Impacts of microbiome metabolites on immune regulation and autoimmunity

Haase, Stefanie; Haghikia, Aiden; Wilck, Nicola; Müller, Dominik N.; Linker, Ralf A.

doi:10.1111/imm.12933

Cited by 239Gut microbiota and healthMultiple Sclerosis Research StudiesT-cell and B-cell Immunology

Impacts of microbiome metabolites on immune regulation and autoimmunity

Open access

Haase, Stefanie, Haghikia, Aiden, Wilck, Nicola, Müller, Dominik N., Linker, Ralf A.·2018·Immunology

DOI 10.1111/imm.12933PMC PMC5980218

Open this paper in CoChat — free account Open PDF

Abstract

A vast number of studies have demonstrated a remarkable role for the gut microbiota and their metabolites in the pathogenesis of inflammatory diseases, including multiple sclerosis (MS). Recent studies in experimental autoimmune encephalomyelitis, an animal model of MS, have revealed that modifying certain intestinal bacterial populations may influence immune cell priming in the periphery, resulting in dysregulation of immune responses and neuroinflammatory processes in the central nervous system (CNS). Conversely, some commensal bacteria and their antigenic products can protect against inflammation within the CNS. Specific components of the gut microbiome have been implicated in the production of pro-inflammatory cytokines and subsequent generation of Th17 cells. Similarly, commensal bacteria and their metabolites can also promote the generation of regulatory T-cells (Treg), contributing to immune suppression. Short-chain fatty acids may induce Treg either by G-protein-coupled receptors or inhibition of histone deacetylases. Tryptophan metabolites may suppress inflammatory responses by acting on the aryl hydrocarbon receptor in T-cells or astrocytes. Interestingly, secretion of these metabolites can be impaired by excess consumption of dietary components, such as long-chain fatty acids or salt, indicating that the diet represents an environmental factor affecting the complex crosstalk between the gut microbiota and the immune system. This review discusses new aspects of host-microbiota interaction and the immune system with a special focus on MS as a prototype T-cell-mediated autoimmune disease of the CNS.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

Integrity signals

Registry

Crossref · 10.1111/imm.12933

Cites

116 of 116 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

SCFAs promote the development of naive CD4+ T cells into regulatory T cells, induce "tolerogenic" dendritic cells in the intestinal mucosa, and limit autoimmunity.
“SCFAs promote the development of naive CD4+ T cells into regulatory T cells (31, 32), induce “tolerogenic” dendritic cells in the intestinal mucosa (33), and limit autoimmity (34, 35).”
From Respiratory viral infection-induced microbiome alterations and secondary bacterial pneumonia. (2018) · cites this paper as [35]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

