Skip to main content
SpringerLink
Log in

Pathogenesis and Consequences of a Disruption to the Intestinal Barrier Functions in Patients with Hematologic Malignancies

  • Chapter
  • First Online:
Interdisciplinary Cancer Research

Part of the book series: Interdisciplinary Cancer Research

Abstract

The intestinal barrier is a complex structure that plays a pivotal role in the regulation of the influx of luminal contents into the systemic circulation and maintains homeostasis of immune cells, microbes, and metabolites. Disruption in the intestinal barrier functions has been implicated in the development of many systemic diseases such as nonalcoholic steatohepatitis, inflammatory bowel disease, multiple sclerosis, atherosclerosis, type 2 diabetes mellitus, and cancer. Therefore, the intestinal barrier presents a potential target for therapeutic intervention to alter the course and mitigate complications associated with these diseases. Patients with hematologic malignancies are particularly at high risk for developing a disruption to the intestinal barrier functions due to the disease processes and to therapeutic interventions, either to treat the underlying disease or to support the patient following treatment. In this chapter, we not only discuss the pathogenesis and nature of the intestinal barrier function disruption in patients with hematologic malignancies but also examine the associated complications. We explore methods available to modulate the complications and their associated challenges.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution

Institutional subscriptions

References

  • Agirman G, Yu KB, Hsiao EY (2021) Signaling inflammation across the gut-brain axis. Science 374:1087–1092

    Google Scholar 

  • Aguilar-Guisado M, Espigado I, Martín-Peña A, Gudiol C, Royo-Cebrecos C, Falantes J, Vázquez-López L, Montero MI, Rosso-Fernández C, de la Luz Martino M, Parody R, González-Campos J, Garzón-López S, Calderón-Cabrera C, Barba P, Rodríguez N, Rovira M, Montero-Mateos E, Carratalá J, Pérez-Simón JA et al (2017) Optimisation of empirical antimicrobial therapy in patients with haematological malignancies and febrile neutropenia (how long study): an open-label, randomised, controlled phase 4 trial. Lancet Haematol 4:e573–e583

    Google Scholar 

  • Aigelsreiter A, Gerlza T, Deutsch AJA, Leitner E, Beham-Schmid C, Beham A, Popper H, Borel N, Pospischil A, Raderer M, Kessler HH, Neumeister P (2011) Chlamydia psittaci infection in nongastrointestinal extranodal MALT lymphomas and their precursor lesions. Am J Clin Pathol 135:70–75

    Google Scholar 

  • Aitken SL, Nagel JL, Abbo L, Alegria W, Barreto JN, Dadwal S, Freifeld AG, Jain R, Pergam SA, Tverdek FP, Seo SK, Antimicrobial Stewardship in Cancer Consortium ASCC (2019) Antimicrobial stewardship in cancer patients: the time is now. J Natl Compr Cancer Netw 17:772–775

    Google Scholar 

  • Altınel E, Yarali N, Isık P, Bay A, Kara A, Tunc B (2012) Typhlitis in acute childhood Leukemia. Med Princ Pract 21:36–39

    Google Scholar 

  • Appleton J (2018) The gut-brain Axis: influence of microbiota on mood and mental health. Integr Med Clin J 17:28–32

    Google Scholar 

  • Ara T, Hashimoto D, Hayase E, Noizat C, Kikuchi R, Hasegawa Y, Matsuda K, Ono S, Matsuno Y, Ebata K, Ogasawara R, Takahashi S, Ohigashi H, Yokoyama E, Matsuo K, Sugita J, Onozawa M, Okumura R, Takeda K, Teshima T (2020) Intestinal goblet cells protect against GVHD after allogeneic stem cell transplantation via Lypd8. Sci Transl Med 12:eaaw0720

    Google Scholar 

  • Athar U, Gentile TC (2009) Keratinocyte growth factor. Expert Opin Biol Ther 9:779–787

    Google Scholar 

  • Bai L, Zhou P, Li D, Ju X (2017) Changes in the gastrointestinal microbiota of children with acute lymphoblastic leukaemia and its association with antibiotics in the short term. J Med Microbiol 66:1297–1307

    Google Scholar 

  • Baur D, Gladstone BP, Burkert F, Carrara E, Foschi F, Döbele S, Tacconelli E (2017) Effect of antibiotic stewardship on the incidence of infection and colonisation with antibiotic-resistant bacteria and Clostridium difficile infection: a systematic review and meta-analysis. Lancet Infect Dis 17:990–1001

    Google Scholar 

  • Baxter NT, Schmidt AW, Venkataraman A, Kim KS, Waldron C, Schmidt TM (2019) Dynamics of human gut microbiota and short-chain fatty acids in response to dietary interventions with three fermentable fibers. MBio 10:e02566-18

    Google Scholar 

  • Benamu E, Deresinski S (2018) Vancomycin-resistant enterococcus infection in the hematopoietic stem cell transplant recipient: an overview of epidemiology, management, and prevention. F1000Research 7:3

    Google Scholar 

  • Beutheu Youmba S, Belmonte L, Galas L, Boukhettala N, Bôle-Feysot C, Déchelotte P, Coëffier M (2012) Methotrexate modulates tight junctions through NF-κB, MEK, and JNK pathways. J Pediatr Gastroenter Nutr 54:463–470

    Google Scholar 

  • Blijlevens NMA, van’t Land B, Donnelly JP, M’Rabet L, de Pauw BE (2004) Measuring mucosal damage induced by cytotoxic therapy. Support Care Cancer 12:227–233

    Google Scholar 

  • Bradford PA (2001) Extended-spectrum beta-lactamases in the 21st century: characterization, epidemiology, and detection of this important resistance threat. Clin Microbiol Rev 14:933–951. table of contents

    Google Scholar 

  • Buchta Rosean C, Bostic RR, Ferey JCM, Feng T-Y, Azar FN, Tung KS, Dozmorov MG, Smirnova E, Bos PD, Rutkowski MR (2019) Preexisting commensal dysbiosis is a host-intrinsic regulator of tissue inflammation and tumor cell dissemination in hormone receptor–positive breast cancer. Cancer Res 79:3662–3675

