Could paraprobiotics be a safer alternative to probiotics for managing cancer chemotherapy-induced gastrointestinal toxicities?

Nobre, L.M.S.; Fernandes, C.; Florêncio, K.G.D.; Alencar, N.M.N.; Wong, D.V.T.; Lima-Júnior, R.C.P.

doi:10.1590/1414-431X2022e12522

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Brazilian Journal of Medical and Biological Research

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Review • Braz. J. Med. Biol. Res. 55 • 2022 • https://doi.org/10.1590/1414-431X2022e12522 copy

Could paraprobiotics be a safer alternative to probiotics for managing cancer chemotherapy-induced gastrointestinal toxicities?

Authorship SCIMAGO INSTITUTIONS RANKINGS

Clinical oncology has shown outstanding progress improving patient survival due to the incorporation of new drugs. However, treatment success may be reduced by the emergency of dose-limiting side effects, such as intestinal mucositis and diarrhea. Mucositis and diarrhea management is symptomatic, and there is no preventive therapy. Bacterial and fungal-based compounds have been suggested as an alternative for preventing the development of diarrhea in cancer patients. Using probiotics is safe and effective in immunocompetent individuals, but concerns remain during immunosuppressive conditions. Paraprobiotics, formulations composed of non-viable microorganisms, have been proposed to overcome such limitation. The present literature review discusses current evidence regarding the possible use of paraprobiotics as an alternative to probiotics to prevent gastrointestinal toxicity of cancer chemotherapy.