A human gut microbial gene catalogue established by metagenomic sequencing
MetaHIT Consortium, Qin, J., Li, R., Raes, J., Arumugam, M., Burgdorf, K. S., Manichanh, C., Nielsen, T., Pons, N., Levenez, F., et al. (2010) · Nature · doi:10.1038/nature08821 · Cited by 11,624 · see citing works
Human gut microbiome viewed across age and geography
Yatsunenko, T., Rey, F. E., Manary, M. J., Trehan, I., Dominguez-Bello, M. G., Contreras, M., Magris, M., Hidalgo, G., Baldassano, R. N., Anokhin, A. P., et al. (2012) · Nature · doi:10.1038/nature11053 · Cited by 7,815 · see citing works
Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells
Furusawa, Y., Obata, Y., Fukuda, S., Endo, T. A., Nakato, G., Takahashi, D., Nakanishi, Y., Uetake, C., Kato, K., Kato, T., et al. (2013) · Nature · doi:10.1038/nature12721 · Cited by 5,549 · see citing works
Revised Estimates for the Number of Human and Bacteria Cells in the Body
Sender, R., Fuchs, S., & Milo, R. (2016) · PLOS Biology · doi:10.1371/journal.pbio.1002533 · Cited by 5,425 · see citing works
The Microbial Metabolites, Short-Chain Fatty Acids, Regulate Colonic T reg Cell Homeostasis
Smith, P. M., Howitt, M. R., Panikov, N., Michaud, M., Gallini, C. A., Bohlooly-Y, M., Glickman, J. N., & Garrett, W. S. (2013) · Science · doi:10.1126/science.1241165 · Cited by 5,413 · see citing works
IL-17 and th17 cells
Korn, T., Bettelli, E., Oukka, M., & Kuchroo, V. K. (2009) · Annual Review of Immunology · doi:10.1146/annurev.immunol.021908.132710 · Cited by 4,873 · see citing works
Metabolites produced by commensal bacteria promote peripheral regulatory T-cell generation
Arpaia, N., Campbell, C., Fan, X., Dikiy, S., van der Veeken, J., deRoos, P., Liu, H., Cross, J. R., Pfeffer, K., Coffer, P. J., et al. (2013) · Nature · doi:10.1038/nature12726 · Cited by 4,838 · see citing works
Induction of Intestinal Th17 Cells by Segmented Filamentous Bacteria
Ivanov, I. I., Atarashi, K., Manel, N., Brodie, E. L., Shima, T., Karaoz, U., Wei, D., Goldfarb, K. C., Santee, C. A., Lynch, S. V., et al. (2009) · Cell · doi:10.1016/j.cell.2009.09.033 · Cited by 4,554 · see citing works
Multiple sclerosis
Compston, A., & Coles, A. J. (2008) · The Lancet · doi:10.1016/s0140-6736(08)61620-7 · Cited by 4,459 · see citing works
IL-23 drives a pathogenic T cell population that induces autoimmune inflammation
Langrish, C. L., Chen, Y., Blumenschein, W. M., Mattson, J., Basham, B., Sedgwick, J. D., McClanahan, T., Kastelein, R. A., & Cua, D. J. (2005) · The Journal of Experimental Medicine · doi:10.1084/jem.20041257 · Cited by 4,099 · see citing works
Induction of Colonic Regulatory T Cells by Indigenous Clostridium Species
Atarashi, K., Tanoue, T., Shima, T., Imaoka, A., Kuwahara, T., Momose, Y., Cheng, G., Yamasaki, S., Saito, T., Ohba, Y., et al. (2011) · Science · doi:10.1126/science.1198469 · Cited by 3,752 · see citing works
Host microbiota constantly control maturation and function of microglia in the CNS
Erny, D., Hrabě de Angelis, A. L., Jaitin, D., Wieghofer, P., Staszewski, O., David, E., Keren-Shaul, H., Mahlakoiv, T., Jakobshagen, K., Buch, T., et al. (2015) · Nature Neuroscience · doi:10.1038/nn.4030 · Cited by 3,569 · see citing works
Short chain fatty acids in human large intestine, portal, hepatic and venous blood
Cummings, J. H., Pomare, E. W., Branch, W. J., Naylor, C. P., & Macfarlane, G. T. (1987) · Gut · doi:10.1136/gut.28.10.1221 · Cited by 3,119 · see citing works
Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain
Cua, D. J., Sherlock, J., Chen, Y., Murphy, C. A., Joyce, B., Seymour, B., Lucian, L., To, W., Kwan, S., Churakova, T., et al. (2003) · Nature · doi:10.1038/nature01355 · Cited by 2,906 · see citing works
Gut Microbiota Metabolism of Dietary Fiber Influences Allergic Airway Disease and Hematopoiesis
Trompette, A., Gollwitzer, E. S., Yadava, K., Sichelstiel, A. K., Sprenger, N., Ngom-Bru, C., Blanchard, C., Junt, T., Nicod, L. P., Harris, N. L., et al. (2014) · Nature Medicine · doi:10.1038/nm.3444 · Cited by 2,862 · see citing works
Tryptophan catabolites from microbiota engage aryl hydrocarbon receptor and balance mucosal reactivity via interleukin-22
Zelante, T., Iannitti, R. G., Cunha, C., De Luca, A., Giovannini, G., Pieraccini, G., Zecchi, R., D’Angelo, C., Massi-Benedetti, C., Fallarino, F., et al. (2013) · Immunity · doi:10.1016/j.immuni.2013.08.003 · Cited by 2,614 · see citing works
Succession of microbial consortia in the developing infant gut microbiome
Koenig, J. E., Spor, A., Scalfone, N., Fricker, A. D., Stombaugh, J., Knight, R., Angenent, L. T., & Ley, R. E. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1000081107 · Cited by 2,540 · see citing works
Development, maintenance and disruption of the blood-brain barrier
Obermeier, B., Daneman, R., & Ransohoff, R. M. (2013) · Nature Medicine · doi:10.1038/nm.3407 · Cited by 2,452 · see citing works
Activation of Gpr109a, receptor for niacin and the commensal metabolite butyrate, suppresses colonic inflammation and carcinogenesis
Singh, N., Gurav, A., Sivaprakasam, S., Brady, E., Padia, R., Shi, H., Thangaraju, M., Prasad, P. D., Manicassamy, S., Munn, D. H., et al. (2014) · Immunity · doi:10.1016/j.immuni.2013.12.007 · Cited by 2,368 · see citing works
Inducible Foxp3 + regulatory T-cell development by a commensal bacterium of the intestinal microbiota
Round, J. L., & Mazmanian, S. K. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0909122107 · Cited by 2,233 · see citing works
The microbial metabolite butyrate regulates intestinal macrophage function via histone deacetylase inhibition.
Chang, P. V., Hao, L., Offermanns, S., & Medzhitov, R. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1322269111 · Cited by 2,175 · see citing works
Reciprocal T H 17 and Regulatory T Cell Differentiation Mediated by Retinoic Acid
Mucida, D., Park, Y., Kim, G., Turovskaya, O., Scott, I., Kronenberg, M., & Cheroutre, H. (2007) · Science · doi:10.1126/science.1145697 · Cited by 1,982 · see citing works
Regulation of short-chain fatty acid production
Macfarlane, S., & Macfarlane, G. T. (2003) · Proceedings of the Nutrition Society · doi:10.1079/pns2002207 · Cited by 1,939 · see citing works
Control of Treg and TH17 cell differentiation by the aryl hydrocarbon receptor
Quintana, F. J., Basso, A. S., Iglesias, A. H., Korn, T., Farez, M. F., Bettelli, E., Caccamo, M., Oukka, M., & Weiner, H. L. (2008) · Nature · doi:10.1038/nature06880 · Cited by 1,865 · see citing works
Loss of Functional Suppression by CD4+CD25+ Regulatory T Cells in Patients with Multiple Sclerosis
Viglietta, V., Baecher‐Allan, C., Weiner, H. L., & Hafler, D. A. (2004) · The Journal of Experimental Medicine · doi:10.1084/jem.20031579 · Cited by 1,858 · see citing works
Divergent Pro- and Antiinflammatory Roles for IL-23 and IL-12 in Joint Autoimmune Inflammation
Murphy, C. A., Langrish, C. L., Chen, Y., Blumenschein, W., McClanahan, T., Kastelein, R. A., Sedgwick, J. D., & Cua, D. J. (2003) · The Journal of Experimental Medicine · doi:10.1084/jem.20030896 · Cited by 1,669 · see citing works
Th1-specific cell surface protein Tim-3 regulates macrophage activation and severity of an autoimmune disease
Monney, L., Sabatos, C. A., Gaglia, J. L., Ryu, A., Waldner, H., Chernova, T., Manning, S., Greenfield, E. A., Coyle, A. J., Sobel, R. A., et al. (2002) · Nature · doi:10.1038/415536a · Cited by 1,648 · see citing works
The aryl hydrocarbon receptor links TH17-cell-mediated autoimmunity to environmental toxins
Veldhoen, M., Hirota, K., Westendorf, A. M., Buer, J., Dumoutier, L., Renauld, J.-C., & Stockinger, B. (2008) · Nature · doi:10.1038/nature06881 · Cited by 1,634 · see citing works
Type I interferons and microbial metabolites of tryptophan modulate astrocyte activity and central nervous system inflammation via the aryl hydrocarbon receptor
Rothhammer, V., Mascanfroni, I. D., Bunse, L., Takenaka, M. C., Kenison, J. E., Mayo, L., Chao, C.-C., Patel, B., Yan, R., Blain, M., et al. (2016) · Nature Medicine · doi:10.1038/nm.4106 · Cited by 1,559 · see citing works
Molecular mimicry in T cell-mediated autoimmunity: Viral peptides activate human T cell clones specific for myelin basic protein
Wucherpfennig, K. W., & Strominger, J. L. (1995) · Cell · doi:10.1016/0092-8674(95)90348-8 · Cited by 1,545 · see citing works
IL-17 plays an important role in the development of experimental autoimmune encephalomyelitis
Komiyama, Y., Nakae, S., Matsuki, T., Nambu, A., Ishigame, H., Kakuta, S., Sudo, K., & Iwakura, Y. (2006) · The Journal of Immunology · doi:10.4049/jimmunol.177.1.566 · Cited by 1,536 · see citing works
Sodium chloride drives autoimmune disease by the induction of pathogenic TH17 cells
Kleinewietfeld, M., Manzel, A., Titze, J., Kvakan, H., Yosef, N., Linker, R. A., Muller, D. N., & Hafler, D. A. (2013) · Nature · doi:10.1038/nature11868 · Cited by 1,394 · see citing works
Self-citation
Instability of the transcription factor Foxp3 leads to the generation of pathogenic memory T cells in vivo
Zhou, X., Bailey-Bucktrout, S. L., Jeker, L. T., Peñaranda, C., Martínez‐Llordella, M., Ashby, M., Nakayama, M., Rosenthal, W. L., & Bluestone, J. A. (2009) · Nature Immunology · doi:10.1038/ni.1774 · Cited by 1,374 · see citing works
Salt-responsive gut commensal modulates TH17 axis and disease
Wilck, N., Matus, M. G., Kearney, S. M., Olesen, S. W., Forslund, K., Bartolomaeus, H., Haase, S., Mähler, A., Balogh, A., Markó, L., et al. (2017) · Nature · doi:10.1038/nature24628 · Cited by 1,310 · see citing works
Short-chain fatty acids induce both effector and regulatory T cells by suppression of histone deacetylases and regulation of the mTOR–S6K pathway
Park, J., Kim, M., Kang, S. G., Jannasch, A. H., Cooper, B., Patterson, J., & Kim, C. H. (2015) · Mucosal Immunology · doi:10.1038/mi.2014.44 · Cited by 1,307 · see citing works
Alterations of the human gut microbiome in multiple sclerosis
Jangi, S., Gandhi, R., Cox, L. M., Li, N., von Glehn, F., Yan, R., Patel, B., Mazzola, M. A., Liu, S., Glanz, B. L., et al. (2016) · Nature Communications · doi:10.1038/ncomms12015 · Cited by 1,307 · see citing works
Commensal microbiota and myelin autoantigen cooperate to trigger autoimmune demyelination
Berer, K., Mues, M., Koutrolos, M., Rasbi, Z. A., Boziki, M., Johner, C., Wekerle, H., & Krishnamoorthy, G. (2011) · Nature · doi:10.1038/nature10554 · Cited by 1,251 · see citing works
Interleukin-17 Production in Central Nervous System-Infiltrating T Cells and Glial Cells Is Associated with Active Disease in Multiple Sclerosis
Tzartos, J. S., Friese, M. A., Craner, M. J., Palace, J. A., Newcombe, J., Esiri, M. M., & Fugger, L. H. (2007) · American Journal Of Pathology · doi:10.2353/ajpath.2008.070690 · Cited by 1,180 · see citing works
Recognition of peptidoglycan from the microbiota by Nod1 enhances systemic innate immunity
Clarke, T. B., Davis, K. M., Lysenko, E. S., Zhou, A. Y., Yu, Y., & Weiser, J. N. (2010) · Nature Medicine · doi:10.1038/nm.2087 · Cited by 1,154 · see citing works
Molecular Antagonism and Plasticity of Regulatory and Inflammatory T Cell Programs
Yang, X. O., Nurieva, R., Martínez, G., Kang, H. S., Chung, Y., Pappu, B. P., Shah, B., Chang, S. H., Schluns, K. S., Watowich, S. S., et al. (2008) · Immunity · doi:10.1016/j.immuni.2008.05.007 · Cited by 1,129 · see citing works
ATP drives lamina propria TH17 cell differentiation
Atarashi, K., Nishimura, J., Shima, T., Umesaki, Y., Yamamoto, M., Onoue, M., Yagita, H., Ishii, N., Evans, R., Honda, K., et al. (2008) · Nature · doi:10.1038/nature07240 · Cited by 1,089 · see citing works
Induction of pathogenic TH17 cells by inducible salt-sensing kinase SGK1
Wu, C., Yosef, N., Thalhamer, T., Zhu, C., Xiao, S., Kishi, Y., Regev, A., & Kuchroo, V. K. (2013) · Nature · doi:10.1038/nature11984 · Cited by 1,022 · see citing works
Brain-gut-microbe communication in health and disease
Grenham, S., Clarke, G., Cryan, J. F., & Dinan, T. G. (2011) · Frontiers in Physiology · doi:10.3389/fphys.2011.00094 · Cited by 952 · see citing works
T cells in multiple sclerosis and experimental autoimmune encephalomyelitis
Fletcher, J. M., Lalor, S. J., Sweeney, C. M., Tubridy, N. J., & Mills, K. H. G. (2010) · Clinical & Experimental Immunology · doi:10.1111/j.1365-2249.2010.04143.x · Cited by 937 · see citing works
Dietary fatty acids directly impact central nervous system autoimmunity via the small intestine
Haghikia, A., Jörg, S., Duscha, A., Berg, J., Manzel, A., Waschbisch, A., Hammer, A., Lee, D.-H., May, C., Wilck, N., et al. (2015) · Immunity · doi:10.1016/j.immuni.2015.09.007 · Cited by 927 · see citing works
Deacetylase inhibition promotes the generation and function of regulatory T cells
Tao, R. N., de Zoeten, E. F., Özkaynak, E., Chen, C., Wang, L., Porrett, P. M., Li, B., Turka, L. A., Olson, E. N., Greene, M. I., et al. (2007) · Nature Medicine · doi:10.1038/nm1652 · Cited by 927 · see citing works
Dysbiosis in the Gut Microbiota of Patients with Multiple Sclerosis, with a Striking Depletion of Species Belonging to Clostridia XIVa and IV Clusters
Miyake, S., Kim, S., Suda, W., Oshima, K., Nakamura, M., Matsuoka, T., Chihara, N., Tomita, A., Sato, W., Kim, S.-W., et al. (2015) · PLoS ONE · doi:10.1371/journal.pone.0137429 · Cited by 809 · see citing works
Th1, Th17, and Th9 Effector Cells Induce Experimental Autoimmune Encephalomyelitis with Different Pathological Phenotypes
Jäger, A., Dardalhon, V., Sobel, R. A., Bettelli, E., & Kuchroo, V. K. (2009) · The Journal of Immunology · doi:10.4049/jimmunol.0901906 · Cited by 783 · see citing works
Human CD25highFoxp3pos regulatory T cells differentiate into IL-17–producing cells
Koenen, H. J. P. M., Smeets, R. L., Vink, P. M., van Rijssen, E., Boots, A. M. H., & Joosten, I. (2008) · Blood · doi:10.1182/blood-2008-01-133967 · Cited by 735 · see citing works
Cutting Edge: Regulatory T Cells Induce CD4+CD25−Foxp3− T Cells or Are Self-Induced to Become Th17 Cells in the Absence of Exogenous TGF-β
Xu, L., Kitani, A., Fuss, I. J., & Strober, W. (2007) · The Journal of Immunology · doi:10.4049/jimmunol.178.11.6725 · Cited by 733 · see citing works
Suppressive effect of short-chain fatty acids on production of proinflammatory mediators by neutrophils
Vinolo, M. A. R., Rodrigues, H. G., Hatanaka, E., Sato, F. T., Sampaio, S. C., & Curi, R. (2010) · The Journal of Nutritional Biochemistry · doi:10.1016/j.jnutbio.2010.07.009 · Cited by 714 · see citing works
Gut microbiota-derived short-chain Fatty acids, T cells, and inflammation
Kim, C. H., Park, J., & Kim, M. (2014) · Immune Network · doi:10.4110/in.2014.14.6.277 · Cited by 704 · see citing works
Regulated virulence controls the ability of a pathogen to compete with the gut microbiota
Kamada, N., Kim, Y.-G., Sham, H. P., Vallance, B. A., Puente, J. L., Martens, E. C., & Núñez, G. (2012) · Science · doi:10.1126/science.1222195 · Cited by 682 · see citing works
Role of Gut Commensal Microflora in the Development of Experimental Autoimmune Encephalomyelitis
Ochoa-Repáraz, J., Mielcarz, D. W., Ditrio, L. E., Burroughs, A. R., Foureau, D. M., Haque-Begum, S., & Kasper, L. H. (2009) · The Journal of Immunology · doi:10.4049/jimmunol.0900747 · Cited by 590 · see citing works
Vagal pathways for microbiome-brain-gut axis communication
Forsythe, P., Bienenstock, J., & Kunze, W. A. (2014) · Advances in Experimental Medicine and Biology · doi:10.1007/978-1-4939-0897-4_5 · Cited by 576 · see citing works
Human cerebrospinal fluid central memory CD4 + T cells: Evidence for trafficking through choroid plexus and meninges via P-selectin
Kivisäkk, P., Mahad, D., Callahan, M. K., Trebst, C., Tucky, B. H., Wei, T., Wu, L., Bækkevold, E. S., Lassmann, H., Staugaitis, S. M., et al. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1433000100 · Cited by 546 · see citing works
The Indispensable Roles of Microglia and Astrocytes during Brain Development
Reemst, K., Noctor, S. C., Lucassen, P. J., & Hol, E. M. (2016) · Frontiers in Human Neuroscience · doi:10.3389/fnhum.2016.00566 · Cited by 516 · see citing works
Commensal DNA Limits Regulatory T Cell Conversion and Is a Natural Adjuvant of Intestinal Immune Responses
Hall, J. A., Bouladoux, N. J., Sun, C., Wohlfert, E. A., Blank, R. B., Zhu, Q., Grigg, M. E., Berzofsky, J. A., & Belkaid, Y. (2008) · Immunity · doi:10.1016/j.immuni.2008.08.009 · Cited by 490 · see citing works
A Novel Probiotic Mixture Exerts a Therapeutic Effect on Experimental Autoimmune Encephalomyelitis Mediated by IL-10 Producing Regulatory T Cells
Lavasani, S., Dzhambazov, B. M., Nouri, M., Fåk, F., Buske, S., Molin, G., Thorlacius, H., Alenfall, J., Jeppsson, B. W., & Weström, B. R. (2010) · PLoS ONE · doi:10.1371/journal.pone.0009009 · Cited by 450 · see citing works