    Google Scholar 

  • Buschmann MM, Shen L, Rajapakse H, Raleigh DR, Wang Y, Wang Y, Lingaraju A, Zha J, Abbott E, McAuley EM, Breskin LA, Wu L, Anderson K, Turner JR, Weber CR (2013) Occludin OCEL-domain interactions are required for maintenance and regulation of the tight junction barrier to macromolecular flux. Mol Biol Cell 24:3056–3068

    Google Scholar 

  • Butel M-J (2014) Probiotics, gut microbiota and health. Med Mal Infect 44:1–8

    Google Scholar 

  • Carabotti M, Scirocco A, Maselli MA, Severi C (2015) The gut-brain axis: interactions between enteric microbiota, central and enteric nervous systems. Ann Gastroenterol 28:203–209

    Google Scholar 

  • Chanez-Paredes SD, Abtahi S, Kuo W-T, Turner JR (2021) Differentiating between tight junction-dependent and tight junction-independent intestinal barrier loss in vivo. Methods Mol Biol 2367:249–271

    Google Scholar 

  • Chavez JC, Locke FL (2018) CAR T cell therapy for B-cell lymphomas. Best Pract Res Clin Haematol 31:135–146

    Google Scholar 

  • Chebl RB, Safa R, Sabra M, Chami A, Berbari I, Jamali S, Makki M, Tamim H, Dagher GA (2021) Sepsis in patients with haematological versus solid cancer: a retrospective cohort study. BMJ Open 11:e038349

    Google Scholar 

  • Chiang H-Y, Perencevich EN, Nair R, Nelson RE, Samore M, Khader K, Chorazy ML, Herwaldt LA, Blevins A, Ward MA, Schweizer ML (2017) Incidence and outcomes associated with infections caused by vancomycin-resistant enterococci in the United States: systematic literature review and meta-analysis. Infect Control Hosp Epidemiol 38:203–215

    Google Scholar 

  • Chua LL, Rajasuriar R, Lim YAL, Woo YL, Loke P, Ariffin H (2020) Temporal changes in gut microbiota profile in children with acute lymphoblastic leukemia prior to commencement-, during-, and post-cessation of chemotherapy. BMC Cancer 20:151

    Google Scholar 

  • Cooke KR, Hill GR, Crawford JM, Bungard D, Brinson YS, Delmonte J, Ferrara JL (1998) Tumor necrosis factor- alpha production to lipopolysaccharide stimulation by donor cells predicts the severity of experimental acute graft-versus-host disease. J Clin Invest 102:1882–1891

    Google Scholar 

  • Cooke KR, Gerbitz A, Crawford JM, Teshima T, Hill GR, Tesolin A, Rossignol DP, Ferrara JLM (2001) LPS antagonism reduces graft-versus-host disease and preserves graft-versus-leukemia activity after experimental bone marrow transplantation. J Clin Invest 107:1581–1589

    Google Scholar 

  • Crawford J, Dale DC, Lyman GH (2004) Chemotherapy-induced neutropenia. Cancer 100:228–237

    Google Scholar 

  • Crenn P, Messing B, Cynober L (2008) Citrulline as a biomarker of intestinal failure due to enterocyte mass reduction. Clin Nutr 27:328–339

    Google Scholar 

  • Dao MC, Everard A, Aron-Wisnewsky J, Sokolovska N, Prifti E, Verger EO, Kayser BD, Levenez F, Chilloux J, Hoyles L, MICRO-Obes Consortium, Dumas M-E, Rizkalla SW, Doré J, Cani PD, Clément K (2016) Akkermansia muciniphila and improved metabolic health during a dietary intervention in obesity: relationship with gut microbiome richness and ecology. Gut 65:426–436

    Google Scholar 

  • de Moreno de LeBlanc A, del Carmen S, Zurita-Turk M, Santos Rocha C, van de Guchte M, Azevedo V, Miyoshi A, LeBlanc JG (2011) Importance of IL-10 modulation by probiotic microorganisms in gastrointestinal inflammatory diseases. ISRN Gastroenterol 2011:1–11

    Google Scholar 

  • DeFilipp Z, Bloom PP, Torres Soto M, Mansour MK, Sater MRA, Huntley MH, Turbett S, Chung RT, Chen Y-B, Hohmann EL (2019) Drug-Resistant E. coli Bacteremia transmitted by fecal microbiota transplant. N Engl J Med 381:2043–2050

    Google Scholar 

  • Delano MJ, Ward PA (2016a) Sepsis-induced immune dysfunction: can immune therapies reduce mortality? J Clin Invest 126:23–31

    Google Scholar 

  • Delano MJ, Ward PA (2016b) The immune system’s role in sepsis progression, resolution, and long-term outcome. Immunol Rev 274:330–353

    Google Scholar 

  • Depommier C, Everard A, Druart C, Plovier H, Van Hul M, Vieira-Silva S, Falony G, Raes J, Maiter D, Delzenne NM, de Barsy M, Loumaye A, Hermans MP, Thissen J-P, de Vos WM, Cani PD (2019) Supplementation with Akkermansia muciniphila in overweight and obese human volunteers: a proof-of-concept exploratory study. Nat Med 25:1096–1103

    Google Scholar 

  • Desai MS, Seekatz AM, Koropatkin NM, Kamada N, Hickey CA, Wolter M, Pudlo NA, Kitamoto S, Terrapon N, Muller A, Young VB, Henrissat B, Wilmes P, Stappenbeck TS, Núñez G, Martens EC (2016) A dietary fiber-deprived gut microbiota degrades the colonic mucus barrier and enhances pathogen susceptibility. Cell 167:1339–1353.e21

    Google Scholar 

  • Drossman DA, Tack J, Ford AC, Szigethy E, Törnblom H, Van Oudenhove L (2018) Neuromodulators for functional gastrointestinal disorders (disorders of gut-brain interaction): a Rome foundation working team report. Gastroenterology 154:1140–1171.e1

    Google Scholar 

  • Dutta D, Lim SH (2020) Bidirectional interaction between intestinal microbiome and cancer: opportunities for therapeutic interventions. Biomark Res 8:31

    Google Scholar 

  • Dutta D, Methe B, Amar S, Morris A, Lim SH (2019) Intestinal injury and gut permeability in sickle cell disease. J Transl Med 17:183

