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Microbial Translocation Across the GI Tract
Open accessAbstract
The lumen of the gastrointestinal (GI) tract is home to an enormous quantity of different bacterial species, our microbiota, that thrive in an often symbiotic relationship with the host. Given that the healthy host must regulate contact between the microbiota and its immune system to avoid overwhelming systemic immune activation, humans have evolved several mechanisms to attenuate systemic microbial translocation (MT) and its consequences. However, several diseases are associated with the failure of one or more of these mechanisms, with consequent immune activation and deleterious effects on health. Here, we discuss the mechanisms underlying MT, diseases associated with MT, and therapeutic interventions that aim to decrease it.
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“However, in the absence of infection, endotoxin still crosses the mucosal membranes of gut, gums, nose or lungs, the main source being intestinal permeability [36, 37].”
From The endotoxin hypothesis of neurodegeneration (2019) · cites this paper as [37]
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Shah, N. B., Allegretti, A. S., Nigwekar, S. U., Kalim, S., Zhao, S. J., Lelouvier, B., Servant, F., Serena, G., Thadhani, R., Raj, D. S., et al. (2019) · Clinical Journal of the American Society of Nephrology · doi:10.2215/cjn.12161018 · Cited by 115
Spotlight on the Gut Microbiome in Menopause: Current Insights
Peters, B. A., Santoro, N. F., Kaplan, R. C., & Qi, Q. (2022) · International Journal of Women s Health · doi:10.2147/ijwh.s340491 · Cited by 129
“Menopause and Microbial Translocation The gut microbiota may exert their influence on human health not only through metabolic activities, but also via microbial translocation, a process in which gut epithelial barrier dysfunction allows microbes and microbial products to translocate from the gut lumen to the systemic…”
BackgroundVogt, L. M., Meyer, D., Pullens, G., Faas, M. M., Venema, K., Ramasamy, U. S., Schols, H. A., & de Vos, P. (2014) · Journal of Nutrition · doi:10.3945/jn.114.191643 · Cited by 114
Probiotics ameliorate intestinal pathophysiology in a mouse model of Alzheimer’s disease
Kaur, H., Nagamoto‐Combs, K., Golovko, S. A., Golovko, M. Y., Klug, M. G., & Combs, C. K. (2020) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2020.04.009 · Cited by 115
“For example, a disrupted intestinal barrier results in translocation of luminal contents including microbes and their products into the systemic circulation which certainly have detrimental consequences, including activation of the peripheral immune system (Brenchley and Douek, 2012).”
BackgroundChevalier, M. F., Petitjean, G., Dunyach‐Remy, C., Didier, C., Girard, P., Manea, M. E., Campa, P., Meyer, L., Rouzioux, C., Lavigne, J., et al. (2013) · PLoS Pathogens · doi:10.1371/journal.ppat.1003453 · Cited by 122
“Th17 cells, involved in the maintenance of the intestinal mucosal barrier integrity and in the defence against microbial infections were reported to be depleted in advanced HIV disease [15,17].”
BackgroundSevere COVID-19: A Review of Recent Progress With a Look Toward the Future
Xie, P., Ma, W., Tang, H., & Liu, D. (2020) · Frontiers in Public Health · doi:10.3389/fpubh.2020.00189 · Cited by 118
“High inflammatory responses disrupt the intestinal barrier and increases permeability, causing bacterial translocation into the circulation and secondary systemic infection (54).”
BackgroundAltered gut microbiome composition in HIV infection
Bandera, A., Benedetto, I. D., Bozzi, G., & Gori, A. (2017) · Current Opinion in HIV and AIDS · doi:10.1097/coh.0000000000000429 · Cited by 111
The Th17 Lineage: From Barrier Surfaces Homeostasis to Autoimmunity, Cancer, and HIV-1 Pathogenesis
Wacleche, V. S., LANDAY, A. L., Routy, J., & Ancuța, P. (2017) · Viruses · doi:10.3390/v9100303 · Cited by 109
Pallikkuth, S., Micci, L., Ende, Z. S., Iriele, R. I., Cervasi, B., Lawson, B., McGary, C. S., Rogers, K. A., Else, J. G., Silvestri, G., et al. (2013) · PLoS Pathogens · doi:10.1371/journal.ppat.1003471 · Cited by 105
“Chronic immune activation related to loss of mucosal barrier integrity and microbial translocation has been implicated in other pathological conditions including graft versus host disease, inflammatory bowel disease, and pancreatitis (reviewed in [12]).”