IL-17A and IL-17F do not contribute vitally to autoimmune neuro-inflammation in mice
Haak, S., Croxford, A. L., Kreymborg, K., Heppner, F. L., Pouly, S., Becher, B., & Waisman, A. (2008) · Journal of Clinical Investigation · doi:10.1172/jci35997 · Cited by 398 · see citing works
The plasticity of human Treg and Th17 cells and its role in autoimmunity
Kleinewietfeld, M., & Hafler, D. A. (2013) · Seminars in Immunology · doi:10.1016/j.smim.2013.10.009 · Cited by 389 · see citing works
Compromised CD4+ CD25high regulatory T‐cell function in patients with relapsing‐remitting multiple sclerosis is correlated with a reduced frequency of FOXP3‐positive cells and reduced FOXP3 expression at the single‐cell level
Venken, K., Hellings, N., Thewissen, M. M., Somers, V. A., Hensen, K., Rummens, J., Medaer, R., Hupperts, R., & Stinissen, P. (2007) · Immunology · doi:10.1111/j.1365-2567.2007.02690.x · Cited by 360 · see citing works
Retinoic Acid Enhances Foxp3 Induction Indirectly by Relieving Inhibition from CD4+CD44hi Cells
Hill, J. A., Hall, J. A., Sun, C., Cai, Q., Ghyselinck, N. B., Chambon, P., Belkaid, Y., Mathis, D. J., & Benoist, C. O. (2008) · Immunity · doi:10.1016/j.immuni.2008.09.018 · Cited by 358 · see citing works
Sodium chloride inhibits the suppressive function of FOXP3+ regulatory T cells
Hernandez, A., Kitz, A., Wu, C., Lowther, D. E., Rodriguez, D. M., Vudattu, N. K., Deng, S., Herold, K. C., Kuchroo, V. K., Kleinewietfeld, M., et al. (2015) · Journal of Clinical Investigation · doi:10.1172/jci81151 · Cited by 340 · see citing works
High frequency of intestinal T H 17 cells correlates with microbiota alterations and disease activity in multiple sclerosis
Cosorich, I., Dalla-Costa, G., Sorini, C., Ferrarese, R., Messina, M. J., Dolpady, J., Radice, E., Mariani, A., Testoni, P. A., Canducci, F., et al. (2017) · Science Advances · doi:10.1126/sciadv.1700492 · Cited by 338 · see citing works
Myelin basic protein‐specific T lymphocyte lines from MS patients and healthy individuals
Pette, M., Fujita, K., Kitze, B., Whitaker, J. N., Albert, E., Kappos, L., & Wekerle, H. (1990) · Neurology · doi:10.1212/wnl.40.11.1770 · Cited by 333 · see citing works
Role of Th17 Cells in the Pathogenesis of Human IBD
Gálvez, J. (2014) · ISRN Inflammation · doi:10.1155/2014/928461 · Cited by 317 · see citing works
Multiple Sclerosis in Rural Norway
SWANK, R. L., Lerstad, O., Ström, A., & Backer, J. F. A. D. (1952) · New England Journal of Medicine · doi:10.1056/nejm195205082461901 · Cited by 316 · see citing works
Induction of T helper type 1–like regulatory cells that express Foxp3 and protect against airway hyper-reactivity
Stock, P., Akbari, O., Berry, G. J., Freeman, G. J., DeKruyff, R. H., & Umetsu, D. T. (2004) · Nature Immunology · doi:10.1038/ni1122 · Cited by 313 · see citing works
Butyrate and trichostatin A attenuate nuclear factor κB activation and tumor necrosis factor α secretion and increase prostaglandin E2 secretion in human peripheral blood mononuclear cells
Usami, M., Kishimoto, K., Ohata, A., Miyoshi, M., Aoyama, M., Fueda, Y., & Kotani, J. (2008) · Nutrition Research · doi:10.1016/j.nutres.2008.02.012 · Cited by 309 · see citing works
Microbiota-gut-brain axis and the central nervous system
Zhu, X., Han, Y., Du, J., Liu, R., Jin, K., & Yi, W. (2017) · Oncotarget · doi:10.18632/oncotarget.17754 · Cited by 308 · see citing works
Nanoparticle-mediated codelivery of myelin antigen and a tolerogenic small molecule suppresses experimental autoimmune encephalomyelitis
Yeste, A., Nadeau, M., Burns, E. J., Weiner, H. L., & Quintana, F. J. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1120611109 · Cited by 303 · see citing works
Spontaneous relapsing-remitting EAE in the SJL/J mouse: MOG-reactive transgenic T cells recruit endogenous MOG-specific B cells
Pöllinger, B., Krishnamoorthy, G., Berer, K., Lassmann, H., Bösl, M. R., Dunn, R., Domingues, H. S., Holz, A., Kurschus, F. C., & Wekerle, H. (2009) · The Journal of Experimental Medicine · doi:10.1084/jem.20090299 · Cited by 297 · see citing works
Blockade of dendritic cell development by bacterial fermentation products butyrate and propionate through a transporter (Slc5a8)-dependent inhibition of histone deacetylases
Singh, N., Thangaraju, M., Prasad, P. D., Martin, P. M., Lambert, N. A., Boettger, T., Offermanns, S., & Ganapathy, V. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.102947 · Cited by 293 · see citing works
Childhood body mass index and multiple sclerosis risk: a long-term cohort study
Munger, K. L., Bentzen, J., Laursen, B., Stenager, E., Koch‐Henriksen, N., Sørensen, T. I. A., & Baker, J. L. (2013) · Multiple Sclerosis Journal · doi:10.1177/1352458513483889 · Cited by 292 · see citing works
High salt reduces the activation of IL-4– and IL-13–stimulated macrophages
Binger, K. J., Gebhardt, M., Heinig, M., Rintisch, C., Schroeder, A., Neuhofer, W., Hilgers, K. F., Manzel, A., Schwartz, C., Kleinewietfeld, M., et al. (2015) · Journal of Clinical Investigation · doi:10.1172/jci80919 · Cited by 280 · see citing works
DC activated via dectin‐1 convert Treg into IL‐17 producers
Osorio, F., LeibundGut‐Landmann, S., Lochner, M., Lahl, K., Sparwasser, T. D., Eberl, G., & Sousa, C. R. E. (2008) · European Journal of Immunology · doi:10.1002/eji.200838950 · Cited by 273 · see citing works
bHLH-PAS proteins in cancer
Bersten, D. C., Sullivan, A. E., Peet, D. J., & Whitelaw, M. L. (2013) · Nature Reviews Cancer · doi:10.1038/nrc3621 · Cited by 267 · see citing works
Human Gut-Derived Commensal Bacteria Suppress CNS Inflammatory and Demyelinating Disease
Mangalam, A., Shahi, S. K., Luckey, D., Karau, M., Marietta, E., Luo, N., Choung, R. S., Ju, J., Sompallae, R., Gibson-Corley, K., et al. (2017) · Cell Reports · doi:10.1016/j.celrep.2017.07.031 · Cited by 266 · see citing works
Gut microbiota, immune development and function
Bengmark, S. (2012) · Pharmacological Research · doi:10.1016/j.phrs.2012.09.002 · Cited by 264 · see citing works
Sodium intake is associated with increased disease activity in multiple sclerosis
Farez, M., Fiol, M. P., Gaitán, M. I., Quintana, F. J., & Correale, J. D. (2014) · Journal of Neurology Neurosurgery & Psychiatry · doi:10.1136/jnnp-2014-307928 · Cited by 264 · see citing works
Brain microglia and blood-derived macrophages: molecular profiles and functional roles in multiple sclerosis and animal models of autoimmune demyelinating disease.
Raivich, G., & Banati, R. (2004) · Brain research. Brain research reviews · doi:10.1016/j.brainresrev.2004.06.006 · Cited by 263 · see citing works
Natural Treg cells spontaneously differentiate into pathogenic helper cells in lymphopenic conditions
Duarte, J. H., Zelenay, S., Bergman, M., Martins, A. C., & Demengeot, J. (2009) · European Journal of Immunology · doi:10.1002/eji.200839196 · Cited by 250 · see citing works
Expansion and Functional Relevance of High-Avidity Myelin-Specific CD4+ T Cells in Multiple Sclerosis
Bielekova, B., Sung, M., Kadom, N., Simon, R. M., McFarland, H. F., & Martinꝉ, R. (2004) · The Journal of Immunology · doi:10.4049/jimmunol.172.6.3893 · Cited by 241 · see citing works
Regulatory T cells in autoimmune neuroinflammation
Kleinewietfeld, M., & Hafler, D. A. (2014) · Immunological Reviews · doi:10.1111/imr.12169 · Cited by 230 · see citing works
Host adaptive immunity alters gut microbiota
Zhang, H., Sparks, J. B., Karyala, S. V., Settlage, R. E., & Luo, X. (2014) · The ISME Journal · doi:10.1038/ismej.2014.165 · Cited by 213 · see citing works
Type 17 T helper cells-origins, features and possible roles in rheumatic disease.
Annunziato, F., Cosmi, L., Liotta, F., Maggi, E., & Romagnani, S. (2009) · Nature Reviews Rheumatology · doi:10.1038/nrrheum.2009.80 · Cited by 212 · see citing works
Communicating systems in the body: how microbiota and microglia cooperate
Erny, D., de Angelis, A. L. H., & Prinz, M. (2016) · Immunology · doi:10.1111/imm.12645 · Cited by 190 · see citing works
Investigation of probiotics in multiple sclerosis
Tankou, S. K., Regev, K., Healy, B. C., Cox, L. M., Tjon, E., Kivisakk, P., Vanande, I. P., Cook, S., Gandhi, R., Glanz, B., et al. (2018) · Multiple Sclerosis Journal · doi:10.1177/1352458517737390 · Cited by 156 · see citing works
The SCFA butyrate stimulates the epithelial production of retinoic acid via inhibition of epithelial HDAC
Schilderink, R., Verseijden, C., Seppen, J., Muncan, V., BRINK, G. R. V. D., Lambers, T. T., van Tol, E. A. F., & de Jonge, W. J. (2016) · American Journal of Physiology-Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.00411.2015 · Cited by 153 · see citing works
CD11c-expressing cells reside in the juxtavascular parenchyma and extend processes into the glia limitans of the mouse nervous system
Prodinger, C., Bunse, J., Krüger, M., Schiefenhövel, F., Brandt, C., Laman, J. D., Greter, M., Immig, K., Heppner, F. L., Becher, B., et al. (2010) · Acta Neuropathologica · doi:10.1007/s00401-010-0774-y · Cited by 147 · see citing works
Bacterial peptidoglycan and immune reactivity in the central nervous system in multiple sclerosis
Schrijver, I. A. (2001) · Brain · doi:10.1093/brain/124.8.1544 · Cited by 143 · see citing works
Bifidobacterium animalis in combination with human origin of Lactobacillus plantarum ameliorate neuroinflammation in experimental model of multiple sclerosis by altering CD4+ T cell subset balance
Salehipour, Z., Haghmorad, D., Sankian, M., Rastin, M., Nosratabadi, R., Dallal, M. M. S., Tabasi, N. S., Khazaee, M., Nasiraie, L. R., & Mahmoudi, M. (2017) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2017.08.117 · Cited by 139 · see citing works
DIET AND THE GEOGRAPHICAL DISTRIBUTION OF MULTIPLE SCLEROSIS
Agranoff, B. W., & GOLDBERG, D. J. (1974) · The Lancet · doi:10.1016/s0140-6736(74)92163-1 · Cited by 131 · see citing works
The Niacin/Butyrate Receptor GPR109A Suppresses Mammary Tumorigenesis by Inhibiting Cell Survival
Elangovan, S., Pathania, R., Ramachandran, S., Ananth, S., Padia, R. N., Lan, L., Singh, N., Martin, P. M., Hawthorn, L., Prasad, P. D., et al. (2013) · Cancer Research · doi:10.1158/0008-5472.can-13-1451 · Cited by 127 · see citing works
Th17 Cells in Immunopathogenesis and treatment of rheumatoid arthritis
Azizi, G., Jadidi‐Niaragh, F., & Mirshafiey, A. (2013) · International Journal of Rheumatic Diseases · doi:10.1111/1756-185x.12132 · Cited by 124 · see citing works
Proinflammatory Bacterial Peptidoglycan as a Cofactor for the Development of Central Nervous System Autoimmune Disease
Visser, L. H., de Heer, H. J., Boven, L. A., van Riel, D. A. J., van Meurs, M., Melief, M., Zähringer, U., van Strijp, J. A. G., Lambrecht, B. N., Nieuwenhuis, E. E. S., et al. (2005) · The Journal of Immunology · doi:10.4049/jimmunol.174.2.808 · Cited by 119 · see citing works
IFNβ secreted by microglia mediates clearance of myelin debris in CNS autoimmunity
Kocur, M., Schneider, R., Pulm, A.-K., Bauer, J., Kropp, S., Gliem, M., Ingwersen, J., Goebels, N., Alferink, J., Prozorovski, T., et al. (2015) · Acta Neuropathologica Communications · doi:10.1186/s40478-015-0192-4 · Cited by 117 · see citing works
Dietary Inhibitors of Histone Deacetylases in Intestinal Immunity and Homeostasis
Schilderink, R., Verseijden, C., & de Jonge, W. J. (2013) · Frontiers in Immunology · doi:10.3389/fimmu.2013.00226 · Cited by 115 · see citing works
Therapies for multiple sclerosis: translational achievements and outstanding needs
Haghikia, A., Hohlfeld, R., Gold, R., & Fugger, L. H. (2013) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2013.03.004 · Cited by 108 · see citing works
Brain microbiota disruption within inflammatory demyelinating lesions in multiple sclerosis
Branton, W. G., Lu, J., Surette, M. G., Holt, R. A., Lind, J. C., Laman, J. D., & Power, C. (2016) · Scientific Reports · doi:10.1038/srep37344 · Cited by 104 · see citing works
Higher intake of omega-3 polyunsaturated fatty acids is associated with a decreased risk of a first clinical diagnosis of central nervous system demyelination: Results from the Ausimmune Study
Hoare, S., Lithander, F. E., van der Mei, I. A. F., Ponsonby, A., Lucas, R. M., for the Ausimmune Investigator Group, Chapman, C., Coulthard, A., Dear, K. B. G., Dwyer, T., et al. (2015) · Multiple Sclerosis Journal · doi:10.1177/1352458515604380 · Cited by 98 · see citing works
Anti-inflammatory nutritional intervention in patients with relapsing-remitting and primary-progressive multiple sclerosis: A pilot study
Riccio, P., Rossano, R., Larocca, M., Trotta, V., Mennella, I., Vitaglione, P., Ettorre, M., Graverini, A., Santis, A. D., Monte, E. D., et al. (2016) · Experimental Biology and Medicine · doi:10.1177/1535370215618462 · Cited by 96 · see citing works
Regulatory T cells fail to suppress CD4+ T‐bet+ T cells in relapsing multiple sclerosis patients
Frisullo, G., Nociti, V., Iorio, R., Patanella, A. K., Caggiula, M., Marti, A., Sancricca, C., Angelucci, F., Massimiliano Mirabella, A., Tonali, P. A., et al. (2008) · Immunology · doi:10.1111/j.1365-2567.2008.02963.x · Cited by 90 · see citing works
Butyrate-induced GPR41 Activation Inhibits Histone Acetylation and Cell Growth
Wu, J., Zhou, Z., Hu, Y., & Dong, S. (2012) · Journal of genetics and genomics/Journal of Genetics and Genomics · doi:10.1016/j.jgg.2012.05.008 · Cited by 81 · see citing works
Mediterranean diet adherence and risk of multiple sclerosis: a case-control study.
Sedaghat, F., Jessri, M., Behrooz, M., Mirghotbi, M., & Rashidkhani, B. (2016) · PubMed · doi:10.6133/apjcn.2016.25.2.12 · Cited by 78 · see citing works
High salt drives Th17 responses in experimental autoimmune encephalomyelitis without impacting myeloid dendritic cells
Haase, S., Kissel, J., Manzel, A., Kleinewietfeld, M., Haghikia, A., Gold, R., Müller, D. N., & Linker, R. A. (2016) · Experimental Neurology · doi:10.1016/j.expneurol.2016.03.010 · Cited by 73 · see citing works
Molecular Mechanisms of the Action of Vitamin A in Th17/Treg Axis in Multiple Sclerosis
Abdolahi, M., Yavari, P., Honarvar, N. M., Bitarafan, S., Mahmoudi, M., & Saboor-Yaraghi, A. A. (2015) · Journal of Molecular Neuroscience · doi:10.1007/s12031-015-0643-1 · Cited by 68 · see citing works
Phagocytes Containing a Disease-Promoting Toll-Like Receptor/Nod Ligand Are Present in the Brain during Demyelinating Disease in Primates
Visser, L. H., Melief, M., van Riel, D. A. J., van Meurs, M., Sick, E. A., Inamura, S., Bajramovic, J. J., Amor, S., Hintzen, R. Q., Boven, L. A., et al. (2006) · American Journal Of Pathology · doi:10.2353/ajpath.2006.060143 · Cited by 66 · see citing works
Multiple sclerosis: immunopathogenesis and controversies in defining the cause
Holmøy, T., & Hestvik, A. L. K. (2008) · Current Opinion in Infectious Diseases · doi:10.1097/qco.0b013e3282f88b48 · Cited by 54 · see citing works
Interferon‐β affects the tryptophan metabolism in multiple sclerosis patients
Amirkhani, A., Rajda, C., Arvidsson, B., Bencsik, K., Boda, K., Seres, E., Markides, K. E., Vécsei, L., & Bergquist, J. (2005) · European Journal of Neurology · doi:10.1111/j.1468-1331.2005.01041.x · Cited by 52 · see citing works
Autoimmunity's next top models
Wekerle, H., Flügel, A., Fugger, L. H., Schett, G. A., & SERREZE, D. V. (2012) · Nature Medicine · doi:10.1038/nm.2635 · Cited by 50 · see citing works
Synergistic effects of atorvastatin and all-trans retinoic acid in ameliorating animal model of multiple sclerosis
Froushani, S. M. A., Delirezh, N., Hobbenaghi, R., & Mosayebi, G. (2013) · Immunological Investigations · doi:10.3109/08820139.2013.825269 · Cited by 47 · see citing works
Cytokine secretion profile of myelin basic protein-specific T cells in multiple sclerosis
Rohowsky‐Kochan, C., Molinaro, D., & Cook, S. D. (2000) · Multiple Sclerosis Journal · doi:10.1177/135245850000600203 · Cited by 45 · see citing works
Bacillus-derived poly-γ-glutamic acid reciprocally regulates the differentiation of T helper 17 and regulatory T cells and attenuates experimental autoimmune encephalomyelitis
Lee, K. N., Hwang, S., Paik, D. J., Kim, W. K., Kim, J. M., & Youn, J. (2012) · Clinical & Experimental Immunology · doi:10.1111/j.1365-2249.2012.04637.x · Cited by 27 · see citing works
Bacillus subtilis-specific poly- -glutamic acid regulates development pathways of naive CD4+ T cells through antigen-presenting cell-dependent and -independent mechanisms
Kim, S., Yang, J., Lee, K. N., Oh, K., Gi, M., Kim, J. M., Paik, D. J., Hong, S., & Youn, J. (2009) · International Immunology · doi:10.1093/intimm/dxp065 · Cited by 24 · see citing works