    Google Scholar 

  • Engevik MA, Engevik AC, Engevik KA, Auchtung JM, Chang-Graham AL, Ruan W, Luna RA, Hyser JM, Spinler JK, Versalovic J (2021) Mucin-degrading microbes release monosaccharides that chemoattract clostridioides difficile and facilitate colonization of the human intestinal mucus layer. ACS Infect Dis 7:1126–1142

    Google Scholar 

  • Eriguchi Y, Takashima S, Oka H, Shimoji S, Nakamura K, Uryu H, Shimoda S, Iwasaki H, Shimono N, Ayabe T, Akashi K, Teshima T (2012) Graft-versus-host disease disrupts intestinal microbial ecology by inhibiting Paneth cell production of α-defensins. Blood 120:223–231

    Google Scholar 

  • Erny D, Hrabě de Angelis AL, Jaitin D, Wieghofer P, Staszewski O, David E, Keren-Shaul H, Mahlakoiv T, Jakobshagen K, Buch T, Schwierzeck V, Utermöhlen O, Chun E, Garrett WS, McCoy KD, Diefenbach A, Staeheli P, Stecher B, Amit I, Prinz M (2015) Host microbiota constantly control maturation and function of microglia in the CNS. Nat Neurosci 18:965–977

    Google Scholar 

  • Faron ML, Ledeboer NA, Buchan BW (2016) Resistance mechanisms, epidemiology, and approaches to screening for vancomycin-resistant enterococcus in the health care setting. J Clin Microbiol 54:2436–2447

    Google Scholar 

  • Fasano A, Not T, Wang W, Uzzau S, Berti I, Tommasini A, Goldblum SE (2000) Zonulin, a newly discovered modulator of intestinal permeability, and its expression in coeliac disease. Lancet 355:1518–1519

    Google Scholar 

  • Fiorentino M, Sapone A, Senger S, Camhi SS, Kadzielski SM, Buie TM, Kelly DL, Cascella N, Fasano A (2016) Blood–brain barrier and intestinal epithelial barrier alterations in autism spectrum disorders. Mol Autism 7(1). https://doi.org/10.1186/s13229-016-0110-z

  • France MM, Turner JR (2017) The mucosal barrier at a glance. J Cell Sci 130:307–314

    Google Scholar 

  • Gorschlüter M, Mey U, Strehl J, Ziske C, Schepke M, Schmidt-Wolf IGH, Sauerbruch T, Glasmacher A (2005) Neutropenic enterocolitis in adults: systematic analysis of evidence quality. Eur J Haematol 75:1–13

    Google Scholar 

  • Grander C, Adolph TE, Wieser V, Lowe P, Wrzosek L, Gyongyosi B, Ward DV, Grabherr F, Gerner RR, Pfister A, Enrich B, Ciocan D, Macheiner S, Mayr L, Drach M, Moser P, Moschen AR, Perlemuter G, Szabo G, Cassard AM et al (2018) Recovery of ethanol-induced Akkermansia muciniphila depletion ameliorates alcoholic liver disease. Gut 67:891–901

    Google Scholar 

  • Guarana M, Nucci M, Nouér SA (2019) Shock and early death in hematologic patients with febrile neutropenia. Antimicrob Agents Chemother 63:e01250-19

    Google Scholar 

  • Guerra L, Guidi R, Frisan T (2011) Do bacterial genotoxins contribute to chronic inflammation, genomic instability and tumor progression? FEBS J 278:4577–4588

    Google Scholar 

  • Hakim H, Dallas R, Wolf J, Tang L, Schultz-Cherry S, Darling V, Johnson C, Karlsson EA, Chang T-C, Jeha S, Pui C-H, Sun Y, Pounds S, Hayden RT, Tuomanen E, Rosch JW (2018) Gut microbiome composition predicts infection risk during chemotherapy in children with acute lymphoblastic Leukemia. Clin Infect Dis 67:541–548

    Google Scholar 

  • Hayase E, Hashimoto D, Nakamura K, Noizat C, Ogasawara R, Takahashi S, Ohigashi H, Yokoi Y, Sugimoto R, Matsuoka S, Ara T, Yokoyama E, Yamakawa T, Ebata K, Kondo T, Hiramine R, Aizawa T, Ogura Y, Hayashi T, Mori H et al (2017) R-Spondin1 expands Paneth cells and prevents dysbiosis induced by graft-versus-host disease. J Exp Med 214:3507–3518

    Google Scholar 

  • Heidt PJ, Vossen JM (1992) Experimental and clinical gnotobiotics: influence of the microflora on graft-versus-host disease after allogeneic bone marrow transplantation. J Med 23:161–173

    Google Scholar 

  • Heinsen F-A, Knecht H, Neulinger SC, Schmitz RA, Knecht C, Kühbacher T, Rosenstiel PC, Schreiber S, Friedrichs AK, Ott SJ (2015) Dynamic changes of the luminal and mucosa-associated gut microbiota during and after antibiotic therapy with paromomycin. Gut Microbes 6:243–254

    Google Scholar 

  • Heisel RW, Sutton RR, Mascara GP, Winger DG, Weber DR, Lim SH, Oleksiuk L-M (2017) Vancomycin-resistant enterococci in acute myeloid leukemia and myelodysplastic syndrome patients undergoing induction chemotherapy with idarubicin and cytarabine. Leuk Lymphoma 58:2565–2572

    Google Scholar 

  • Horowitz A, Chanez-Paredes SD, Haest X, Turner JR (2023) Paracellular permeability and tight junction regulation in gut health and disease. Nat Rev Gastroenterol Hepatol 20:417–432

    Google Scholar 

  • Hryckowian AJ, Van Treuren W, Smits SA, Davis NM, Gardner JO, Bouley DM, Sonnenburg JL (2018) Microbiota-accessible carbohydrates suppress Clostridium difficile infection in a murine model. Nat Microbiol 3:662–669

    Google Scholar 

  • Huber-Lang MS, Sarma JV, McGuire SR, Lu KT, Guo RF, Padgaonkar VA, Younkin EM, Laudes IJ, Riedemann NC, Younger JG, Ward PA (2001) Protective effects of anti-C5a peptide antibodies in experimental sepsis. FASEB J 15:568–570