Diarrhea; Probiotics; Paraprobiotics; Cancer; Chemotherapy

	Definition	Commonly used species	Application
Probiotic	Live microorganisms that confer a health benefit when consumed in adequate amounts (⁶⁶66. Vallianou N, Stratigou T, Christodoulatos GS, Tsigalou C, Dalamaga M. Probiotics, prebiotics, synbiotics, postbiotics, and obesity: current evidence, controversies, and perspectives. Curr Obes Rep 2020; 9: 179-192, doi: 10.1007/s13679-020-00379-w. https://doi.org/10.1007/s13679-020-00379... ).	Genus Lactobacillus: Lactobacillus acidophilus, L. casei, L. paracasei, L. rhamnosus, L. delbrueckii subsp. bulgaricus, L. brevis, L. johnsonii, L. plantarum and L. fermentum (⁶⁷67. Walter J. Ecological role of lactobacilli in the gastrointestinal tract: Implications for fundamental and biomedical research. Appl Environ Microbiol 2008; 74: 4985-4996, doi: 10.1128/AEM.00753-08. https://doi.org/10.1128/AEM.00753-08... ), genus Bifidobacterium: Bifidobacterium infantis, B. adolescentis, B. animalis subsp animalis, B. animalis subsp lactis, B. bifidum, B. longum, B. breve (⁶⁸68. Fijan S. Microorganisms with claimed probiotic properties: an overview of recent literature. Int J Environ Res Public Health 2014; 11: 4745-4767, doi: 10.3390/ijerph110504745. https://doi.org/10.3390/ijerph110504745... ), Saccharomyces: S. boulardii (⁶⁹69. Choi CH, Jo SY, Park HJ, Chang SK, Byeon JS, Myung SJ. A randomized, double-blind, placebo-controlled multicenter trial of Saccharomyces boulardii in irritable bowel syndrome: effect on quality of life. J Clin Gastroenterol 2011; 45: 679-683, doi: 10.1097/MCG.0b013e318204593e. https://doi.org/10.1097/MCG.0b013e318204... ,⁷⁰70. Guslandi M, Giollo P, Testoni PA. A pilot trial of Saccharomyces boulardii in ulcerative colitis. Eur J Gastroenterol Hepatol 2003; 15: 697-698, doi: 10.1097/00042737-200306000-00017. https://doi.org/10.1097/00042737-2003060... ).	Diarrhea (⁷¹71. Lai H, Chiu CH, Kong MS, Chang CJ, Chen CC. Nutrients probiotic Lactobacillus casei: effective for managing childhood diarrhea by altering gut microbiota and attenuating fecal inflammatory markers. Nutrients 2019; 11: 1150, doi: 10.3390/nu11051150. https://doi.org/10.3390/nu11051150... ,⁷²72. Zhao R, Wang Y, Huang Y, Cui Y, Xia L, Rao Z, et al. Effects of fiber and probiotics on diarrhea associated with enteral nutrition in gastric cancer patients: a prospective randomized and controlled trial. Medicine (Baltimore) 2017; 96: e8418, doi: 10.1097/MD.0000000000008418. https://doi.org/10.1097/MD.0000000000008... ), irritable bowel syndrome (⁷³73. Ishaque SM, Khosruzzaman SM, Ahmed DS, Sah MP. A randomized placebo-controlled clinical trial of a multi-strain probiotic formulation (Bio-Kult®) in the management of diarrhea-predominant irritable bowel syndrome. BMC Gastroenterol 2018; 18: 71, doi: 10.1186/s12876-018-0788-9. https://doi.org/10.1186/s12876-018-0788-... ), constipation (⁷⁴74. Kommers MJ, Rodrigues RAS, Miyajima F, Zavala AAZ, Ultramari VRLM, Fett WCR, et al. Effects of probiotic use on quality of life and physical activity in constipated female university students: a randomized, double-blind placebo-controlled