Flagged first, then by citations

Research works printed but not linked: 3

Smith PM, Howitt MR, Panikov N, Michaud M, Gallini CA, Bohlooly-Y M et al. The microbial metabolites, short-chain fatty acids, regulate colonic Treg cell homeostasis. Science 2013; 341:569-73.
Mucida D, Park Y, Kim G, Turovskaya O, Scott I, Kronenberg M et al. Reciprocal TH17 and regulatory T cell differentiation mediated by retinoic acid. Science 2007; 317:256-60.
Cosorich I, Dalla-Costa G, Sorini C, Ferrarese R, Messina MJ, Dolpady J et al. High frequency of intestinal TH17 cells correlates with microbiota alterations and disease activity in multiple sclerosis. Sci Adv 2017; 3:e1700492.

Sorted by citations

Alterations of the Gut Microbiota in Patients With Coronavirus Disease 2019 or H1N1 Influenza
Gu, S., Chen, Y., Wu, Z., Chen, Y., Gao, H., Lv, L., Guo, F., Zhang, X., Luo, R., Huang, C., et al. (2020) · Clinical Infectious Diseases · doi:10.1093/cid/ciaa709 · Cited by 790 · see citing works
“and other commensal bacteria with important physiological functions may promote the overgrowth of intestinal conditional pathogenic bacteria and increase both intestinal mucosal permeability and endotoxin concentrations in the blood, ultimately triggering inflammation, which exacerbates cytokine release[36, 37].”
Background
Impact of microbiota on central nervous system and neurological diseases: the gut-brain axis
Ma, Q., Xing, C., Long, W., Wang, H. Y., Liu, Q., & Wang, R. (2019) · Journal of Neuroinflammation · doi:10.1186/s12974-019-1434-3 · Cited by 752 · see citing works
“EAE model, an autoimmune animal model induced by CD4+ T cells, is widely used to investigate MS [143], and studies have suggested that oral administration of antibiotics significantly reduces disease severity as it enhances the recruitment and proliferation of Foxp3+ Tregs [144].”
BackgroundInfluential
Gut-Microbiota-Derived Metabolites Maintain Gut and Systemic Immune Homeostasis
Wang, J., Zhu, N., Su, L., Gao, Y., & Yang, R. (2023) · Cells · doi:10.3390/cells12050793 · Cited by 624 · see citing works
Respiratory viral infection-induced microbiome alterations and secondary bacterial pneumonia.
Hanada, S., Pirzadeh, M., Carver, K. Y., & Deng, J. C. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.02640 · Cited by 495 · see citing works
“In addition to being a major energy source for intestinal epithelial cells, SCFAs promote the development of naive CD4 T cells into regulatory T cells (31, 32), induce “tolerogenic” dendritic cells in the intestinal mucosa (33), and limit autoimmity (34, 35).”
Background
Nutritional Components in Western Diet Versus Mediterranean Diet at the Gut Microbiota–Immune System Interplay. Implications for Health and Disease
Montero, C. G., Fraile‐Μartinez, O., Gomez-Lahoz, A. M., Pekarek, L., Castellanos, A. J., Noguerales-Fraguas, F., Coca, S., Guijarro, L. G., García‐Honduvilla, N., Asúnsolo, Á., et al. (2021) · Nutrients · doi:10.3390/nu13020699 · Cited by 452 · see citing works
Modulation of Gut Microbiota and Immune System by Probiotics, Pre-biotics, and Post-biotics
Liu, Y., Wang, J., & Wu, C. (2022) · Frontiers in Nutrition · doi:10.3389/fnut.2021.634897 · Cited by 393 · see citing works
Metal Drugs and the Anticancer Immune Response
Englinger, B., Pirker, C., Heffeter, P., Terenzi, A., Kowol, C. R., Keppler, B. K., & Berger, W. (2019) · Chemical Reviews · doi:10.1021/acs.chemrev.8b00396 · Cited by 355 · see citing works
Potential intestinal infection and faecal–oral transmission of SARS-CoV-2
Guo, M., Tao, W., Flavell, R. A., & Zhu, S. (2021) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-021-00416-6 · Cited by 305 · see citing works
Bridging intestinal immunity and gut microbiota by metabolites
Wang, G., Huang, S., Wang, Y., Cai, S., Yu, H., Liu, H., Zeng, X., Zhang, G., & Qiao, S. (2019) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-019-03190-6 · Cited by 299 · see citing works
“Acetate and propionate, but not butyrate, can be detected in the peripheral circulation, indicating that distinct SCFAs have different functions in the immune system [227, 228].”
Background
Short-chain fatty acids as modulators of redox signaling in health and disease
González‐Bosch, C., Boorman, E., Zunszain, P. A., & Mann, G. E. (2021) · Redox Biology · doi:10.1016/j.redox.2021.102165 · Cited by 285 · see citing works
“In vitro and in vivo studies have shown that the physiological functions of free fatty acid receptors (FFARs) contribute not only to the regulation of metabolic energy but also affect the immune system [24].”
Background
Characterizing Dysbiosis of Gut Microbiome in PD: Evidence for Overabundance of Opportunistic Pathogens
Wallen, Z. D., Appah, M., Dean, M. N., Sesler, C. L., Factor, S. A., Molho, E., Zabetian, C. P., Standaert, D. G., & Payami, H. (2020) · npj Parkinson s Disease · doi:10.1038/s41531-020-0112-6 · Cited by 252 · see citing works
Intestinal Microbiota-Derived Short Chain Fatty Acids in Host Health and Disease
Cong, J., Zhou, P., & Zhang, R. (2022) · Nutrients · doi:10.3390/nu14091977 · Cited by 234 · see citing works
“Butyrate may increase Treg level in colon lamina propria and induce IL-10 secretion in DCs and macrophages to regulate immune functions, which helps to prevent the progression of multiple sclerosis [29].”
Background
Probiotics, Prebiotics and Postbiotics on Mitigation of Depression Symptoms: Modulation of the Brain–Gut–Microbiome Axis
Chudzik, A., Orzyłowska, A., Rola, R., & Stanisz, G. J. (2021) · Biomolecules · doi:10.3390/biom11071000 · Cited by 212 · see citing works
The Role of Gut Bacterial Metabolites in Brain Development, Aging and Disease
Tran, S. M.-S., & Mohajeri, M. H. (2021) · Nutrients · doi:10.3390/nu13030732 · Cited by 207 · see citing works
“The non-exhaustive list of reported effects includes improved gut barrier and BBB integrity [19–22] and an overall shift towards anti-inflammatory processes [13,28,29,74,75,91].”
BackgroundResult
Porphyromonas gingivalis aggravates colitis via a gut microbiota-linoleic acid metabolism-Th17/Treg cell balance axis
Lü, J., Jiang, Y., Wu, L., Fu, J., Du, J., Luo, Z., Guo, L., Xu, J., & Liu, Y. F. (2024) · Nature Communications · doi:10.1038/s41467-024-45473-y · Cited by 210 · see citing works
“Some com-mensalbacteriaandtheirmetabolitescanalsopromotethegeneration of Treg cells, contributing to immune suppression 48 .”
Radiotherapy and the gut microbiome: facts and fiction
Liu, J., Liu, C., & Yue, J. (2021) · Radiation Oncology · doi:10.1186/s13014-020-01735-9 · Cited by 183 · see citing works
Multi-Omic Analysis of the Microbiome and Metabolome in Healthy Subjects Reveals Microbiome-Dependent Relationships Between Diet and Metabolites
Tang, Z.-Z., Chen, G., Hong, Q., Huang, S., Smith, H., Shah, R. D., Scholz, M. B., & Ferguson, J. F. (2019) · Frontiers in Genetics · doi:10.3389/fgene.2019.00454 · Cited by 170 · see citing works
“Microbiome metabolites have been shown to affect inflammation and immune regulation (Levy et al., 2017; Haase et al., 2018), and we observed some association between enterotype-mediated metabolism and plasma CRP.”
Background
The role of short-chain fatty acids in inflammatory skin diseases
Xiao, X., Hu, X., Yao, J., Cao, W., Zou, Z., Wang, L., Qin, H., Zhong, D., Li, Y., Xue, P., et al. (2023) · Frontiers in Microbiology · doi:10.3389/fmicb.2022.1083432 · Cited by 163 · see citing works
“The binding of these receptors to SCFAs activates intracellular signaling pathways that regulate cellular responses, immune function, and inflammation (Marinissen and Gutkind, 2001; Trompette et al., 2014; Haase et al., 2018).”
Background
Natural Products for the Treatment of Autoimmune Arthritis: Their Mechanisms of Action, Targeted Delivery, and Interplay with the Host Microbiome
Dudics, S., Langan, D., Meka, R. R., Venkatesha, S. H., Berman, B., Che, C., & Moudgil, K. D. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19092508 · Cited by 160 · see citing works
“In addition to propionate and acetate, these essential short-chain fatty acids (SCFAs) affect host cells by inhibiting histone-deacetylase to promote anti-inflammatory responses [198].”
Background
The role of Th17 cells in inflammatory bowel disease and the research progress
Chen, L., Ruan, G., Cheng, Y., Yi, A., Chen, D., & Wei, Y. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2022.1055914 · Cited by 155 · see citing works
“After treating IBD mice with Porphyromonas gingivalis, Lactobacillus rhamnosus GG, Ruminococcaceae or Lactobacillus paracasei R3, intestinal Frontiers in Immunology 11 inflammation was relieved, where Tregs increased significantly in the intestinal tissue, while Th17 cells decreased, and intestinal inflammation was re…”
BackgroundInfluential
The correlation between the Th17/Treg cell balance and bone health
Zhu, L., Hua, F., Ding, W., Ding, K., Zhang, Y., & Xu, C. (2020) · Immunity & Ageing · doi:10.1186/s12979-020-00202-z · Cited by 146 · see citing works
Molecules Produced by Probiotics and Intestinal Microorganisms with Immunomodulatory Activity
Delgado, S., Sánchez, B., Margollés, A., Ruas‐Madiedo, P., & Ruíz, L. (2020) · Nutrients · doi:10.3390/nu12020391 · Cited by 139 · see citing works
“reuteri is one of the tryptophanase-positive bacteria that generate these indole metabolites and can stimulate AhR activity suppressing pro-inflammatory activities [65,66].”
Background
Smart Nanomedicine to Enable Crossing Blood–Brain Barrier Delivery of Checkpoint Blockade Antibody for Immunotherapy of Glioma
Wang, H., Chao, Y., Zhao, H., Zhou, X., Zhang, F., Zhang, Z., Li, Z., Pan, J., Wang, J., Chen, Q., et al. (2022) · ACS Nano · doi:10.1021/acsnano.1c08120 · Cited by 118 · see citing works
Short-Chain Fatty Acids in Chronic Kidney Disease: Focus on Inflammation and Oxidative Stress Regulation
Magliocca, G., Mone, P., Iorio, B. R. D., Heidland, A., & Marzocco, S. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23105354 · Cited by 121 · see citing works
“SCFAs are versatile molecules involved in cell signalling in a wide range of physiological and pathological conditions [40].”
Background
Thinking outside the box: non-canonical targets in multiple sclerosis
Bierhansl, L., Hartung, H., Aktaş, O., Ruck, T., Roden, M., & Meuth, S. G. (2022) · Nature Reviews Drug Discovery · doi:10.1038/s41573-022-00477-5 · Cited by 119 · see citing works
Sex differences in autoimmune disorders of the central nervous system
Gold, S. M., Willing, A., Leypoldt, F., Paul, F., & Friese, M. A. (2018) · Seminars in Immunopathology · doi:10.1007/s00281-018-0723-8 · Cited by 117 · see citing works
Probiotics: If It Does Not Help It Does Not Do Any Harm. Really?
Lerner, A., Shoenfeld, Y., & Matthias, T. (2019) · Microorganisms · doi:10.3390/microorganisms7040104 · Cited by 117 · see citing works
Pharmacogenomics‐Driven Prediction of Antidepressant Treatment Outcomes: A Machine‐Learning Approach With Multi‐trial Replication
Athreya, A. P., Neavin, D. R., Carrillo‐Roa, T., Skime, M. K., Biernacka, J. M., Frye, M. A., Rush, A. J., Wang, L., Binder, E. B., Iyer, R. K., et al. (2019) · Clinical Pharmacology & Therapeutics · doi:10.1002/cpt.1482 · Cited by 114 · see citing works
“25,35 The identification of these “top hit” SNPs during GWAS was performed for quantitative biological traits (i.e., metabolite concentrations), rather than measures of MDD clinical symptom severity (i.e., HDRS or QIDS-C), as our use of phenotypes represented a conscious attempt to move our…”
Method
Polysaccharides from Auricularia auricula: Preparation, structural features and biological activities
Chen, N., Zhang, H., Zong, X., Li, S., Wang, J., Wang, Y., & Jin, M. (2020) · Carbohydrate Polymers · doi:10.1016/j.carbpol.2020.116750 · Cited by 113 · see citing works
Carbohydrates great and small, from dietary fiber to sialic acids: How glycans influence the gut microbiome and affect human health
Coker, J. K. C., Moyne, O., Rodionov, D. A., & Zengler, K. (2021) · Gut Microbes · doi:10.1080/19490976.2020.1869502 · Cited by 112 · see citing works
“Notably, SCFAs downregulate the production of pro-inflammatory cytokines by colonic macrophages(29) and promote the differentiation of naive CD4 + T cells into immunosuppressive regulatory T cells (Treg),(30,31) by binding to G-protein coupled receptors(32) or by inhibiting histone deacetylases.(29,33,34) SCFAs derive…”
Background
Gut-joint axis: Gut dysbiosis can contribute to the onset of rheumatoid arthritis via multiple pathways
Romero-Figueroa, M. D. S., Ramírez‐Durán, N., Montiel-Jarquín, Á. J., & Horta‐Baas, G. (2023) · Frontiers in Cellular and Infection Microbiology · doi:10.3389/fcimb.2023.1092118 · Cited by 107 · see citing works