    Google Scholar 

  • Ido A, Numata M, Kodama M, Tsubouchi H (2005) Mucosal repair and growth factors: recombinant human hepatocyte growth factor as an innovative therapy for inflammatory bowel disease. J Gastroenterol 40:925–931

    Google Scholar 

  • Ijiri K, Potten CS (1983) Response of intestinal cells of differing topographical and hierarchical status to ten cytotoxic drugs and five sources of radiation. Br J Cancer 47:175–185

    Google Scholar 

  • Jansen SA, Nieuwenhuis EES, Hanash AM, Lindemans CA (2022) Challenges and opportunities targeting mechanisms of epithelial injury and recovery in acute intestinal graft-versus-host disease. Mucosal Immunol 15:605–619

    Google Scholar 

  • Johnson WF, DiPalma CR, Ziegler TR, Scully S, Farrell CL (2000) Keratinocyte growth factor enhances early gut adaptation in a rat model of short bowel syndrome. Vet Surg 29:17–27

    Google Scholar 

  • Kamboj M, Xiao K, Kaltsas A, Huang Y-T, Sun J, Chung D, Wu S, Sheahan A, Sepkowitz K, Jakubowski AA, Papanicolaou G (2014) Clostridium difficile infection after allogeneic hematopoietic stem cell transplant: strain diversity and outcomes associated with NAP1/027. Biol Blood Marrow Transplant 20:1626–1633

    Google Scholar 

  • Katz JA, Wagner ML, Gresik MV, Mahoney DH, Fernbach DJ (1990) Typhlitis. An 18-year experience and postmortem review. Cancer 65:1041–1047

    Google Scholar 

  • Kim M-H, Kim H (2017) The roles of glutamine in the intestine and its implication in intestinal diseases. Int J Mol Sci 18:1051

    Google Scholar 

  • Kinashi Y, Hase K (2021) Partners in leaky gut syndrome: intestinal dysbiosis and autoimmunity. Front Immunol 12:673708

    Google Scholar 

  • Krantz EM, Zier J, Stohs E, Ogimi C, Sweet A, Marquis S, Klaassen J, Pergam SA, Liu C (2020) Antibiotic prescribing and respiratory viral testing for acute upper respiratory infections among adult patients at an ambulatory cancer center. Clin Infect Dis 70:1421–1428

    Google Scholar 

  • Ladas EJ, Bhatia M, Chen L, Sandler E, Petrovic A, Berman DM, Hamblin F, Gates M, Hawks R, Sung L, Nieder M (2016) The safety and feasibility of probiotics in children and adolescents undergoing hematopoietic cell transplantation. Bone Marrow Transplant 51:262–266

    Google Scholar 

  • Lalaoui R, Javelle E, Bakour S, Ubeda C, Rolain J-M (2020) Infections due to Carbapenem-resistant bacteria in patients with hematologic malignancies. Front Microbiol 11:1422

    Google Scholar 

  • Lemiale V, Pons S, Mirouse A, Tudesq J-J, Hourmant Y, Mokart D, Pène F, Kouatchet A, Mayaux J, Nyunga M, Bruneel F, Meert A-P, Borcoman E, Bisbal M, Legrand M, Benoit D, Azoulay E, Darmon M, Zafrani L (2020) Sepsis and septic shock in patients with malignancies: a Groupe de Recherche Respiratoire en Réanimation Onco-Hématologique Study. Crit Care Med 48:822–829

    Google Scholar 

  • Le-Trilling VTK, Ebel J-F, Baier F, Wohlgemuth K, Pfeifer KR, Mookhoek A, Krebs P, Determann M, Katschinski B, Adamczyk A, Lange E, Klopfleisch R, Lange CM, Sokolova V, Trilling M, Westendorf AM (2023) Acute cytomegalovirus infection modulates the intestinal microbiota and targets intestinal epithelial cells. Eur J Immunol 53:2249940

    Google Scholar 

  • Li J, Zhao F, Wang Y, Chen J, Tao J, Tian G, Wu S, Liu W, Cui Q, Geng B, Zhang W, Weldon R, Auguste K, Yang L, Liu X, Chen L, Yang X, Zhu B, Cai J (2017) Gut microbiota dysbiosis contributes to the development of hypertension. Microbiome 5:14

    Google Scholar 

  • Li G, Lin J, Zhang C, Gao H, Lu H, Gao X, Zhu R, Li Z, Li M, Liu Z (2021) Microbiota metabolite butyrate constrains neutrophil functions and ameliorates mucosal inflammation in inflammatory bowel disease. Gut Microbes 13:1968257

    Google Scholar 

  • Lichtman SM (1995) Physiological aspects of aging: implications for the treatment of cancer. Drugs Aging 7:212–225

    Google Scholar 

  • Lifschitz CH, Mahoney DH (1989) Low-dose methotrexate-induced changes in intestinal permeability determined by polyethylene glycol polymers. J Pediatr Gastroenterol Nutr 9:301

    Google Scholar 

  • Litvak Y, Byndloss MX, Bäumler AJ (2018) Colonocyte metabolism shapes the gut microbiota. Science (New York, NY) 362:eaat9076

    Google Scholar 

  • Logan AC, Venket Rao A, Irani D (2003) Chronic fatigue syndrome: lactic acid bacteria may be of therapeutic value. Med Hypotheses 60:915–923

    Google Scholar 

  • Logan RM, Stringer AM, Bowen JM, Yeoh AS-J, Gibson RJ, Sonis ST, Keefe DMK (2007) The role of pro-inflammatory cytokines in cancer treatment-induced alimentary tract mucositis: pathobiology, animal models and cytotoxic drugs. Cancer Treat Rev 33:448–460

    Google Scholar 

  • Logan RM, Stringer AM, Bowen JM, Gibson RJ, Sonis ST, Keefe DMK (2008) Serum levels of NF-κB and pro-inflammatory cytokines following administration of mucotoxic drugs. Cancer Biol Ther 7:1139–1145