study. J Altern Complement Med 2019; 25: 1163-1171, doi: 10.1089/acm.2019.0134. https://doi.org/10.1089/acm.2019.0134... ), diabetes (⁷⁵75. Kijmanawat A, Panburana P, Reutrakul S, Tangshewinsirikul C. Effects of probiotic supplements on insulin resistance in gestational diabetes mellitus: a double-blind randomized controlled trial. J Diabetes Investig 2019; 10: 163-170, doi: 10.1111/jdi.12863. https://doi.org/10.1111/jdi.12863... ), depression (⁷⁶76. Kazemi A, Noorbala AA, Azam K, Eskandari MH, Djafarian K. Effect of probiotic and prebiotic vs placebo on psychological outcomes in patients with major depressive disorder: a randomized clinical trial. Clin Nutr 2019; 38: 522-528, doi: 10.1016/j.clnu.2018.04.010. https://doi.org/10.1016/j.clnu.2018.04.0... ).
Paraprobiotic	Inactivated microbial cells or cell fractions that confer health benefit to the host (⁷⁷77. Teame T, Wang A, Xie M, Zhang Z, Yang Y, Ding Q, et al. Paraprobiotics and postbiotics of probiotic Lactobacilli, their positive effects on the host and action mechanisms: a review. Front Nutr 2020; 7: 570344, doi: 10.3389/fnut.2020.570344. https://doi.org/10.3389/fnut.2020.570344... ).	Lactobacillus casei (⁵⁹59. Salas-Lais AG, Robles-Contreras A, Balderas-López JA, Bautista-de Lucio VM. Immunobiotic and paraprobiotic potential effect of Lactobacillus casei in a systemic toxoplasmosis murine model. Microorganisms 2020; 8: 113, doi: 10.3390/microorganisms8010113. https://doi.org/10.3390/microorganisms80... ,⁶⁰60. Arai S, Iwabuchi N, Takahashi S, Xiao JZ, Abe F, Hachimura S. Orally administered heat-killed Lactobacillus paracasei MCC1849 enhances antigen-specific IgA secretion and induces follicular helper T cells in mice. PLoS One 2018; 13: e0199018, doi: 10.1371/journal.pone.0199018. https://doi.org/10.1371/journal.pone.019... ), Lacticaseibacillus casei (⁶¹61. Brandão LR, Alves JLB, da Costa WKA, Ferreira GDAH, de Oliveira MP, da Cruz AG, et al. Live and ultrasound-inactivated: Lacticaseibacillus casei modulate the intestinal microbiota and improve biochemical and cardiovascular parameters in male rats fed a high-fat diet. Food Funct 2021; 12: 5287-5300, doi: 10.1039/D1FO01064F. https://doi.org/10.1039/D1FO01064F... ), Lactobacillus rhamnosus GG (⁷⁸78. Orlando A, Refolo MG, Messa C, Amati L, Lavermicocca P, Guerra V, et al. Antiproliferative and proapoptotic effects of viable or heat-killed Lactobacillus paracasei IMPC2.1 and Lactobacillus rhamnosus GG in HGC-27 gastric and DLD-1 colon cell lines. Nutr Cancer 2012; 64: 1103-1111, doi: 10.1080/01635581.2012.717676. https://doi.org/10.1080/01635581.2012.71... ), Saccharomyces boulardii (⁶⁴64. Generoso SV, Viana ML, Santos RG, Arantes RME, Martins FS, Nicoli JR, et al. Protection against increased intestinal permeability and bacterial translocation induced by intestinal obstruction in mice treated with viable and heat-killed Saccharomyces boulardii. Eur J Nutr. 2011; 50: 261-269, doi: 10.1007/s00394-010-0134-7. https://doi.org/10.1007/s00394-010-0134-... ), Lactobacillus gasseri (⁶³63. Sugawara T, Sawada D, Ishida Y, Aihara K, Aoki Y, Takehara I, et al. Regulatory effect of paraprobiotic