“In another study, SCFAs positively correlated with Tregs and negatively correlated with pro-inflammatory cytokines (IL-17A, IL-6, TNF-a) in CIA rats (Fan et al., 2020a).”
BackgroundInfluential
A diet high in sugar and fat influences neurotransmitter metabolism and then affects brain function by altering the gut microbiota
Guo, Y., Zhu, X., Zeng, M., Qi, L., Tang, X., Wang, D., Zhang, M., Xie, Y., Li, H., Yang, X., et al. (2021) · Translational Psychiatry · doi:10.1038/s41398-021-01443-2 · Cited by 104 · see citing works
Unraveling the Gut Microbiota: Implications for Precision Nutrition and Personalized Medicine
Abeltino, A., Hatem, D., Serantoni, C., Riente, A., Giulio, M. M. D., Spirito, M. D., Maio, F. D., & Maulucci, G. (2024) · Nutrients · doi:10.3390/nu16223806 · Cited by 108 · see citing works
Microbiome in Multiple Sclerosis: Where Are We, What We Know and Do Not Know
Boziki, M. K., Kesidou, E., Theotokis, P., Mentis, A. A., Karafoulidou, E., Melnikov, M., Sviridova, A. A., Rogovskii, V., Boyко, A., & Grigoriadis, N. (2020) · Brain Sciences · doi:10.3390/brainsci10040234 · Cited by 90 · see citing works
“Tryptophan metabolites may also promote the Th17 pro-inflammatory phenotype by acting on AHR, a signaling pathway known to also affect astrocyte activation in the CNS as a response to microbial stimuli from the systemic circulation [38].”
BackgroundInfluential
The dynamic shifts of IL-10-producing Th17 and IL-17-producing Treg in health and disease: a crosstalk between ancient "Yin-Yang" theory and modern immunology
Cui, H., Wang, N., Li, H., Bian, Y., Wen, W., Kong, X., & Wang, F. (2024) · Cell Communication and Signaling · doi:10.1186/s12964-024-01505-0 · Cited by 92 · see citing works
“Metabolites generated by the intestinal flora constitute one of the mechanisms by which they regulate Treg and Th17 differentiation [124, 125].”
Background
Tumor microbiome – an integral part of the tumor microenvironment
Čierniková, S., Ševčíková, A., Števurková, V., & Mego, M. (2022) · Frontiers in Oncology · doi:10.3389/fonc.2022.1063100 · Cited by 84 · see citing works
“A significant impact of the gut microbiome on the host physiology has been described mainly via modulation of the host immune system, specific function in host metabolism, production of microbiota-derived metabolites, and protection against pathogens (1, 2).”
Background
Tolerating Factor VIII: Recent Progress
Lacroix‐Desmazes, S., Voorberg, J., Lillicrap, D., Scott, D. W., & Pratt, K. P. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2019.02991 · Cited by 71 · see citing works
IRT5 Probiotics Changes Immune Modulatory Protein Expression in the Extraorbital Lacrimal Glands of an Autoimmune Dry Eye Mouse Model
Choi, S. H., Oh, J., Ryu, J. S., Kim, H. M., Im, S., Kim, K. P., & Kim, M. K. (2020) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.61.3.42 · Cited by 68 · see citing works
Is There a Brain Microbiome?
Link, C. D. (2021) · Neuroscience Insights · doi:10.1177/26331055211018709 · Cited by 67 · see citing works
Multiple sclerosis and obesity: The role of adipokines
Correale, J. D., & Marrodán, M. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.1038393 · Cited by 67 · see citing works
“The intestine of people with obesity has also shown increased permeability compared to lean people (47), and metabolites from the gut microbiota can enter the bloodstream and directly modulate the host’s immune system (49).”
Background
Oncobiosis and Microbial Metabolite Signaling in Pancreatic Adenocarcinoma
Kiss, B., Mikó, E., Sebő, É., Tóth, J., Ujlaki, G., Szabó, J., Uray, K., Bai, P., & Árkosy, P. (2020) · Cancers · doi:10.3390/cancers12051068 · Cited by 66 · see citing works
The role of the gut microbiota and microbial metabolites in neuroinflammation
Haase, S., Wilck, N., Haghikia, A., Gold, R., Mueller, D. N., & Linker, R. A. (2020) · European Journal of Immunology · doi:10.1002/eji.201847807 · Cited by 64 · see citing works
The Impact of Gut Microbiota-Derived Metabolites in Autism Spectrum Disorders
Marzal, L. N. P., Prince, N., Bajić, D., Roussin, L., Naudon, L., Rabot, S., Garssen, J., Kraneveld, A. D., & Perez‐Pardo, P. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms221810052 · Cited by 63 · see citing works
“Altogether, excessive amounts of SCFAs like propionate affect a multitude of molecular processes including signalling processes, epigenetic changes, barrier integrity, immune function and neurotransmitter synthesis and release [104,105].”
Background
Gut microbiota metabolites as integral mediators in cardiovascular diseases (Review)
Zhu, Y., Shui, X., Liang, Z., Huang, Z., Qi, Y., He, Y., Chen, C., Luo, H., & Lei, W. (2020) · International Journal of Molecular Medicine · doi:10.3892/ijmm.2020.4674 · Cited by 60 · see citing works
“Metabolites from AAAs (such as Trp) inhibit inflammation by upregulating the aryl hydrocarbon receptor (AhR) in astrocytes or T-cells; however, excessive intake of foods containing long-chain FAs is likely to affect the production of metabolites (69).”
Background
Fatty acids role in multiple sclerosis as “metabokines”
Yu, H., Bai, S., Hao, Y., & Guan, Y. (2022) · Journal of Neuroinflammation · doi:10.1186/s12974-022-02502-1 · Cited by 58 · see citing works
“Specifically, SCFAs and MCFAs by exercising either protective or damaging effects, mediate the complicated crosstalk between gut microbiota and immune system [52, 53], as will be discussed later [54].”
Background
Bacterial infections in lupus: Roles in promoting immune activation and in pathogenesis of the disease
Battaglia, M. C., & Garrett‐Sinha, L. A. (2020) · Journal of Translational Autoimmunity · doi:10.1016/j.jtauto.2020.100078 · Cited by 56 · see citing works
The effects of microbiota-derived short-chain fatty acids on T lymphocytes: From autoimmune diseases to cancer
Saadh, M. J., Allela, O. Q. B., Ballal, S., Mahdi, M. S., Chahar, M., Verma, R., Al-Hussein, R. K. A., Adil, M., Jawad, M. J., & Al-Nuaimi, A. M. A. (2025) · Seminars in Oncology · doi:10.1016/j.seminoncol.2025.152398 · Cited by 57 · see citing works
Gut Microbial Dysbiosis and Plasma Metabolic Profile in Individuals With Vitiligo
Ni, Q., Ye, Z., Wang, Y., Chen, J., Zhang, W., Ma, C., Li, K., Liu, Y., Liu, L., Han, Z., et al. (2020) · Frontiers in Microbiology · doi:10.3389/fmicb.2020.592248 · Cited by 56 · see citing works
Time of Feeding Alters Obesity-Associated Parameters and Gut Bacterial Communities, but Not Fungal Populations, in C57BL/6 Male Mice
van der Merwe, M., Sharma, S., Caldwell, J. L., Smith, N. J., Gomes, C., Bloomer, R. J., Buddington, R. K., & Pierre, J. F. (2019) · Current Developments in Nutrition · doi:10.1093/cdn/nzz145 · Cited by 52 · see citing works
“Microbial production of small molecules and fermentative by-products, including SCFAs and lactate, has been shown to stimulate host receptors within the intestinal epithelium and peripheral tissues that influence immune priming and tolerance (3) and host energy balance (4, 5).”
Background
Gut microbiome and multiple sclerosis: New insights and perspective
Amini, M. E., Shomali, N., Bakhshi, A., Rezaei, S., Hemmatzadeh, M., Hosseinzadeh, R., Eslami, S., Babaie, F., Aslani, S., Torkamandi, S., et al. (2020) · International Immunopharmacology · doi:10.1016/j.intimp.2020.107024 · Cited by 53 · see citing works
Traditional Chinese Medicine and Natural Products: Potential Approaches for Inflammatory Bowel Disease
Yuan, S., Li, Y., Li, J., Xue, J.-C., Wang, Q., Hou, X.-T., Meng, H., Nan, J., & Zhang, Q. (2022) · Frontiers in Pharmacology · doi:10.3389/fphar.2022.892790 · Cited by 52 · see citing works
“Once this balance is upset, various autoimmune diseases, including IBD, can occur (Haase et al., 2018).”
Background
The involvement of oncobiosis and bacterial metabolite signaling in metastasis formation in breast cancer
Kovàcs, T., Mikó, E., Ujlaki, G., Yousef, H., Csontos, V., Uray, K., & Bai, P. (2021) · Cancer and Metastasis Reviews · doi:10.1007/s10555-021-10013-3 · Cited by 52 · see citing works
Microbiota-derived short-chain fatty acids functions in the biology of B lymphocytes: From differentiation to antibody formation
Qu, S., Gao, Y., Ma, J., & Yan, Q. (2023) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2023.115773 · Cited by 51 · see citing works
Regulation of Microbiota by Vitamin D Receptor: A Nuclear Weapon in Metabolic Diseases
Bakke, D., Chatterjee, I., Agrawal, A., Dai, Y. D., & Sun, J. (2018) · Nuclear Receptor Research · doi:10.11131/2018/101377 · Cited by 48 · see citing works
The Gut-Brain Axis
Hattori, N., & Yamashiro, Y. (2021) · Annals of Nutrition and Metabolism · doi:10.1159/000512226 · Cited by 47 · see citing works
Impact of Microbiome–Brain Communication on Neuroinflammation and Neurodegeneration
Stolzer, I., Scherer, E., Süß, P., Rothhammer, V., Winner, B., Neurath, M. F., & Günther, C. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms241914925 · Cited by 47 · see citing works
“Colonization of the GI tract starts directly after birth [13,132].”
Implications of Probiotics on the Maternal-Neonatal Interface: Gut Microbiota, Immunomodulation, and Autoimmunity
Swartwout, B. K., & Luo, X. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.02840 · Cited by 45 · see citing works
“Short chain fatty acids, like butyrate, are another metabolic derivative of probiotics that are implicated in reducing disease severity in cancer and autoimmunity (14, 15).”
Background
The Role of Depletion of Gut Microbiota in Osteoporosis and Osteoarthritis: A Narrative Review
Guan, Z., Luo, L., Liu, S., Guan, Z., Zhang, Q., Li, X., & Tao, K. (2022) · Frontiers in Endocrinology · doi:10.3389/fendo.2022.847401 · Cited by 44 · see citing works
“For instance, gut microbiota in the production of pro-inflammatory cytokines and subsequent generation of Th17 cells and also promote the generation of regulatory T cells which contribute to immune suppression (50).”
Background
Inflammatory bowel disease: an overview of Chinese herbal medicine formula-based treatment
Yuan, S., Wang, Q., Li, J., Xue, J.-C., Li, Y., Meng, H., Hou, X.-T., Nan, J., & Zhang, Q. (2022) · Chinese Medicine · doi:10.1186/s13020-022-00633-4 · Cited by 44 · see citing works
A deep transcriptome meta-analysis reveals sex differences in multiple sclerosis
Català-Senent, J. F., Andreu, Z., Hidalgo, M. R., Soler-Sáez, I., Roig, F. J., Yanguas‐Casás, N., Neva-Alejo, A., López‐Cerdán, A., de la Iglesia-Vayá, M., Stranger, B. E., et al. (2023) · Neurobiology of Disease · doi:10.1016/j.nbd.2023.106113 · Cited by 43 · see citing works
Opportunities and Challenges of the Human Microbiome in Ovarian Cancer
Cheng, H., Wang, Z., Cui, L., Wen, Y. L., Chen, X., Gong, F., & Yi, H. (2020) · Frontiers in Oncology · doi:10.3389/fonc.2020.00163 · Cited by 44 · see citing works
Effect of temperature stress on gut-brain axis in mice: Regulation of intestinal microbiome and central NLRP3 inflammasomes
Yi, W., Cheng, J., Wei, Q., Pan, R., Song, S., He, Y., Tang, C. K., Liu, X., Zhou, Y., & Su, H. (2021) · The Science of The Total Environment · doi:10.1016/j.scitotenv.2020.144568 · Cited by 42 · see citing works
Targeting gut microbiota: new therapeutic opportunities in multiple sclerosis
Kujawa, D., Łaczmański, Ł., Budrewicz, S. P., Pokryszko‐Dragan, A., & Podbielska, M. (2023) · Gut Microbes · doi:10.1080/19490976.2023.2274126 · Cited by 44 · see citing works
“97,107 IAld was found to inhibit Th17 polarization, to reduce production of IL17 98 , and to induce mucosal IL-22 via AhR.”
Background
Opening avenues for treatment of neurodegenerative disease using post-biotics: Breakthroughs and bottlenecks in clinical translation
Bashir, B., Alam, S., Khandale, N. B., Birla, D., Vishwas, S., Pandey, N. K., Gupta, G., Paudel, K. R., Dureja, H., Kumar, P., et al. (2024) · Ageing Research Reviews · doi:10.1016/j.arr.2024.102236 · Cited by 39 · see citing works
Propionate supplementation promotes the expansion of peripheral regulatory T-Cells in patients with end-stage renal disease
Meyer, F., Seibert, F. S., Nienen, M., Welzel, M., Beißer, D., Bauer, F., Rohn, B., Westhoff, T. H., Stervbo, U., & Babel, N. (2020) · Journal of Nephrology · doi:10.1007/s40620-019-00694-z · Cited by 39 · see citing works
“Besides propionate, further SCFA such as butyrate and acetate have been reported to induce Treg expansion [29].”
Background
Convergent pathways of the gut microbiota–brain axis and neurodegenerative disorders
Gubert, C., Gasparotto, J., & Morais, L. H. (2022) · Gastroenterology report · doi:10.1093/gastro/goac017 · Cited by 40 · see citing works
“actions have also been considered in MS [70, 71].”
The Effectiveness and Safety of Probiotic Supplements for Psoriasis: A Systematic Review and Meta-Analysis of Randomized Controlled Trials and Preclinical Trials