BackgroundGootenberg, D. B., Paer, J. M., Luévano, J. M., & Kwon, D. S. (2016) · Current Opinion in Infectious Diseases · doi:10.1097/qco.0000000000000341 · Cited by 103
“acid metabolism [63], or causing increased trans-”
The potential of the microbiota to influence vaccine responses
Lynn, D. J., & Pulendran, B. (2017) · Journal of Leukocyte Biology · doi:10.1189/jlb.5mr0617-216r · Cited by 99
“Increased serum endotoxin was likely due to increased intestinal permeability, allowing microbial products to translocate out of the gut [47, 48].”
BackgroundShastri, P., McCarville, J. L., Kalmokoff, M. L., Brooks, S. P. J., & Green-Johnson, J. M. (2015) · Biology of Sex Differences · doi:10.1186/s13293-015-0031-0 · Cited by 103
“In both rats and humans, liver macrophages (Kupffer cells) are involved in the removal of IgA-opsonized bacteria and antigens via FCRα1 receptors, an important role when gut barrier function is reduced [75, 76].”
BackgroundMultiple Organ Dysfunction Syndrome in Humans and Animals
Osterbur, K., Mann, F. A., Kuroki, K., & DeClue, A. E. (2014) · Journal of Veterinary Internal Medicine · doi:10.1111/jvim.12364 · Cited by 103
“The incidence of overall gastrointestinal dysfunction in people and animals is difficult to gauge compared to other forms of organ dysfunction because of the lack of a clear definition and subjective nature of its assessment(69,82); however, it is considered to be common.(68,69,83)”
BackgroundLi, Q., Wang, C., Tang, C. X., Zhao, X., He, Q., & Li, J. (2018) · Frontiers in Cellular and Infection Microbiology · doi:10.3389/fcimb.2018.00005 · Cited by 96
“…be a normal physiological event, and under healthy conditions the enteric organisms can move across the “intact” intestinal epithelium into normally sterile tissues including blood, contributing to development of systemic and/or organ immune system (Brenchley and Douek, 2012; Wiest et al., 2014).”
Gut barrier dysfunction and microbial translocation in cancer cachexia
Klein, G. L., Petschow, B. W., Shaw, A. L., & Weaver, E. M. (2013) · Current Opinion in Supportive and Palliative Care · doi:10.1097/spc.0000000000000017 · Cited by 95
Impaired Barrier Function and Autoantibody Generation in Malnutrition Enteropathy in Zambia
Amadi, B., Besa, E. C., Zyambo, K., Kaonga, P., Louis-Auguste, J., Chandwe, K., Tarr, P. I., Denno, D. M., Nataro, J. P., Faubion, W. A., et al. (2017) · EBioMedicine · doi:10.1016/j.ebiom.2017.07.017 · Cited by 93
“, 2016), we recently reported that the small intestinal mucosa has increased permeability in EE and that diminished barrier integrity is associated with microbial translocation (Brenchley and Douek, 2012; Marchetti et al., 2013).”
Yuan, S., Ye, Y., Chen, D., Qiu, Q., Zhan, Z., Lian, F., Li, H., Liang, L., Xu, H., & Yang, X. (2013) · Seminars in Arthritis and Rheumatism · doi:10.1016/j.semarthrit.2013.11.005 · Cited by 93
Early microbial translocation blockade reduces SIV-mediated inflammation and viral replication
Kristoff, J., Haret-Richter, G. S., Ma, D., Ribeiro, R. M., Xu, C., Cornell, E. S., Stock, J. L., He, T., Mobley, A. D., Ross, S., et al. (2014) · Journal of Clinical Investigation · doi:10.1172/jci75090 · Cited by 91
“However, while abundant correlative data support a role of microbial translocation in the pathogenesis of HIV infection (3, 6), there have been conflicting reports (7), and this hypothesis has never been tested directly.”
Kelly, P. M., Besa, E. C., Zyambo, K., Louis-Auguste, J., Lees, J. D., Banda, T., Soko, R., Banda, R., Amadi, B., & Watson, A. J. M. (2016) · PLoS neglected tropical diseases · doi:10.1371/journal.pntd.0004600 · Cited by 91
“This is in contrast to work in the USA and elsewhere which suggests that HIV may predispose to bacterial translocation [10,36].”
