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Gut Microbial Metabolites Fuel Host Antibody Responses
Open accessAbstract
Antibody production is a metabolically demanding process that is regulated by gut microbiota, but the microbial products supporting B cell responses remain incompletely identified. We report that short-chain fatty acids (SCFAs), produced by gut microbiota as fermentation products of dietary fiber, support host antibody responses. In B cells, SCFAs increase acetyl-CoA and regulate metabolic sensors to increase oxidative phosphorylation, glycolysis, and fatty acid synthesis, which produce energy and building blocks supporting antibody production. In parallel, SCFAs control gene expression to express molecules necessary for plasma B cell differentiation. Mice with low SCFA production due to reduced dietary fiber consumption or microbial insufficiency are defective in homeostatic and pathogen-specific antibody responses, resulting in greater pathogen susceptibility. However, SCFA or dietary fiber intake restores this immune deficiency. This B cell-helping function of SCFAs is detected from the intestines to systemic tissues and conserved among mouse and human B cells, highlighting its importance.
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“Since microbial metabolites can be utilized by T cells for their metabolic demand to enhance glycolysis and oxidative phosphorylation28,29”
From Microbial short-chain fatty acids modulate CD8+ T cell responses and improve adoptive immunotherapy for cancer (2021) · cites this paper as [28]
In the citing paper
“Intriguingly, they further found that SCFAs in parallel modulate the energy metabolism of B cells to promote production of antibodies (M. Kim et al., 2016).”
From Understanding the Holobiont: How Microbial Metabolites Affect Human Health and Shape the Immune System (2017) · cites this paper as M. Kim et al., 2016
In the citing paper
“Kim et al. shed further light on this observation and demonstrated that SCFAs support antibody responses by regulating gene expression through HDAC inhibition.”
From Understanding the Holobiont: How Microbial Metabolites Affect Human Health and Shape the Immune System (2017) · cites this paper as M. Kim et al., 2016
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“A uthor M anuscript A uthor M anuscript A uthor M anuscript A uthor M anuscript comparable to the C3 levels created by HFD (Figure S2A).”
BackgroundInfluentialThe Microbial Metabolites, Short-Chain Fatty Acids, Regulate Colonic T reg Cell Homeostasis
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“…and analyzed data and drafted the manuscript with MK. anuscript A uthor M anuscript Keywords Short chain fatty acids; antibody; B cells; metabolism INTRODUCTION Host and gut microbial flora functionally interact in the gut for mutual benefits (Brown et al., 2013; Tremaroli and Backhed, 2012).”
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“Several studies have shown that SCFAs may promote Bcell responses to intestinal commensals and ingested antigens.(15,16) In mice fed high-fiber diets, an increase in immunoglobulin A (IgA)-producing B cells and decrease in IgE secretion were observed.”
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“IgA ASCs can utilize diet-and gut microbiota-derived SCFAs as one carbon source to maintain metabolism (227).”
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“Taken together, our results are consistent with recent findings indicating that cancer related changes in gut microbial composition may induce interferon associated responses that contribute to the early progression of colon cancer in animal models as well as humans (26,37-40).”
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“[41] demonstrated that SCFAs, produced by the intestinal microbiota from the fermentation of dietary fibre, support host antibody responses by regulating the gene expression required for plasma B cell differentiation.”
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InfluentialGut microbiome metabolites in lung cancer: The emerging importance of short-chain fatty acids
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Commensal Microbes Affect Host Humoral Immunity to Bordetella pertussis Infection
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“The enhancing effect of SCFAs on B cell antibody production essentially works by reshaping the energy metabolism pathway of B cells and indirectly consolidating the intestinal immune barrier (45).”
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“Similarly, SCFAs such as butyrate and propionate, produced by taxa, are thought to synergize with ICIs by modulating epigenetic regulation (via HDAC inhibition), upregulating cell-cycle inhibitors, and providing metabolic support to immune cells [56,61,62].”
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How Microbial Food Fermentation Supports a Tolerant Gut
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Effects of Dietary Alteration on the Gut Microbiome and Metabolome of the Rescued Bengal Slow Loris
Ni, Q., Zhang, C., Li, D., Xu, H., Yao, Y., Zhang, M., Fan, X., Zeng, B., Yang, D., & Xie, M. (2021) · Frontiers in Microbiology · doi:10.3389/fmicb.2021.650991 · Cited by 9
Mining the Gut Microbiota for Microbial-Based Therapeutic Strategies in Cancer Immunotherapy
Li, B., Gong, T., Hao, Y., Zhou, X., & Cheng, L. (2021) · Frontiers in Oncology · doi:10.3389/fonc.2021.721249 · Cited by 9
“SCFAs enhance the generation of macrophage and DC precursors and their phagocytic capacity (30), induce antiinflammatory regulatory T cells (Tregs) (31), and facilitate antibody production of B cells (32).”