Lactobacillus gasseri CP2305 on gut environment and function . Microb Ecol Heal Dis 2016; 27: 30259, doi: 10.3402/mehd.v27.30259. https://doi.org/10.3402/mehd.v27.30259... ), Enterococcus faecalis (⁷⁹79. Chung IC, OuYang CN, Yuan SN, Lin HC, Huang KY, Wu PS, et al. Pretreatment with a heat-killed probiotic modulates the NLRP3 inflammasome and attenuates colitis-associated colorectal cancer in mice. Nutrients 2019; 11: 516, doi: 10.3390/nu11030516. https://doi.org/10.3390/nu11030516... ), Lactobacillus paracasei (⁸⁰80. Karimi Ardestani S, Tafvizi F, Tajabadi Ebrahimi M. Heat-killed probiotic bacteria induce apoptosis of HT-29 human colon adenocarcinoma cell line via the regulation of Bax/Bcl2 and caspases pathway. Hum Exp Toxicol 2019; 38: 1069-1081, doi: 10.1177/0960327119851255. https://doi.org/10.1177/0960327119851255... ), Lactobacillus crispatus (⁸¹81. Motevaseli E, Khorramizadeh MR, Hadjati J, Bonab SF, Eslami S, Ghafouri-Fard S. Investigation of antitumor effects of Lactobacillus crispatus in experimental model of breast cancer in BALB/c mice. Immunotherapy 2018; 10: 119-129, doi: 10.2217/imt-2017-0088. https://doi.org/10.2217/imt-2017-0088... ).	Intestinal mucositis (⁶⁵65. Nobre LMS, Lopes MHS, Geraix J, Cajado AG, Silva JMR, Ribeiro LR, et al. Paraprobiotic Enterococcus faecalis EC-12 prevents the development of irinotecan-induced intestinal mucositis in mice. Life Sci 2022; 296: 120445, doi: 10.1016/j.lfs.2022.120445. https://doi.org/10.1016/j.lfs.2022.12044... ), modulation of the microbiota and improvement of intestinal function (⁶³63. Sugawara T, Sawada D, Ishida Y, Aihara K, Aoki Y, Takehara I, et al. Regulatory effect of paraprobiotic Lactobacillus gasseri CP2305 on gut environment and function . Microb Ecol Heal Dis 2016; 27: 30259, doi: 10.3402/mehd.v27.30259. https://doi.org/10.3402/mehd.v27.30259... ), obesity (⁸²82. Seo KH, Jeong J, Kim H. Synergistic effects of heat-killed kefir paraprobiotics and flavonoid-rich prebiotics on western diet-induced obesity. Nutrients 2020; 12: 2465, doi: 10.3390/nu12082465. https://doi.org/10.3390/nu12082465... ).
Postbiotic	Soluble factors (metabolites, metabiotics, supernatants, or cell extracts) released by the lysis of bacteria or secreted by live bacteria, causing benefits to the host (⁵⁷57. Aguilar-Toalá JE, Garcia-Varela R, Garcia HS, Mata-Haro V, González-Córdova AF, Vallejo-Cordoba B, et al. Postbiotics: an evolving term within the functional foods field. Trends Food Sci Technol 2018; 75: 105-114, doi: 10.1016/j.tifs.2018.03.009. https://doi.org/10.1016/j.tifs.2018.03.0... ).	Lactobacillus amylovorus (⁸³83. Sugawara T, Sawada D, Yanagihara S, Aoki Y, Takehara I, Sugahara H, et al. Daily intake of paraprobiotic Lactobacillus amylovorus CP1563 improves pre-obese conditions and affects the gut microbial community in healthy pre-obese subjects: a double-blind, randomized, placebo-controlled study. Microorganisms 2020; 8: 304, doi: 10.3390/microorganisms8020304. https://doi.org/10.3390/microorganisms80... ), Escherichia coli (⁸⁴84. Kiencke P, Viehmann K, Rychlik R. Cost-effectiveness analysis, prevention of atopic dermatitis by