Zeng, L., Yu, G., Wu, Y., Hao, W., & Chen, H. (2021) · Journal of Immunology Research · doi:10.1155/2021/7552546 · Cited by 39 · see citing works
“Insufficiency or deficiency of SCFA is related to cellular energy, nutrient metabolism, physical barriers, and immune inflammatory response [44].”
Background
Tumor microenvironment targeting for glioblastoma multiforme treatment via hybrid cell membrane coating supramolecular micelles
Huang, X., Mu, N., Ding, Y., Huang, R., Wu, W., Li, L. L., & Chen, T. (2024) · Journal of Controlled Release · doi:10.1016/j.jconrel.2023.12.033 · Cited by 36 · see citing works
Antituberculosis Therapy and Gut Microbiota: Review of Potential Host Microbiota Directed-Therapies
Diallo, D., Somboro, A. M., Diabaté, S., Baya, B., Koné, A., Sarro, Y. D. S., Kone, B., Diarra, B., Diallo, S., Diakité, M., et al. (2021) · Frontiers in Cellular and Infection Microbiology · doi:10.3389/fcimb.2021.673100 · Cited by 36 · see citing works
“This is evidenced by studies reporting that, diverse microbial metabolites intensely regulate the immune system via host receptors and other target molecules (Rooks and Garrett, 2016; Levy et al., 2017; Haase et al., 2018; Kim, 2018).”
Background
Modification of Gut Microbiota in Inflammatory Arthritis: Highlights and Future Challenges
Horta‐Baas, G., Sandoval-Cabrera, A., & Romero‐Figueroa, M. D. S. (2021) · Current Rheumatology Reports · doi:10.1007/s11926-021-01031-9 · Cited by 34 · see citing works
Exacerbation of Chikungunya Virus Rheumatic Immunopathology by a High Fiber Diet and Butyrate
Prow, N. A., Hirata, T. D. C., Tang, B., Larcher, T., Mukhopadhyay, P., Alves, T. L., Le, T. T., Gardner, J., Poo, Y. S., Nakayama, E., et al. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.02736 · Cited by 33 · see citing works
“SCFAs mediate effects on a number of cells including T cells (18, 19) particularly regulatory T cells (20), macrophages (21–23) and endothelial cells (24).”
Therapeutic Effect of Bifidobacterium Administration on Experimental Autoimmune Myasthenia Gravis in Lewis Rats
Rinaldi, E., Consonni, A., Cordiglieri, C., Sacco, G., Crasà, C., Fontana, A., Morelli, L., Elli, M., Mantegazza, R., & Baggi, F. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.02949 · Cited by 33 · see citing works
“Moreover, the beneficial effects associated to probiotic administration still deserve proper investigation, due to heterogeneity of metabolic mediators, such as short chain fatty acid (67), produced by the gut flora and involved in the crosstalk between microbiota and the immune system.”
Background
Natural Herbal Remedy Wumei Decoction Ameliorates Intestinal Mucosal Inflammation by Inhibiting Th1/Th17 Cell Differentiation and Maintaining Microbial Homeostasis
Wu, X., Chen, H., Gao, X., Gao, H., He, Q., Li, G., Yao, J., & Liu, Z. (2022) · Inflammatory Bowel Diseases · doi:10.1093/ibd/izab348 · Cited by 33 · see citing works
Inverse association between Mediterranean diet and risk of multiple sclerosis
Alfredsson, L. S., Olsson, T. P., & Hedström, A. K. (2023) · Multiple Sclerosis Journal · doi:10.1177/13524585231181841 · Cited by 32 · see citing works
Age-Related Cognitive Decline and Dementia: Interface of Microbiome–Immune–Neuronal Interactions
Prajapati, S. K., Jain, S., & Yadav, H. (2025) · The Journals of Gerontology Series A · doi:10.1093/gerona/glaf038 · Cited by 35 · see citing works
Prebiotic role of softwood hemicellulose in healthy mice model
Deloule, V., Boisset, C., Hannani, D., Suau, A., Gouëllec, A. L., Chroboczek, J., Botté, C. Y., Yamaryo‐Botté, Y., Chirat, C., & Toussaint, B. (2019) · Journal of Functional Foods · doi:10.1016/j.jff.2019.103688 · Cited by 31 · see citing works
“It plays an important role in several 8 fundamental biological processes, because tryptophan metabolites are ligands of aryl 9 hydrocarbon receptor (AhR), which regulates immune responses and inflammation through its 10 effects on cytokine production [Haase et al, 2018].”
Background
Host factors facilitating SARS‐CoV‐2 virus infection and replication in the lungs
Boutin, S., Hildebrand, D., Boulant, S., Kreuter, M., Rüter, J., Pallerla, S. R., Velavan, T. P., & Nurjadi, D. (2021) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-021-03889-5 · Cited by 32 · see citing works
The microbiota–gut–brain axis: A promising avenue to foster healthy developmental outcomes
Brett, B. E., & de Weerth, C. (2019) · Developmental Psychobiology · doi:10.1002/dev.21824 · Cited by 30 · see citing works
Intestinal epithelial dopamine receptor signaling drives sex-specific disease exacerbation in a mouse model of multiple sclerosis
Peng, H., Qiu, J.-Q., Zhou, Q., Zhang, Y.-K., Chen, Q.-Y., Yin, Y., Su, W., Yu, S., Wang, Y., Cai, Y. A., et al. (2023) · Immunity · doi:10.1016/j.immuni.2023.10.016 · Cited by 30 · see citing works
Invariant NKT Cells Functionally Link Microbiota-Induced Butyrate Production and Joint Inflammation
Lee, S., Koh, J., Chang, Y., Kim, H. Y., & Chung, D. H. (2019) · The Journal of Immunology · doi:10.4049/jimmunol.1801314 · Cited by 30 · see citing works
“Among these metabolites, SCFAs play diverse roles in host immunity and autoimmunity (15).”
Background
Bugs as drugs: The role of microbiome in cancer focusing on immunotherapeutics
Araujo, D. V., Watson, G. A., Oliva, M., Heirali, A., Coburn, B., Spreafico, A., & Siu, L. L. (2021) · Cancer Treatment Reviews · doi:10.1016/j.ctrv.2020.102125 · Cited by 29 · see citing works
Advantages and limitations of experimental autoimmune encephalomyelitis in breaking down the role of the gut microbiome in multiple sclerosis
Melamed, E., Palmer, J. L., & Fonken, C. (2022) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2022.1019877 · Cited by 27 · see citing works
What is Needed for Evidence‐Based Dietary Recommendations for Migraine: A Call to Action for Nutrition and Microbiome Research
Slavin, M., Li, H., Frankenfeld, C. L., & Cheskin, L. J. (2019) · Headache The Journal of Head and Face Pain · doi:10.1111/head.13658 · Cited by 28 · see citing works
Role of microbiota and microbiota‐derived short‐chain fatty acids in PDAC
TEMEL, H. Y., Kaymak, Ö., Kaplan, S., Bahcivanci, B., Gkoutos, G. V., & Acharjee, A. (2022) · Cancer Medicine · doi:10.1002/cam4.5323 · Cited by 27 · see citing works
Intestinal Mucosal Immune Barrier: A Powerful Firewall Against Severe Acute Pancreatitis-Associated Acute Lung Injury via the Gut-Lung Axis
Li, F., Wang, Z., Cao, Y., Pei, B., Luo, X., Liu, J., Ge, P., Luo, Y., Ma, S., & Chen, H. (2024) · Journal of Inflammation Research · doi:10.2147/jir.s448819 · Cited by 27 · see citing works
“182 Another group of metabolites, which are tryptophan metabolites, have been proven to perform the activities in inhibiting inflammatory responses via aryl hydrocarbon receptors in T cells or astrocytes.”
Background
Gut Microbiota and Immune Responses
Dong, L., Xie, J., Wang, Y., & Zuo, D. (2020) · Advances in experimental medicine and biology · doi:10.1007/978-981-15-2385-4_10 · Cited by 27 · see citing works
Characteristics of CD8+ and CD4+ Tissue-Resident Memory Lymphocytes in the Gastrointestinal Tract
Li, P., Zhang, Y., Xu, Y., Cao, H., & Li, L. (2022) · Advanced Gut & Microbiome Research · doi:10.1155/2022/9157455 · Cited by 28 · see citing works
“Enriched with abundant immune cells and a myriad of commensal microbiota, GI acts as a habitat for the dynamic interactions among the host mucosal nonimmune system, immune system, commensal microbiota, and their metabolites [8, 9].”
Background
Gastrointestinal Tract, Microbiota and Multiple Sclerosis (MS) and the Link Between Gut Microbiota and CNS
Yousefi, B., Babaeizad, A., Banihashemian, S. Z., Feyzabadi, Z. K., Dadashpour, M., Pahlevan, D., Ghaffari, H., & Eslami, M. (2022) · Current Microbiology · doi:10.1007/s00284-022-03150-7 · Cited by 29 · see citing works
“Thus, the microbiota can affect the immune system and CNS in different ways [20].”
Background
Biomimetic nanocarriers harnessing microbial metabolites usher the path for brain disease therapy
Gong, Y., Liu, Z., Zhou, P., Li, J., & Miao, Y. (2023) · Nano TransMed · doi:10.1016/j.ntm.2023.100020 · Cited by 26 · see citing works
Oligosaccharides as Potential Regulators of Gut Microbiota and Intestinal Health in Post-COVID-19 Management
Cheong, K., Chen, S., Teng, B., Veeraperumal, S., Zhong, S., & Tan, K. (2023) · Pharmaceuticals · doi:10.3390/ph16060860 · Cited by 25 · see citing works
“They interact with various immune cells such as dendritic cells, macrophages, and T cells [83], thereby influencing the production of pro-inflammatory cytokines such as interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α.”
Background
Alterations in the human gut microbiome in anti‐N‐methyl‐D‐aspartate receptor encephalitis
Gong, X., Liu, X., Li, C., Chen, C., Lin, J., Li, A., An, D., Zhou, D., & Hong, Z. (2019) · Annals of Clinical and Translational Neurology · doi:10.1002/acn3.50874 · Cited by 26 · see citing works
“The gut microbiota, which is also referred to as the second brain, may affect brain activity through the gut-microbiota-brain axis under both physiological and pathological conditions.(8) Dysbiosis in the gastrointestinal microbiota influences proinflammatory T-cell”
Background
Effects of Lactococcus lactis subsp. cremoris YRC3780 daily intake on the HPA axis response to acute psychological stress in healthy Japanese men
Matsuura, N., Motoshima, H., Uchida, K., & Yamanaka, Y. (2021) · European Journal of Clinical Nutrition · doi:10.1038/s41430-021-00978-3 · Cited by 26 · see citing works
Gut Microbiome and the Role of Metabolites in the Study of Graves’ Disease
Liu, H., Liu, H., Liu, C., Shang, M., Wei, T., & Yin, P. (2022) · Frontiers in Molecular Biosciences · doi:10.3389/fmolb.2022.841223 · Cited by 23 · see citing works
“Commensal bacteria and their metabolites can also promote Treg generation and suppress the immune system (Haase et al., 2018).”
Background
Autoimmune diseases and gut microbiota: a bibliometric and visual analysis from 2004 to 2022
Zhang, Y., Peng, Y., & Xu, X. (2023) · Clinical and Experimental Medicine · doi:10.1007/s10238-023-01028-x · Cited by 24 · see citing works
The gut microbiome: an important role in neurodegenerative diseases and their therapeutic advances
Li, S., Zhao, L., Xiao, J., Guo, Y., Fu, R., Zhang, Y., & Xu, S. (2023) · Molecular and Cellular Biochemistry · doi:10.1007/s11010-023-04853-6 · Cited by 22 · see citing works
“…play an essential role in the pathogenesis of MS, and the microbial tryptophan metabolite indole-3-acetic acid (IAA) promotes the production of regulatory T cells (Treg) and reduces Th17 cells, and restoring the balance of the gut microbiota helps suppress the inflammatory response [79, 80].”
Short-chain fatty acids and intestinal inflammation in multiple sclerosis: modulation of female susceptibility by microbial products?
Becker, A., Abuazab, M., Schwiertz, A., Walter, S., Fassbender, K. C., Fousse, M., & Unger, M. M. (2021) · Autoimmunity Highlights · doi:10.1186/s13317-021-00149-1 · Cited by 22 · see citing works
“They lead to epigenetic modulations in T lymphocytes by inhibiting histone deacetylase activity [11], thus leading to higher frequencies of Tregs [12].”
BackgroundInfluential
Understanding the Effects of Metabolites on the Gut Microbiome and Severe Acute Pancreatitis
Ye, S., Si, C., Deng, J., Chen, X., Kong, L., Zhou, X., & Wang, W. (2021) · BioMed Research International · doi:10.1155/2021/1516855 · Cited by 21 · see citing works
“reuteri is a major producer of these metabolites and can stimulate AhR activity, which inhibits proinflammatory activity [100, 105].”
Background
The gut microbiome molecular mimicry piece in the multiple sclerosis puzzle
Elsayed, N. S., Aston, P., Bayanagari, V. R., & Shukla, S. K. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.972160 · Cited by 21 · see citing works
“Consistent with a role for gut microbiota in MS, treatment of the EAE experimental mice with non-absorbing oral antibiotics, kanamycin, colistin, and vancomycin for reducing the bacterial load in the gut led to the improvement of EAE development in those mice (33).”
BackgroundInfluential
Biopsychosocial model of resilience in young adults with multiple sclerosis (BPS-ARMS): an observational study protocol exploring psychological reactions early after diagnosis
Gajofatto, A., Donisi, V., Busch, I., Gobbin, F., Butturini, E., Calabrese, M., de Prati, A. C., Cesari, P., del Piccolo, L., Donadelli, M., et al. (2019) · BMJ Open · doi:10.1136/bmjopen-2019-030469 · Cited by 19 · see citing works
Propionic Acid Impact on Multiple Sclerosis: Evidence and Challenges
Lorefice, L., & Zoledziewska, M. (2024) · Nutrients · doi:10.3390/nu16223887 · Cited by 20 · see citing works