BackgroundRegulation of follicular T helper cell differentiation in antitumor immunity
Hou, Y., Cao, Y., Dong, L., Huang, Y., Zhang, Z., Bi, Y., & Liu, G. (2022) · International Journal of Cancer · doi:10.1002/ijc.34368 · Cited by 10
“(SCDs), which are endoplasmic reticulum-localized proteins that catalyze the synthesis of monounsaturated fatty acids from saturated fatty acids (SFAs), can promote Tfh differentiation and increase the Tfh:Tfr ratio.(70,71) However, the mechanism whereby fatty acid metabolism regulates Tfh differentiation remains uncl…”
BackgroundGut Microbiome: An Intersection between Human Genome, Diet, and Epigenetics
Muhammad, A. Y., Amonov, M., Baig, A. A., & Alvi, F. J. (2024) · Advanced Gut & Microbiome Research · doi:10.1155/2024/6707728 · Cited by 13
The cellular biology of plasma cells: Unmet challenges and opportunities
Bonaud, A., Khamyath, M., & Espéli, M. (2023) · Immunology Letters · doi:10.1016/j.imlet.2023.01.005 · Cited by 10
Li, Z., Wang, F., xing, J.-J., Hu, X., Gou, X., Li, J., Pang, R., & Zhang, A. (2024) · Experimental Neurology · doi:10.1016/j.expneurol.2024.114866 · Cited by 8
Kadim, M., Darma, A., Kartjito, M. S., Dilantika, C., Basrowi, R. W., Sungono, V., & Jo, J. (2025) · Pediatric Gastroenterology Hepatology & Nutrition · doi:10.5223/pghn.2025.28.1.1 · Cited by 10
Gut microbiota is associated with persistence of longer-term BNT162b2 vaccine immunogenicity
Ng, H. Y., Liao, Y., Cheung, C. L., Zhang, R., Chan, K. H., Seto, W., Leung, W. K., Hung, I. F., Lam, T. T., & Cheung, K. S. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2025.1534787 · Cited by 8
“The former increases antibody production through promoting energy production in B cells (8), while the latter was negatively correlated with in fl ammatory signatures following in fl uenza vaccination (9).”
Chen, Y., Wei, X., Rui, B., Du, Y., Lei, Z., Guo, X., Wang, C., Yuan, D., Wang, X., Li, M., et al. (2025) · Biology · doi:10.3390/biology14030312 · Cited by 9
“Specifically, SCFAs, particularly butyrate, serve as an energy source for B cell proliferation [63], while MHC-II-mediated T cell activation primes adaptive responses against immunosuppressive insults.”
Unraveling the Role of the Microbiota in Cancer Immunotherapy: A New Frontier
Wang, S., Li, S., Zhang, M., Liu, R., Ye, X., Mao, S., Yu, J., Xie, X., & Tan, W. (2025) · Research · doi:10.34133/research.0744 · Cited by 11
The interplay between host immunity and Clostridioides difficile infection
Li, D., & Saavedra, P. H. V. (2025) · mBio · doi:10.1128/mbio.03562-24 · Cited by 9
Satô, K., Nakashima, A., Fukuda, S., Inoue, J., & Kim, Y. (2025) · BMC Microbiology · doi:10.1186/s12866-025-04140-y · Cited by 8
Yang, L., Shang, W., Chen, D., Qian, H., Zhang, S., Pan, X., Huang, S., Liu, J., & Chen, D. (2025) · Scientific Reports · doi:10.1038/s41598-025-06463-2 · Cited by 8
“Previous studies discovered that SCFAs enhanced the IRF4 expression in B cells, which is indispensable in differentiation and antibody production 20 .”
Regulation of allergies across the body by microbial metabolites
Kim, C. H., & Baker, J. R. (2026) · Experimental & Molecular Medicine · doi:10.1038/s12276-026-01642-1 · Cited by 11
“The intestinal epithelial cells require microbial metabolites for the maintenance of intestinal barrier and immunological functions 29,86,87,130 .”