oral application of bacterial lysate in newborns/small children. Eur J Health Econ 2013; 14: 995-1002, doi: 10.1007/s10198-012-0448-x. https://doi.org/10.1007/s10198-012-0448-... ), Enterococcus faecalis (⁸⁴84. Kiencke P, Viehmann K, Rychlik R. Cost-effectiveness analysis, prevention of atopic dermatitis by oral application of bacterial lysate in newborns/small children. Eur J Health Econ 2013; 14: 995-1002, doi: 10.1007/s10198-012-0448-x. https://doi.org/10.1007/s10198-012-0448-... ), Haemophilus influenzae, Streptococcus pneumoniae, Klebsiella pneumoniae ssp. pneumoniae, Klebsiella pneumoniae ssp. ozaenae, Staphylococcus aureus, Streptococcus pyogenes, Streptococcus sanguinis and Moraxella (Branhamella) catarrhalis (Broncho-Vaxom^®) (⁸⁵85. Heintz B, Schlenter WW, Kirsten R, Nelson K. Clinical efficacy of Broncho-Vaxom in adult patients with chronic purulent sinusitis--a multi-centric, placebo-controlled, double-blind study. Int J Clin Pharmacol Ther Toxicol 1989; 27: 530-534.-86. Lu Y, Li Y, Xu L, Xia M, Cao L. Bacterial lysate increases the percentage of natural killer T cells in peripheral blood and alleviates asthma in children. Pharmacology 2015; 95: 139-144, doi: 10.1159/000377683. https://doi.org/10.1159/000377683... ⁸⁷87. Zhang M, Luan H, Zhang Q, Wang L, Lv YM, He F, et al. Prevention of infection in immunosuppressive patients with autoimmune nephrosis by using an immunostimulating bacterial lysate Broncho-vaxom. Hum Vaccines Immunother 2012; 8: 1802-1807, doi: 10.4161/hv.21874. https://doi.org/10.4161/hv.21874... ).	Obesity 9⁸³83. Sugawara T, Sawada D, Yanagihara S, Aoki Y, Takehara I, Sugahara H, et al. Daily intake of paraprobiotic Lactobacillus amylovorus CP1563 improves pre-obese conditions and affects the gut microbial community in healthy pre-obese subjects: a double-blind, randomized, placebo-controlled study. Microorganisms 2020; 8: 304, doi: 10.3390/microorganisms8020304. https://doi.org/10.3390/microorganisms80... ), atopic dermatitis (⁸⁴84. Kiencke P, Viehmann K, Rychlik R. Cost-effectiveness analysis, prevention of atopic dermatitis by oral application of bacterial lysate in newborns/small children. Eur J Health Econ 2013; 14: 995-1002, doi: 10.1007/s10198-012-0448-x. https://doi.org/10.1007/s10198-012-0448-... ), sinusitis (⁸⁵85. Heintz B, Schlenter WW, Kirsten R, Nelson K. Clinical efficacy of Broncho-Vaxom in adult patients with chronic purulent sinusitis--a multi-centric, placebo-controlled, double-blind study. Int J Clin Pharmacol Ther Toxicol 1989; 27: 530-534.), asthma (⁸⁶86. Lu Y, Li Y, Xu L, Xia M, Cao L. Bacterial lysate increases the percentage of natural killer T cells in peripheral blood and alleviates asthma in children. Pharmacology 2015; 95: 139-144, doi: 10.1159/000377683. https://doi.org/10.1159/000377683... ), prevention of respiratory infections (⁸⁷87. Zhang M, Luan H, Zhang Q, Wang L, Lv YM, He F, et al. Prevention of infection in immunosuppressive patients with autoimmune nephrosis by using an immunostimulating bacterial lysate Broncho-vaxom. Hum Vaccines Immunother 2012; 8: 1802-1807, doi: 10.4161/hv.21874. https://doi.org/10.4161/hv.21874... ).