    Google Scholar 

  • Louis P, Flint HJ (2017) Formation of propionate and butyrate by the human colonic microbiota. Environ Microbiol 19:29–41

    Google Scholar 

  • Luznik L, Jones RJ, Fuchs EJ (2010) High-dose cyclophosphamide for graft-versus-host disease prevention. Curr Opin Hematol 17:493–499

    Google Scholar 

  • Ma TY, Iwamoto GK, Hoa NT, Akotia V, Pedram A, Boivin MA, Said HM (2004) TNF-alpha-induced increase in intestinal epithelial tight junction permeability requires NF-kappa B activation. Am J Physiol Gastrointest Liver Physiol 286:G367–G376

    Google Scholar 

  • Ma TY, Boivin MA, Ye D, Pedram A, Said HM (2005) Mechanism of TNF-α modulation of Caco-2 intestinal epithelial tight junction barrier: role of myosin light-chain kinase protein expression. Am J Physiol Gastrointest Liver Physiol 288:G422–G430

    Google Scholar 

  • Madsen K, Cornish A, Soper P, McKaigney C, Jijon H, Yachimec C, Doyle J, Jewell L, De Simone C (2001) Probiotic bacteria enhance murine and human intestinal epithelial barrier function. Gastroenterology 121:580–591

    Google Scholar 

  • Maidji E, Somsouk M, Rivera JM, Hunt PW, Stoddart CA (2017) Replication of CMV in the gut of HIV-infected individuals and epithelial barrier dysfunction. PLoS Pathog 13:e1006202

    Google Scholar 

  • Manzo VE, Bhatt AS (2015) The human microbiome in hematopoiesis and hematologic disorders. Blood 126:311–318

    Google Scholar 

  • Marchesi F, Pimpinelli F, Ensoli F, Mengarelli A (2018) Cytomegalovirus infection in hematologic malignancy settings other than the allogeneic transplant. Hematol Oncol 36:381–391

    Google Scholar 

  • Marcus BC, Wyble CW, Hynes KL, Gewertz BL (1996) Cytokine-induced increases in endothelial permeability occur after adhesion molecule expression. Surgery 120:411–417

    Google Scholar 

  • Masenga SK, Hamooya B, Hangoma J, Hayumbu V, Ertuglu LA, Ishimwe J, Rahman S, Saleem M, Laffer CL, Elijovich F, Kirabo A (2022) Recent advances in modulation of cardiovascular diseases by the gut microbiota. J Hum Hypertens 36:952–959

    Google Scholar 

  • McGlone SM, Bailey RR, Zimmer SM, Popovich MJ, Tian Y, Ufberg P, Muder RR, Lee BY (2012) The economic burden of Clostridium difficile. Clin Microbiol Infect 18:282–289

    Google Scholar 

  • Melichar B, Zezulová M (2011) The significance of altered gastrointestinal permeability in cancer patients. Curr Opin Support Palliat Care 5:47

    Google Scholar 

  • Michielan A, D’Incà R (2015) Intestinal permeability in inflammatory bowel disease: pathogenesis, clinical evaluation, and therapy of leaky gut. Mediat Inflamm 2015:628157

    Google Scholar 

  • Montassier E, Gastinne T, Vangay P, Al-Ghalith GA, Bruley des Varannes S, Massart S, Moreau P, Potel G, de La Cochetière MF, Batard E, Knights D (2015) Chemotherapy-driven dysbiosis in the intestinal microbiome. Aliment Pharmacol Ther 42:515–528

    Google Scholar 

  • Montassier E, Al-Ghalith GA, Ward T, Corvec S, Gastinne T, Potel G, Moreau P, de la Cochetiere MF, Batard E, Knights D (2016) Pretreatment gut microbiome predicts chemotherapy-related bloodstream infection. Genome Med 8:49

    Google Scholar 

  • Moorefield EC, Andres SF, Blue RE, Van Landeghem L, Mah AT, Santoro MA, Ding S (2017) Aging effects on intestinal homeostasis associated with expansion and dysfunction of intestinal epithelial stem cells. Aging (Albany NY) 9:1898–1915

    Google Scholar 

  • Munford RS (2016) Endotoxemia—menace, marker, or mistake? J Leukoc Biol 100:687–698

    Google Scholar 

  • Nalle SC, Zuo L, Ong MLDM, Singh G, Worthylake AM, Choi W, Manresa MC, Southworth AP, Edelblum KL, Baker GJ, Joseph NE, Savage PA, Turner JR (2019) Graft-versus-host disease propagation depends on increased intestinal epithelial tight junction permeability. J Clin Invest 129:902–914

    Google Scholar 

  • Nearing JT, Connors J, Whitehouse S, Van Limbergen J, Macdonald T, Kulkarni K, Langille MGI (2019) Infectious complications are associated with alterations in the gut microbiome in Pediatric patients with acute lymphoblastic Leukemia. Front Cell Infect Microbiol 9:28

    Google Scholar 

  • Nesher L, Rolston KVI (2013) Neutropenic enterocolitis, a growing concern in the era of widespread use of aggressive chemotherapy. Clin Infect Dis 56:711–717

    Google Scholar 

  • Ozdemir E, Aslan A, Turker A, Barista I, Kars A (2015) Gemcitabine in combination with Oxaliplatin (GEMOX) as a salvage regimen in patients with relapsed/refractory Hodgkin’s lymphoma. Blood 126:1517

    Google Scholar 

  • Parker A, Fonseca S, Carding SR (2019) Gut microbes and metabolites as modulators of blood-brain barrier integrity and brain health. Gut Microbes 11:135–157

    Google Scholar 

  • Paterson DL, Bonomo RA (2005) Extended-spectrum beta-lactamases: a clinical update. Clin Microbiol Rev 18:657–686

    Google Scholar 

  • Peled JU, Devlin SM, Staffas A, Lumish M, Khanin R, Littmann ER, Ling L, Kosuri S, Maloy M, Slingerland JB, Ahr KF, Porosnicu Rodriguez KA, Shono Y, Slingerland AE, Docampo MD, Sung AD, Weber D, Alousi AM, Gyurkocza B, Ponce DM et al (2017) Intestinal microbiota and relapse after hematopoietic-cell transplantation. J Clin Oncol Off J Am Soc Clin Oncol 35:1650–1659