InfluentialSelf-citationKafoury, B. M. E., Ebrahim, A. T., Hamid, M. S. A.-E., Mehanna, N. S., Ramadan, G. E.-S. I., & Morsy, W. E. (2023) · Mediterranean Journal of Nutrition and Metabolism · doi:10.3233/mnm-230026 · Cited by 8
“SCFAs especially butyrate may promote anti-inflammatory responses through enhancing regulatory T cell function and Il-10 secretion together with B cell reprogramming to enhance intestinal secretion of antibody IgA [75].”
Li, A., Yang, S., Han, X., Liu, C., Zheng, J., Ma, Y., Cheng, S., Zhao, J., Zhou, W., & Du, P. (2023) · Food Bioscience · doi:10.1016/j.fbio.2023.103437 · Cited by 10
Ong, M. L. Y., Green, C. G., Bongiovanni, T., & Heaney, L. M. (2023) · Beneficial Microbes · doi:10.1163/18762891-20230069 · Cited by 9
Gut Microbiota Disorders and Metabolic Syndrome: Tales of a Crosstalk Process
Nie, P., Hu, L., Feng, X., & Xu, H. (2024) · Nutrition Reviews · doi:10.1093/nutrit/nuae157 · Cited by 10
Gonçalves, E., Guillén, Y., Lama, J. R., Sánchez, J., Brander, C., Paredes, R., & Combadière, B. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.657162 · Cited by 8
Föh, B., Buhre, J. S., Sina, C., & Ehlers, M. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.1004644 · Cited by 7
“One study found that SCFAs can increase FAO in metabolic tissues (61) and another study described that SCFAs can reduce AMPK activity, thereby activating mTORC1 and inducing classswitched PCs (62) (Figure 1).”
BackgroundImmunmodulation durch Ernährung bei kritisch kranken Patienten
Hirschberger, S., Schmid, A., & Kreth, S. (2023) · Die Anaesthesiologie · doi:10.1007/s00101-023-01258-4 · Cited by 8
“tion regulatorischer B-Zellen beschrieben worden [105, 171].”
InfluentialAntibiotic therapy–induced collateral damage: IgA takes center stage in pulmonary host defense
Lohmeyer, J., Morty, R. E., & Herold, S. (2018) · Journal of Clinical Investigation · doi:10.1172/jci122032 · Cited by 8
Kabir, T., Connamacher, C. A., Nadeem, Z., Paul, M. R., Smutny, M. R., Lawler, Z. K., Djomo, A. M., Carroll, T., & Gates, L. A. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.05.07.652677 · Cited by 8
“Furthermore, this suggests that endogenous levels of histone butyrylation and propionylation can be uncovered through HDAC inhibition, which is supported both by the inhibitory action of these metabolites and by the detection of these marks in untreated cells 9,14,26,28 .”
Matsuzaki, C., Takagi, H., Saiga, S., Kinoshita, Y., Yamaguchi, M., Higashimura, Y., Yamamoto, K., & Yamaguchi, M. (2024) · Applied and Environmental Microbiology · doi:10.1128/aem.01445-23 · Cited by 7
“S4), which have been reported to increase in conjunction with intestinal acetate (10, 48).”
BackgroundDiet, microbiome, and probiotics establish a crucial link in vaccine efficacy
Dutta, S., Chatterjee, N., Gallina, N. L. F., Kar, S., Koley, H., Nanda, P. K., Biswas, O., Das, A. K., Biswas, S., Bhunia, A. K., et al. (2025) · Critical Reviews in Microbiology · doi:10.1080/1040841x.2025.2480230 · Cited by 7
“Moreover, ScFAs may facilitate follicular helper t cell (tfh) generation, which helps in B cell differentiation and high-affinity antibody production (Kim M et al. 2016).”
Elbaz, N., Ashour, E. A., Bassiony, S. S., Elsherbeni, A. I., Mahgoub, S. A., Osman, A., Sabike, I. I., Al-Gabri, N. A., Moustafa, M., Al-Shehri, M., et al. (2025) · Animal Biotechnology · doi:10.1080/10495398.2025.2577947 · Cited by 7
Understanding the Effect of B Vitamins on Gut Microbiota: A Comprehensive Review
Karademir, E., Gedik, B. A., Bostan, Z. Z., & Karadağ, M. G. (2025) · Nutrition Reviews · doi:10.1093/nutrit/nuaf236 · Cited by 7
Wang, L., Chen, S., Cai, X. T., Zheng, Y., Zheng, C., & Yao, Y. (2026) · Frontiers in Endocrinology · doi:10.3389/fendo.2025.1720484 · Cited by 11
“Additionally, the antibody production of T cell-dependent B cells is directly associated with exposure to microbial antigens (29).”