The gut microbiota and associated metabolites in multiple sclerosis
Wang, Y., Li, Z., Xu, Y., & Zhang, C. (2023) · Advanced Neurology · doi:10.36922/an.413 · Cited by 3 · see citing works
Microbiome-Derived Metabolites in Multiple Sclerosis: Mechanisms of Immune Regulation and Therapeutic Potential: A Literature Review
Amin, M. N. (2026) · Cureus · doi:10.7759/cureus.117645
Gut microbiota and gut-derived metabolites in defining multiple sclerosis phenotypic continuum
Montini, F., Mangalam, A. K., Zeydan, B., Murray, J., & Kantarci, O. H. (2026) · Frontiers in Immunology · doi:10.3389/fimmu.2026.1858047 · Cited by 1 · see citing works
Microbial Metabolites in Multiple Sclerosis: Implications for Pathogenesis and Treatment
Duarte-Silva, E. P., Meuth, S. G., & Peixoto, C. A. (2022) · Frontiers in Neuroscience · doi:10.3389/fnins.2022.885031 · Cited by 21 · see citing works
The role of gut microbiome and associated metabolome in the regulation of neuroinflammation in multiple sclerosis and its implications in attenuating chronic inflammation in other inflammatory and autoimmune disorders
Dopkins, N., Nagarkatti, P. S., & Nagarkatti, M. (2018) · Immunology · doi:10.1111/imm.12903 · Cited by 107 · see citing works