    Google Scholar 

  • Peng L, Li Z-R, Green RS, Holzman IR, Lin J (2009) Butyrate enhances the intestinal barrier by facilitating tight junction assembly via activation of AMP-activated protein kinase in Caco-2 cell monolayers. J Nutr 139:1619–1625

    Google Scholar 

  • Pizzuti D, Bortolami M, Mazzon E, Buda A, Guariso G, D’Odorico A, Chiarelli S, D’Incà R, De Lazzari F, Martines D (2004) Transcriptional downregulation of tight junction protein ZO-1 in active coeliac disease is reversed after a gluten-free diet. Dig Liver Dis 36:337–341

    Google Scholar 

  • Plaza-Díaz J, Solís-Urra P, Rodríguez-Rodríguez F, Olivares-Arancibia J, Navarro-Oliveros M, Abadía-Molina F, Álvarez-Mercado AI (2020) The gut barrier, intestinal microbiota, and liver disease: molecular mechanisms and strategies to manage. Int J Mol Sci 21:8351

    Google Scholar 

  • Ponziani FR, Bhoori S, Castelli C, Putignani L, Rivoltini L, Del Chierico F, Sanguinetti M, Morelli D, Paroni Sterbini F, Petito V, Reddel S, Calvani R, Camisaschi C, Picca A, Tuccitto A, Gasbarrini A, Pompili M, Mazzaferro V (2019) Hepatocellular carcinoma is associated with gut microbiota profile and inflammation in nonalcoholic fatty liver disease. Hepatology 69:107–120

    Google Scholar 

  • Pop-Began V, Păunescu V, Grigorean V, Pop-Began D, Popescu C (2014) Molecular mechanisms in the pathogenesis of sepsis. J Med Life 7:38–41

    Google Scholar 

  • Poritz LS, Garver KI, Tilberg AF, Koltun WA (2004) Tumor necrosis factor alpha disrupts tight junction assembly. J Surg Res 116:14–18

    Google Scholar 

  • Pouch SM, Satlin MJ (2017) Carbapenem-resistant Enterobacteriaceae in special populations: solid organ transplant recipients, stem cell transplant recipients, and patients with hematologic malignancies. Virulence 8:391–402

    Google Scholar 

  • Rafailidis PI, Mourtzoukou EG, Varbobitis IC, Falagas ME (2008) Severe cytomegalovirus infection in apparently immunocompetent patients: a systematic review. Virol J 5:47

    Google Scholar 

  • Rajagopala SV, Yooseph S, Harkins DM, Moncera KJ, Zabokrtsky KB, Torralba MG, Tovchigrechko A, Highlander SK, Pieper R, Sender L, Nelson KE (2016) Gastrointestinal microbial populations can distinguish pediatric and adolescent Acute Lymphoblastic Leukemia (ALL) at the time of disease diagnosis. BMC Genomics 17:635

    Google Scholar 

  • Raleigh DR, Marchiando AM, Zhang Y, Shen L, Sasaki H, Wang Y, Long M, Turner JR (2010) Tight junction-associated MARVEL proteins marveld3, tricellulin, and occludin have distinct but overlapping functions. Mol Biol Cell 21:1200–1213

    Google Scholar 

  • Rannikko J, Holmberg V, Karppelin M, Arvola P, Huttunen R, Mattila E, Kerttula N, Puhto T, Tamm Ü, Koivula I, Vuento R, Syrjänen J, Hohenthal U (2021) Fungemia and other fungal infections associated with use of Saccharomyces boulardii Probiotic Supplements. Emerg Infect Dis 27. Available at: https://wwwnc.cdc.gov/eid/article/27/8/21-0018_article. Accessed 13 Mar 2023.

  • Rearigh L, Stohs E, Freifeld A, Zimmer A (2020) De-escalation of empiric broad spectrum antibiotics in hematopoietic stem cell transplant recipients with febrile neutropenia. Ann Hematol 99:1917–1924

    Google Scholar 

  • Rendo MJ, Joseph JJ, Phan LM, DeStefano CB (2022) CAR T-cell therapy for patients with multiple myeloma: current evidence and challenges. Blood Lymphat Cancer Targets Ther 12:119–136

    Google Scholar 

  • Rittirsch D, Flierl MA, Ward PA (2008) Harmful molecular mechanisms in sepsis. Nat Rev Immunol 8:776–787

    Google Scholar 

  • Rohlke F, Stollman N (2012) Fecal microbiota transplantation in relapsing Clostridium difficile infection. Ther Adv Gastroenterol 5:403–420

    Google Scholar 

  • Rosenfeldt V, Benfeldt E, Valerius NH, Pærregaard A, Michaelsen KF (2004) Effect of probiotics on gastrointestinal symptoms and small intestinal permeability in children with atopic dermatitis. J Pediatr 145:612–616

    Google Scholar 

  • Rothhammer V, Mascanfroni ID, Bunse L, Takenaka MC, Kenison JE, Mayo L, Chao C-C, Patel B, Yan R, Blain M, Alvarez JI, Kébir H, Anandasabapathy N, Izquierdo G, Jung S, Obholzer N, Pochet N, Clish CB, Prinz M, Prat A et al (2016) Type I interferons and microbial metabolites of tryptophan modulate astrocyte activity and central nervous system inflammation via the aryl hydrocarbon receptor. Nat Med 22:586–597

    Google Scholar 

  • Routy B, Le Chatelier E, Derosa L, Duong CPM, Alou MT, Daillère R, Fluckiger A, Messaoudene M, Rauber C, Roberti MP, Fidelle M, Flament C, Poirier-Colame V, Opolon P, Klein C, Iribarren K, Mondragón L, Jacquelot N, Qu B, Ferrere G et al (2018) Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors. Science (New York, NY) 359:91–97

    Google Scholar 

  • Safadi JM, Quinton AMG, Lennox BR, Burnet PWJ, Minichino A (2022) Gut dysbiosis in severe mental illness and chronic fatigue: a novel trans-diagnostic construct? A systematic review and meta-analysis. Mol Psychiatry 27:141–153