Side effects	Probiotic species	Patients	References
Bacteremia	Lactobacillus rhamnosus	Adult with severe ulcerative colitis treated with corticosteroids and mesalazine	(⁴²⁾42. Meini S, Laureano R, Fani L, Tascini C, Galano A, Antonelli A, et al. Breakthrough Lactobacillus rhamnosus GG bacteremia associated with probiotic use in an adult patient with severe active ulcerative colitis: case report and review of the literature. Infection 2015; 43: 777-781, doi: 10.1007/s15010-015-0798-2. https://doi.org/10.1007/s15010-015-0798-...
	Lactobacillus rhamnosus GG	A child with ulcerative colitis	(⁴³⁾43. Vahabnezhad E, Mochon AB, Wozniak LJ, Ziring DA. Lactobacillus bacteremia associated with probiotic use in a pediatric patient with ulcerative colitis. J Clin Gastroenterol 2013; 47: 437-439, doi: 10.1097/MCG.0b013e318279abf0. https://doi.org/10.1097/MCG.0b013e318279...
	Lactobacillus rhamnosus GG	A child with the short gut syndrome	(⁴⁴⁾44. De Groote MA, Frank DN, Dowell E, Glode MP, Pace NR. Lactobacillus rhamnosus GG bacteremia associated with probiotic use in a child with short gut syndrome. Pediatr Infect Dis J 2005; 24: 278-280, doi: 10.1097/01.inf.0000154588.79356.e6. https://doi.org/10.1097/01.inf.000015458...
	Lactobacillus rhamnosus	Patient with hepatic cirrhosis	(⁴⁹⁾49. Naqvi SSB, Nagendra V, Hofmeyr A. Probiotic related Lactobacillus rhamnosus endocarditis in a patient with liver cirrhosis. IDCases 2018; 13: e00439, doi: 10.1016/j.idcr.2018.e00439. https://doi.org/10.1016/j.idcr.2018.e004...
	Lactobacillus paracasei	Patient with prostate cancer in remission	(⁵⁰⁾50. Franko B, Vaillant M, Recule C, Vautrin E, Brion JP, Pavese P. Lactobacillus paracasei endocarditis in a consumer of probiotics. Med Mal Infect 2013; 43: 171-173, doi: 10.1016/j.medmal.2013.01.007. https://doi.org/10.1016/j.medmal.2013.01...
	Bifidobacterium longum	Preterm infants	(⁵¹51. Esaiassen E, Cavanagh P, Hjerde E, Simonsen GS, Støen R, Klingenberg C. Bifidobacterium longum subspecies infantis bacteremia in 3 extremely preterm infants receiving probiotics. Emerg Infect Dis 2016; 22: 1664-1666, doi: 10.3201/eid2209.160033. https://doi.org/10.3201/eid2209.160033... ,⁸⁸⁾88. Bertelli C, Pillonel T, Torregrossa A, Prod'hom G, Julie Fischer C, Greub G, et al. Bifidobacterium longum bacteremia in preterm infants receiving probiotics. Clin Infect Dis 2015; 60: 924-927, doi: 10.1093/cid/ciu946. https://doi.org/10.1093/cid/ciu946...
	Bifidobacterium breve	Newborn with multiple abdominal organ abnormalities	(⁵²⁾52. Sato S, Uchida T, Kuwana S, Sasaki K, Watanabe T, Saito J, et al. Bacteremia induced by Bifidobacterium breve in a newborn with cloacal exstrophy. Pediatr Int 2016; 58: 1226-1228, doi: 10.1111/ped.13103. https://doi.org/10.1111/ped.13103...
	Bifidobacterium spp.	A child with heart disease	(⁵³⁾53. Pruccoli G, Silvestro E, Napoleone CP, Aidala E, Garazzino S, Scolfaro C. Are probiotics safe? Bifidobacterium bacteremia in a child with severe heart failure. Infez Med 2019; 27: 175-178.
	Lactobacillus acidophilus	Immunosuppressed patient	(⁵⁴⁾54. LeDoux D, LaBombardi VJ, Karter D. Lactobacillus acidophilus bacteraemia after use of a probiotic in a patient with AIDS and Hodgkin's disease. Int J STD AIDS 2006; 17: 280-282, doi: 10.1258/095646206776253507. https://doi.org/10.1258/0956462067762535...
Epidural and retropharyngeal abscess	Lactobacillus rhamnosus	Adult with severe ulcerative colitis	(⁴⁵⁾45. Conen A, Zimmerer S, Trampuz A, Frei R, Battegay M, Elzi L. A pain in the neck: probiotics for ulcerative colitis. Ann Int Med 2009; 151: 895-897, doi: 10.7326/0003-4819-151-12-200912150-00020. https://doi.org/10.7326/0003-4819-151-12...
Hepatic abscess	Lactobacillus rhamnosus	Adult with hypertension and diabetes	(⁴⁶⁾46. Rautio M, Jousimies-Somer H, Kauma H, Pietarinen I, Saxelin M, Tynkkynen S, et al. Liver abscess due to a Lactobacillus rhamnosus strain indistinguishable from L. rhamnosus Strain GG. Clin Infect Dis 1999; 28: 1159-1160, doi: 10.1086/514766. https://doi.org/10.1086/514766...
Endocarditis	Lactobacillus rhamnosus, Streptococcus faecalis, and Lactobacillus acidophilus	Adult with mild mitral valve regurgitation	(⁴⁷⁾47. Mackay AD, Taylor MB, Kibbler CC, Hamilton-Miller JMT. Lactobacillus endocarditis caused by a probiotic organism. Clin Microbiol Infect 1999; 5: 290-292, doi: 10.1111/j.1469-0691.1999.tb00144.x. https://doi.org/10.1111/j.1469-0691.1999...
	Lactobacillus rhamnosus	Adult with gingival ulceration	(⁴⁸⁾48. Pasala S, Singer L, Arshad T, Roach K. Lactobacillus endocarditis in a healthy patient with probiotic use. IDCases 2020; 22: e00915, doi: 10.1016/j.idcr.2020.e00915. https://doi.org/10.1016/j.idcr.2020.e009...

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[1] Correspondence: R.C.P. Lima-Júnior: <robertocesar@ufc.br>