L. (Umbelliferae) on Blastocystis sp. subtype 3 growth in vitro. Parasitol Res 111:1213–1221. doi:
10.1007/s00436-012-2955-1
")\]. Asafoetida consists principally of volatile oil (4–20%) with isobutyl propanyl disulfide (C8H16S2), resin (40–60%) with ester of asaresinotannol and free ferulic acid, and gum (∼25%) with caffeic acid cinnamyl ester showing moderate activity for inhibiting LPS-induced nitric oxide production in murine macrophage RAW264.7 cells \[[139](/article/10.1007/s10096-017-2965-0#ref-CR139 "Abd El-Razek MH (2007) A new ester isolated from Ferula assa-foetida L. Biosci Biotechnol Biochem 71(9):2300–2303. doi:
10.1271/bbb.70065
")\]. _Blastocystis_ ST3 is also sensitive to Tongkat Ali (_Eurycoma longifolia_), as Girish and colleagues proved in a study in 2015 \[[116](/article/10.1007/s10096-017-2965-0#ref-CR116 "Girish S, Kumar S, Aminudin N (2015) Tongkat Ali (Eurycoma longifolia): a possible therapeutic candidate against Blastocystis sp. Parasit Vectors 8:332. doi:
10.1186/s13071-015-0942-y
")\]. Most likely, four compounds are responsible for antiparasitic activity: 3,4-dihydrochaparrinone, laurycolactone B, β-carboline-1-propionic acid, and canthin-6-one. These compounds have previously been proven to possess therapeutic properties \[[140](/article/10.1007/s10096-017-2965-0#ref-CR140 "Kuo PC, Shi LS, Damu AG, Su CR, Huang CH, Ke CH, Wu JB, Lin AJ, Bastow KF, Lee KH, Wu TS (2003) Cytotoxic and antimalarial beta-carboline alkaloids from the roots of Eurycoma longifolia. J Nat Prod 66(10):1324–1327. doi:
10.1021/np030277n
"), [141](/article/10.1007/s10096-017-2965-0#ref-CR141 "Gutiérrez RMP (2007) Handbook of compounds with antiprotozoal activity isolated from plants. Nova, New York")\]. Recently, there have been many reports which have shown the inhibitory effect of herbal extracts and spices on _Blastocystis_. Vital and Rivera \[[142](/article/10.1007/s10096-017-2965-0#ref-CR142 "Vital PG, Rivera WL (2009) Antimicrobial activity and cytotoxicity of Chromolaena odorata (L. f.) King and Robinson and Uncaria perrottetii (A. Rich) Merr. Extracts. J Med Plants Res 3(7):511–518")\], in 2009, proved that ethanol extracts of leaves of _Chromolaena odorata_ and ethyl acetate extracts of stem bark of _Uncaria perrottetii_ inhibited _Blastocystis_ growth and decreased cell counts at 0.5 and 1.0% concentrations, respectively. Furthermore, Özbílgín et al. \[[143](/article/10.1007/s10096-017-2965-0#ref-CR143 "Özbílgín A, Durmuşkahya C, Kílímcíoğlu AA, Kayalar H, Kurt Ö, Ermíş VÖ, Tabak T, Östan Í (2013) In vitro efficacy of Quercus infectoria Oliv. and Achillea millefolium L. extracts against Blastocystis spp. isolates. Kafkas Univ Vet Fak Derg 19(3):511–516. doi:
10.9775/kvfd.2012.8196
")\], in a 2013 study, demonstrated that the methanol extract of _Achillea millefolium_ gave promising results and could be used as an anti-protozoal agent in the future, especially against _Blastocystis_ STs 1, 2, and 3\. Also, El Wakil \[[144](/article/10.1007/s10096-017-2965-0#ref-CR144 "El Wakil SS (2007) Evaluation of the in vitro effect of Nigella sativa aqueous extract on Blastocystis hominis isolates. J Egypt Soc Parasitol 37:801–813")\], in 2007, showed that an aqueous extract of _Nigella sativa_ significantly inhibits the growth of _Blastocystis_ isolates. In addition, some medicinal plants from Ghana and Thailand showed high activity against _Blastocystis_ \[[145](/article/10.1007/s10096-017-2965-0#ref-CR145 "Brewmer Christensen C, Soelberg J, Stensvold CR, Jäger AK (2015) Activity of medicinal plants from Ghana against the parasitic gut protist Blastocystis. J Ethnopharmacol 174:569–575. doi:
10.1016/j.jep.2015.03.006
"), [146](/article/10.1007/s10096-017-2965-0#ref-CR146 "Sawangjaroen N, Sawangjaroen K (2005) The effects of extracts from anti-diarrheic Thai medicinal plants on the in vitro growth of the intestinal protozoa parasite: Blastocystis hominis. J Ethnopharmacol 98:67–72. doi:
10.1016/j.jep.2004.12.024