    Google Scholar 

  • Santos SS, Brunialti MKC, Rigato O, Machado FR, Silva E, Salomao R (2012) Generation of nitric oxide and reactive oxygen species by neutrophils and monocytes from septic patients and association with outcomes. Shock 38:18–23

    Google Scholar 

  • Scott SA, Fu J, Chang PV (2020) Microbial tryptophan metabolites regulate gut barrier function via the aryl hydrocarbon receptor. Proc Natl Acad Sci 117:19376–19387

    Google Scholar 

  • Selby PJ, Lopes N, Mundy J, Crofts M, Millar JL, McElwain TJ (1987) Cyclophosphamide priming reduces intestinal damage in man following high dose melphalan chemotherapy. Br J Cancer 55:531–533

    Google Scholar 

  • Shen Q-D, Zhu H-Y, Wang L, Fan L, Liang J-H, Cao L, Wu W, Xia Y, Li J-Y, Xu W (2018) Gemcitabine-oxaliplatin plus rituximab (R-GemOx) as first-line treatment in elderly patients with diffuse large B-cell lymphoma: a single-arm, open-label, phase 2 trial. Lancet Haematol 5:e261–e269

    Google Scholar 

  • Sheykhhasan M, Manoochehri H, Dama P (2022) Use of CAR T-cell for acute lymphoblastic leukemia (ALL) treatment: a review study. Cancer Gene Ther 29:1080–1096

    Google Scholar 

  • Silva JPB, Navegantes-Lima KC, Oliveira ALB, Rodrigues DVS, Gaspar SLF, Monteiro VVS, Moura DP, Monteiro MC (2019) Protective mechanisms of butyrate on inflammatory bowel disease. Curr Pharm Des 24:4154–4166

    Google Scholar 

  • Singh AP, Aijaz S (2016) Enteropathogenic E. coli: breaking the intestinal tight junction barrier. F1000Research 4:231

    Google Scholar 

  • Smits WK, Lyras D, Lacy DB, Wilcox MH, Kuijper EJ (2016) Clostridium difficile infection. Nat Rev Dis Prim 2:1–20

    Google Scholar 

  • Snyder M, Pasikhova Y, Baluch A (2017) Early antimicrobial De-escalation and stewardship in adult hematopoietic stem cell transplantation recipients: retrospective review. Open Forum Infect Dis 4:ofx226

    Google Scholar 

  • Song Y, Gyarmati P (2019) Bacterial translocation in acute lymphocytic leukemia. PLoS One 14:e0214526

    Google Scholar 

  • Stojanovska V, McQuade RM, Fraser S, Prakash M, Gondalia S, Stavely R, Palombo E, Apostolopoulos V, Sakkal S, Nurgali K (2018) Oxaliplatin-induced changes in microbiota, TLR4+ cells and enhanced HMGB1 expression in the murine colon. PLoS One 13:e0198359

    Google Scholar 

  • Sun Q, Ji Y-C, Wang Z-L, She X, He Y, Ai Q, Li L-Q (2021) Sodium butyrate alleviates intestinal inflammation in mice with necrotizing enterocolitis. Mediat Inflamm 2021:1–12

    Google Scholar 

  • Sundström GM, Wahlin A, Nordin-Andersson I, Suhr OB (1998) Intestinal permeability in patients with acute myeloid leukemia. Eur J Haematol 61:250–254

    Google Scholar 

  • Taplitz RA, Kennedy EB, Flowers CR (2018) Antimicrobial prophylaxis for adult patients with cancer-related immunosuppression: ASCO and IDSA clinical practice guideline update summary. J Oncol Pract 14:692–695

    Google Scholar 

  • Thomsen M, Vitetta L (2018) Adjunctive treatments for the prevention of chemotherapy- and radiotherapy-induced Mucositis. Integr Cancer Ther 17:1027–1047

    Google Scholar 

  • Torres VBL, Azevedo LCP, Silva UVA, Caruso P, Torelly AP, Silva E, Carvalho FB, Vianna A, Souza PCP, Godoy MMG, Azevedo JRA, Spector N, Bozza FA, Salluh JIF, Soares M (2015) Sepsis-associated outcomes in critically ill patients with malignancies. Ann Am Thorac Soc 12:1185–1192

    Google Scholar 

  • Tsirigotis P, Triantafyllou K, Girkas K, Giannopoulou V, Ioannidou E, Chondropoulos S, Kalli T, Papaxoinis G, Pappa V, Papageorgiou E, Economopoulos T, Ladas SD, Dervenoulas J (2008) Keratinocyte growth factor is effective in the prevention of intestinal mucositis in patients with hematological malignancies treated with high-dose chemotherapy and autologous hematopoietic SCT: a video-capsule endoscopy study. Bone Marrow Transplant 42:337–343

    Google Scholar 

  • Tyszka M, Biliński J, Basak GW (2021) Advances in intestinal barrier preservation and restoration in the allogeneic hematopoietic cell transplantation setting. J Clin Med 10:2508

    Google Scholar 

  • Ubeda C, Taur Y, Jenq RR, Equinda MJ, Son T, Samstein M, Viale A, Socci ND, van den Brink MRM, Kamboj M, Pamer EG (2010) Vancomycin-resistant enterococcus domination of intestinal microbiota is enabled by antibiotic treatment in mice and precedes bloodstream invasion in humans. J Clin Invest 120:4332–4341

    Google Scholar 

  • Usami M, Kishimoto K, Ohata A, Miyoshi M, Aoyama M, Fueda Y, Kotani J (2008) Butyrate and trichostatin A attenuate nuclear factor kappaB activation and tumor necrosis factor alpha secretion and increase prostaglandin E2 secretion in human peripheral blood mononuclear cells. Nutr Res 28:321–328

    Google Scholar 

  • van der Velden WJFM, Blijlevens NMA, Maas FMHM, Schaap NPM, Jansen JH, van der Reijden BA, Feuth T, Dolstra H, Donnelly JP (2009) NOD2 polymorphisms predict severe acute graft-versus-host and treatment-related mortality in T-cell-depleted haematopoietic stem cell transplantation. Bone Marrow Transplant 44:243–248