Authors: Haase, S., Haghikia, A., Wilck, N., Müller, D. N., & Linker, R. A.
Affiliations: Friedrich-Alexander-Universität Erlangen-Nürnberg (DE)
Ruhr University Bochum (DE)
Max Delbrück Center (DE)
Corresponding author: Linker, Ralf A.
ORCID: Haase, Stefanie
Haghikia, Aiden
Wilck, Nicola
Müller, Dominik N.
Linker, Ralf A.
Venue: Immunology
Publisher: Wiley
Published: 2018-04-30
Volume: 154
Issue: 2
Pages: 230-238
ISSN: 0019-2805 (ISSN-L)
1365-2567
DOI: 10.1111/imm.12933
PMC: PMC5980218
OpenAlex: W2797170123
Cited by: 239
References: 116
Citations by year: 2026: 15 · 2025: 30 · 2024: 23 · 2023: 26 · 2022: 39 · 2021: 39 · 2020: 37 · 2019: 18 · 2018: 11
FWCI: 2.57
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: onlinelibrary.wiley.com/termsAndConditions#vor (vor)
Locations: Immunology (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
MDC Repository (Max-Delbrueck-Center for Molecular Medicine) (submittedVersion)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
Health Sciences › Medicine › Pathology and Forensic Medicine › Multiple Sclerosis Research Studies
Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
Keywords: gut microbiota metabolites, multiple sclerosis, experimental autoimmune encephalomyelitis, autoimmunity, short-chain fatty acids, tryptophan metabolites, regulatory T cells, Th17 cells, aryl hydrocarbon receptor, histone deacetylase inhibition, G protein-coupled receptors, commensal bacteria, neuroinflammation, host-microbiota interactions, dietary factors, salt intake, long-chain fatty acids
MeSH terms: Gastrointestinal Microbiome, Animals, Central Nervous System, Disease Susceptibility, Energy Metabolism, Fatty Acids, Volatile, Humans, Tryptophan, Neuroimmunomodulation, Autoimmunity, Probiotics, Autoimmune Diseases of the Nervous System, Immunomodulation, Microbiota

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review

Impacts of microbiome metabolites on immune regulation and autoimmunity

Abstract

Integrity signals

Claims the paper makes

Claims other papers make about this one

Self-check

Cites

Cited by

Related

Record

About these checks