The immunoregulatory effect of short-chain fatty acids in type 2 diabetes mellitus
Li, J., Lv, Z., Fan, Q., Fu, P., Zhou, N., Deng, J., Qi, H., & Yang, M. (2026) · Frontiers in Nutrition · doi:10.3389/fnut.2026.1807302 · Cited by 7
“Acetyl-CoA produced by SCFAs is essential for plasma cell differentiation and antibody production (102).”
TOMIOKA, R., Tanaka, Y., Suzuki, M., & Ebihara, S. (2023) · Journal of Nutritional Science and Vitaminology · doi:10.3177/jnsv.69.326 · Cited by 8
Impact of intestinal microenvironments in obesity and bariatric surgery on shaping macrophages
Leyderman, M., Wilmore, J. R., Shope, T. R., Cooney, R. N., & Urao, N. (2023) · Immunometabolism · doi:10.1097/in9.0000000000000033 · Cited by 8
“SCFA acting through GPR43 promotes B cell differentiation into plasma cells via increased histone acetylation and B cell metabolism [72] .”
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Zhong, Y., Liu, Z., Wang, Y., Cai, S., Qiao, Z., Hu, X., Wang, T., & Yi, J. (2024) · Food Reviews International · doi:10.1080/87559129.2024.2414908 · Cited by 11
“[49,53] In addition, SCFAs also regulate gut microbiota by reducing the intestinal pH and indirectly alleviate colonic tumorigenesis triggered by harmful microbiota.”
Noor Zuhair Bakheet, N. Z., A.J, A.-Q. M., & Falih, I. B. (2020) · The Iraqi Journal of Veterinary Medicine · doi:10.30539/ijvm.v44i2.984 · Cited by 8
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de Oliveira, G. R., de Andrade, C., Bez, I. C. C., Melo, A. D. B., de Almeida, V. V., Magalhães, W. L. E., Wéber, H., Sotomaior, C. S., Luciano, F. B., & Costa, L. B. (2023) · Animals · doi:10.3390/ani13020192 · Cited by 7
“Dietary fiber benefits digestibility, gut health, and commensal gut microbiota in mo‐ nogastric animals [29].”
Kohil, A., Abdalla, W., Ibrahim, W. N., Al-Harbi, K. M., Al-Haidose, A., Al‐Asmakh, M., & Abdallah, A. M. (2023) · Medicina · doi:10.3390/medicina59091629 · Cited by 7
“Studies have shown that SCFAs play a role in B-cell differentiation through histone deacetylase (HDAC) inhibition [54].”
Background
Metadata
- Authors
- Kim, M., Qie, Y., Park, J., & Kim, C. H.
- Affiliations
- Purdue University West Lafayette (US)
- Corresponding author
- Kim, Chang H.
- Venue
- Cell Host & Microbe
- Publisher
- Elsevier BV
- Published
- 2016-08
- Volume
- 20
- Issue
- 2
- Pages
- 202-214
- ISSN
- 1931-3128 (ISSN-L)
- PMC
- PMC4982788
- OpenAlex
- W2491805933
- Cited by
- 893
- References
- 59
- Citations by year
- 2026: 92 · 2025: 129 · 2024: 110 · 2023: 110 · 2022: 107 · 2021: 106 · 2020: 90 · 2019: 61 · 2018: 47 · 2017: 32 · 2016: 8
- FWCI
- 25.63
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell Host & Microbe (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Seoul National University Open Repository (Seoul National University) (submittedVersion)
- Funders
- National Multiple Sclerosis Society
- Purdue University Center for Cancer Research
- National Institutes of Health
- National Cancer Institute (P30CA023168)
- National Institute of Allergy and Infectious Diseases (R01AI121302, R01AI080769, R01AI074745)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK076616)
- National Center for Research Resources (S10RR028293)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Health Sciences › Nursing › Nutrition and Dietetics › Microbial Metabolites in Food Biotechnology
- Keywords
- short-chain fatty acids, gut microbiota, antibody production, B cells, dietary fiber, acetyl-CoA, oxidative phosphorylation, glycolysis, fatty acid synthesis, plasma cell differentiation, immunodeficiency, microbial metabolites
- MeSH terms
- Gastrointestinal Microbiome, Animals, Antibody Formation, B-Lymphocytes, Cell Differentiation, Dietary Fiber, Fatty Acids, Volatile, Fermentation, Gene Expression Regulation, Mice, Inbred C57BL, Gastrointestinal Tract, Metabolic Networks and Pathways
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