    Google Scholar 

  • Vecchio AJ, Rathnayake SS, Stroud RM (2021) Structural basis for Clostridium perfringens enterotoxin targeting of claudins at tight junctions in mammalian gut. Proc Natl Acad Sci 118:e2024651118

    Google Scholar 

  • Verlinden A, Mikulska M, Knelange NS, Averbuch D, Styczynski J, Infectious Diseases Working Party (IDWP) of the European Group for Blood and Marrow Transplantation Group (EBMT) (2020) Current antimicrobial practice in febrile neutropenia across Europe and Asia: the EBMT infectious disease working party survey. Bone Marrow Transplant 55:1588–1594

    Google Scholar 

  • Vinolo MAR, Rodrigues HG, Hatanaka E, Sato FT, Sampaio SC, Curi R (2011) Suppressive effect of short-chain fatty acids on production of proinflammatory mediators by neutrophils. J Nutr Biochem 22:849–855

    Google Scholar 

  • Voth DE, Ballard JD (2005) Clostridium difficile toxins: mechanism of action and role in disease. Clin Microbiol Rev 18:247–263

    Google Scholar 

  • Wang H-B, Wang P-Y, Wang X, Wan Y-L, Liu Y-C (2012) Butyrate enhances intestinal epithelial barrier function via up-regulation of tight junction protein Claudin-1 transcription. Dig Dis Sci 57:3126–3135

    Google Scholar 

  • Wang B, Wu G, Zhou Z, Dai Z, Sun Y, Ji Y, Li W, Wang W, Liu C, Han F, Wu Z (2015) Glutamine and intestinal barrier function. Amino Acids 47:2143–2154

    Google Scholar 

  • Wang R, Yang X, Liu J, Zhong F, Zhang C, Chen Y, Sun T, Ji C, Ma D (2022) Gut microbiota regulates acute myeloid leukaemia via alteration of intestinal barrier function mediated by butyrate. Nat Commun 13:2522

    Google Scholar 

  • Wei L, Wen X-S, Xian CJ (2021) Chemotherapy-induced intestinal microbiota dysbiosis impairs mucosal homeostasis by modulating toll-like receptor Signaling pathways. Int J Mol Sci 22:9474

    Google Scholar 

  • Willems L, Porcher R, Lafaurie M, Casin I, Robin M, Xhaard A, Andreoli AL, Rodriguez-Otero P, Dhedin N, Socié G, Ribaud P, Peffault de Latour R (2012) Clostridium difficile infection after allogeneic hematopoietic stem cell transplantation: incidence, risk factors, and outcome. Biol Blood Marrow Transplant 18:1295–1301

    Google Scholar 

  • Williams DA (2001) Inflammatory cytokines and mucosal injury. JNCI Monogr 2001:26–30

    Google Scholar 

  • Williams MD, Braun LA, Cooper LM, Johnston J, Weiss RV, Qualy RL, Linde-Zwirble W (2004) Hospitalized cancer patients with severe sepsis: analysis of incidence, mortality, and associated costs of care. Crit Care 8:R291–R298

    Google Scholar 

  • Worth LJ, Thursky KA, Seymour JF, Slavin MA (2007) Vancomycin-resistant enterococcus faecium infection in patients with hematologic malignancy: patients with acute myeloid leukemia are at high-risk. Eur J Haematol 79:226–233

    Google Scholar 

  • Yamamoto ML, Schiestl RH (2014) Lymphoma caused by intestinal microbiota. Int J Environ Res Public Health 11:9038–9049

    Google Scholar 

  • Yan H, Ajuwon KM (2017) Butyrate modifies intestinal barrier function in IPEC-J2 cells through a selective upregulation of tight junction proteins and activation of the Akt signaling pathway. PLoS One 12:e0179586

    Google Scholar 

  • Yang H, Wildhaber B, Teitelbaum D (2003) Keratinocyte growth factor improves epithelial function after massive small bowel resection. J Parenter Enter Nutr 27:198–206

    Google Scholar 

  • Ye H, Lv M, Zhao X, Zhao X, Huang X (2012) Plasma level of lipopolysaccharide-binding protein is indicative of acute graft-versus-host disease following allogeneic hematopoietic stem cell transplantation. Int J Hematol 95:680–688

    Google Scholar 

  • Yuan J-H, Xie Q-S, Chen G-C, Huang C-L, Yu T, Chen Q-K, Li J-Y (2021) Impaired intestinal barrier function in type 2 diabetic patients measured by serum LPS, Zonulin, and IFABP. J Diabetes Complicat 35:107766

    Google Scholar 

  • Zaura E, Brandt BW, Teixeira de Mattos MJ, Buijs MJ, Caspers MPM, Rashid M-U, Weintraub A, Nord CE, Savell A, Hu Y, Coates AR, Hubank M, Spratt DA, Wilson M, Keijser BJF, Crielaard W (2015) Same exposure but two radically different responses to antibiotics: resilience of the salivary microbiome versus long-term microbial shifts in feces. MBio 6:e01693-15

    Google Scholar 

  • Zuo L, Kuo W-T, Turner JR (2020) Tight junctions as targets and effectors of mucosal immune homeostasis. Cell Mol Gastroenterol Hepatol 10:327–340

    Google Scholar 

Download references

Acknowledgment

Figures created with Bioender.com.

Conflict of Interest

None.

Funding

None.

Author information

Authors and Affiliations

  1. Division of Hematology and Oncology, Department of Medicine, SUNY Upstate Medical University, Syracuse, NY, USA

    Elio Haroun, Seah H. Lim & Dibyendu Dutta

Authors
  1. Elio Haroun
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Seah H. Lim
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Dibyendu Dutta
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Dibyendu Dutta .

Rights and permissions

Reprints and permissions

Copyright information

© 2024 The Author(s), under exclusive license to Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Haroun, E., Lim, S.H., Dutta, D. (2024). Pathogenesis and Consequences of a Disruption to the Intestinal Barrier Functions in Patients with Hematologic Malignancies. In: Interdisciplinary Cancer Research. Springer, Cham. https://doi.org/10.1007/16833_2024_253

Download citation

  • DOI: https://doi.org/10.1007/16833_2024_253

  • Published:

  • Publisher Name: Springer, Cham

Publish with us

Policies and ethics

Search

Navigation