BackgroundResultInfluentialInsights into the Pathogenesis of Disease in Human Lymphatic Filariasis
Nutman, T. B. (2013) · Lymphatic Research and Biology · doi:10.1089/lrb.2013.0021 · Cited by 90
“Persistent immune activation is associated with elevations of circulating microbial products, acute-phase proteins, and the so-called microbial translocation molecules.(42) Translocation of microbial products from the lumen of the intestine into the periphery is thought to contribute to induction of inflammation by st…”
BackgroundThe microbiome in autoimmune rheumatic disease
Konig, M. F. (2020) · Best Practice & Research Clinical Rheumatology · doi:10.1016/j.berh.2019.101473 · Cited by 95
“Alterations in peristalsis may favor dysbiosis and systemic bacterial translocation, both of which have the potential to alter systemic immune responses[6,59-61].”
BackgroundHIV-1 selectively targets gut-homing CCR6+CD4+ T cells via mTOR-dependent mechanisms
Planas, D., Zhang, Y., Monteiro, P., Goulet, J.-P., Gosselin, A., Grandvaux, N., Hope, T. J., Fassati, A., Routy, J., & Ancuța, P. (2017) · JCI Insight · doi:10.1172/jci.insight.93230 · Cited by 92
“Considering the strategic location of Th17 cells at portal sites of HIV/SIV entry (6, 24, 27, 28, 63), as well as their important role in maintaining mucosal immunity homeostasis in the context of a complex microbiota (6, 64, 65), our results point to the potential beneficial use of mTOR inhibitors in preventing HIV i…”
BackgroundResultThe influence of gut microbiota alteration on age-related neuroinflammation and cognitive decline
Shah, Z., & Alsegiani, A. S. (2022) · Neural Regeneration Research · doi:10.4103/1673-5374.335837 · Cited by 89
“The mucosal barrier dysfunction facilitates the entry of metabolites, byproducts, and cytokines into the blood circulation and stimulation of TLRs (Brenchley and Douek 2012; Konig et al., 2016), and the outcome is a profound increase in the permeability of BBB for unwanted substances (Rezai-Zadeh…”
BackgroundInfluentialOgunrinde, E., Zhou, Z., Luo, Z., Alekseyenko, A. V., Li, Q., Macêdo, D. S., Kamen, D. L., Oates, J. C., Gilkeson, G. S., & Jiang, W. (2019) · Arthritis & Rheumatology · doi:10.1002/art.40935 · Cited by 82
“However, in various disease states, this barrier may be compromised, leading to the translocation of microbial products into the systemic circulation, which may induce chronic inflammation and systemic tissue damage (11,12).”
BackgroundThe intestinal immune system and gut barrier function in obesity and ageing
Shemtov, S. J., Emani, R., Bielska, O., Covarrubias, A. J., Verdin, E. M., Andersen, J. K., & Winer, D. A. (2022) · FEBS Journal · doi:10.1111/febs.16558 · Cited by 86
Conrey, P. E., Denu, L., O’Boyle, K. C., Rozich, I., Green, J., Maslanka, J. R., Lubin, J., Duranova, T., Haltzman, B. L., Gianchetti, L., et al. (2023) · Science Immunology · doi:10.1126/sciimmunol.ade2335 · Cited by 88
“To address the hypothesis that intestinal IgA supports intestinal barrier function and restrains microbial translocation, we measured the serum concentration of soluble CD14 (sCD14), a biomarker for immune response to commensal microbes, to indicate the degree of microbial translocation from the gut to systemic sites…”
BackgroundEffector and memory T cell responses to commensal bacteria
Belkaid, Y., Bouladoux, N. J., & Hand, T. W. (2013) · Trends in Immunology · doi:10.1016/j.it.2013.03.003 · Cited by 83
Safe TNF-based antitumor therapy following p55TNFR reduction in intestinal epithelium
Hauwermeiren, F. V., Armaka, M., Karagianni, N., Kranidioti, K., Vandenbroucke, R. E., Loges, S., Roy, M. V., Staelens, J., Puimège, L., Palagani, A., et al. (2013) · Journal of Clinical Investigation · doi:10.1172/jci65624 · Cited by 78
“…intestinal epithelial permeability, which might lead to influx of gut bacteria or bacterial antigens in the system, as previously suggested (31, 32, 45). p55TNFR-dependent apoptosis was addressed both in vitro by TNF/CHX and in vivo by using the TNF/GalN and TNF/ActD models, in which massive liver…”
Zhou, Z., Bian, C., Luo, Z., Guille, C., Ogunrinde, E., Wu, J., Zhao, M., Fitting, S., Kamen, D. L., Oates, J. C., et al. (2019) · Scientific Reports · doi:10.1038/s41598-019-44448-0 · Cited by 78
Twardowska, A., Makaro, A., Binienda, A., Fichna, J., & Sałaga, M. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23063204 · Cited by 84
“The quantity of microorganisms and their species diversity varies depending on the region of the GI tract [20].”