")\]. Similarly, supplementation with 600 mg emulsified oil of Mediterranean oregano (_Origanum vulgare_) daily lead to the complete disappearance of _Blastocystis_ \[[147](/article/10.1007/s10096-017-2965-0#ref-CR147 "Force M, Sparks WS, Ronzio RA (2000) Inhibition of enteric parasites by emulsified oil of oregano in vivo. Phytother Res 14:213–214")\]. It is also suggested to use _Saccharomyces boulardii_ to cure _Blastocystis_ infection \[[111](/article/10.1007/s10096-017-2965-0#ref-CR111 "Dinleyici EC, Eren M, Dogan N, Reyhanioglu S, Yargic ZA, Vandenplas Y (2011) Clinical efficacy of Saccharomyces boulardii or metronidazole in symptomatic children with Blastocystis hominis infection. Parasitol Res 108:541–545. doi:
10.1007/s00436-010-2095-4
")\]. Commensal yeasts act as a regulator of homeostasis in the gut through preventing the colonization of pathogenic agents on intestinal mucosa and augmenting the local immune response \[[148](/article/10.1007/s10096-017-2965-0#ref-CR148 "Vandenplas Y, Huys G, Daube G (2015) Probiotics: an update. J Pediatr (Rio J) 91(1):6–21. doi:
10.1016/j.jped.2014.08.005
")\]. In a placebo-controlled study, it was found to be more effective against _Blastocystis_ when compared to metronidazole \[[111](/article/10.1007/s10096-017-2965-0#ref-CR111 "Dinleyici EC, Eren M, Dogan N, Reyhanioglu S, Yargic ZA, Vandenplas Y (2011) Clinical efficacy of Saccharomyces boulardii or metronidazole in symptomatic children with Blastocystis hominis infection. Parasitol Res 108:541–545. doi:
10.1007/s00436-010-2095-4
")\].Conclusions
Blastocystis sp. is a parasite which does not need to be cured with the antibiotics that cause side effects, such as metronidazole (MTZ). Mainly, the choice of eradication depends on the Blastocystis subtype, geographic region of occurrence, pathogenicity, immune system of the host, human gut microbiota, or chronic diseases, such as diabetes. Natural herbs, vegetables, or spices as an alternative for blastocystosis treatment not only reduce drug resistance, but also their side effects and the cost of treatment, especially in developing countries. Special diets are effective mainly by inhibiting parasitic enzyme activity, RNA, DNA, and protein synthesis, and, also, nitric oxide (NO) production. Moreover, commensal yeasts and bacteria prevent the colonization of pathogenic agents on intestinal mucosa and augment the local immune response. Certain species of beneficial microorganisms can have a negative influence on parasites by producing molecules that trigger the immune system, but they may also cause protease activity in Blastocystis, leading to symptoms of infection. Further investigation needs to be done to identify the organic compounds causing Blastocystis eradication. Research should address if the treatment directly affects Blastocystis or if it acts by destroying the bacterial flora necessary for its development, or both. We would like to suggest for future research the determination of whether Blastocystis is an agent changing the human gut microbiota or the opposite; does the commensal microbiota help the parasite to colonize the gastrointestinal tract? These questions and many others still remain unclear.
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- Department of Medical Biology, Faculty of Medical Sciences, University of Warmia and Mazury, Żołnierska 14 C, Olsztyn, 10-561, Poland
M. Lepczyńska, E. Dzika & J. Korycińska - Department of Neurology and Neurosurgery, Faculty of Medical Sciences, University of Warmia and Mazury, Warszawska 30, Olsztyn, Poland
J. Białkowska - Department of Nursing, Faculty of Medical Sciences, University of Warmia and Mazury, Żołnierska 14 C, Olsztyn, Poland
K. Piskorz-Ogórek - Regional Specialized Children’s Hospital in Olsztyn, Żołnierska 18A, Olsztyn, Poland
K. Piskorz-Ogórek
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- M. Lepczyńska
- J. Białkowska
- E. Dzika
- K. Piskorz-Ogórek
- J. Korycińska
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Lepczyńska, M., Białkowska, J., Dzika, E. et al. Blastocystis: how do specific diets and human gut microbiota affect its development and pathogenicity?.Eur J Clin Microbiol Infect Dis 36, 1531–1540 (2017). https://doi.org/10.1007/s10096-017-2965-0
- Received: 23 January 2017
- Accepted: 08 March 2017
- Published: 22 March 2017
- Issue date: September 2017
- DOI: https://doi.org/10.1007/s10096-017-2965-0