BackgroundThe Many Faces of Immune Activation in HIV-1 Infection: A Multifactorial Interconnection
Mazzuti, L., Turriziani, O., & Mezzaroma, I. (2023) · Biomedicines · doi:10.3390/biomedicines11010159 · Cited by 77
“The massive depletion of CD4+ T cells in the gastrointestinal tract (GUT) during primary infection and the concomitant accumulation of inflammatory cells, such as dendritic cells, neutrophils, and monocytes, progressively compromise the mucosal integrity and disrupt the mucosal barrier [50,51].”
BackgroundHodges, J. K., Sasaki, G. Y., & Bruno, R. S. (2020) · The Journal of Nutritional Biochemistry · doi:10.1016/j.jnutbio.2020.108478 · Cited by 80
Crossing the barriers: Revisiting the gut feeling in rheumatoid arthritis
Brandl, C., Bucci, L., Schett, G. A., & Zaiss, M. M. (2021) · European Journal of Immunology · doi:10.1002/eji.202048876 · Cited by 77
Recent advances in the epithelial barrier theory
Pat, Y., Yazıcı, D., D’Avino, P., Li, M., Ardıçlı, S., Ardıçlı, Ö., Mitamura, Y., Akdiş, M., Dhir, R., Nadeau, K. C., et al. (2024) · International Immunology · doi:10.1093/intimm/dxae002 · Cited by 84
“Subsequent to the barrier damage, the microbiota can translocate to the subepithelial tissues (105).”
BackgroundCirculating Biomarkers of Pulmonary and Extrapulmonary Tuberculosis in Children
Kumar, N. P., Rajamanickam, A., Andrade, B. B., Suresh, N., Ganesh, R., Shankar, J., Kumaraswami, V., Nutman, T. B., & Babu, S. (2013) · Clinical and Vaccine Immunology · doi:10.1128/cvi.00038-13 · Cited by 76
“Markers of innate immune activation include circulating microbial products, such as LPS and innate host proteins responding to LPS, such as LBP, sCD14, and antibodies to the LPS core (EndoCAb) (20).”
BackgroundSampsell, K., Hao, D., & Reimer, R. A. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21239239 · Cited by 74
“, claudins, occludins, zona occludens) that maintain a tight junction between epithelial cells are compromised, in part due to increased claudin endocytosis [37,39].”
BackgroundInfluentialMucosal immunity in human and simian immunodeficiency lentivirus infections
Brenchley, J. M. (2013) · Mucosal Immunology · doi:10.1038/mi.2013.15 · Cited by 70
Self-citationAnatomical localization of commensal bacteria in immune cell homeostasis and disease
Fung, T. C., Artis, D., & Sonnenberg, G. F. (2014) · Immunological Reviews · doi:10.1111/imr.12186 · Cited by 75
Maher, S., Geoghegan, C., & Brayden, D. J. (2020) · Expert Opinion on Drug Delivery · doi:10.1080/17425247.2021.1825375 · Cited by 71
Metadata
- Authors
- Brenchley, J. M., & Douek, D. C.
- Affiliations
- National Institutes of Health (US)
- Venue
- Annual Review of Immunology
- Publisher
- Annual Reviews
- Published
- 2012-04-23
- Volume
- 30
- Issue
- 1
- Pages
- 149-173
- ISSN
- 0732-0582 (ISSN-L)
- 1545-3278
- PMC
- PMC3513328
- OpenAlex
- W2146488133
- Cited by
- 496
- References
- 222
- Citations by year
- 2026: 22 · 2025: 32 · 2024: 42 · 2023: 30 · 2022: 44 · 2021: 33 · 2020: 42 · 2019: 59 · 2018: 24 · 2017: 40 · 2016: 34 · 2015: 20 · 2014: 27 · 2013: 32 · 2012: 15
- FWCI
- 2.74
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Annual Review of Immunology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- National Institute of Allergy and Infectious Diseases (Z01AI001029, ZIAAI005034)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Health Sciences › Medicine › Gastroenterology › Gastrointestinal motility and disorders
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Keywords
- microbial translocation, gut microbiota, gastrointestinal tract, host-microbe interactions, immune activation, systemic inflammation, therapeutic interventions
- MeSH terms
- Animals, Anti-Infective Agents, Digestive System Diseases, Humans, Immunologic Factors, Probiotics, Gastrointestinal Tract, Host-Pathogen Interactions, Metagenome
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