Potential role of short-chain fatty acids in the development of extraintestinal manifestations of Crohn’s disease

Bakulin I.G.; Akishina Yu.A.; Lyamina S.V.; Maev I.V.

doi:https://doi.org/10.17116/dokgastro20251403144

Close metadata

OBJECTIVE

To compare SCFA levels in patients with CD and UC based on the presence of EIMs and to describe the structure of EIMs in the cohort.

MATERIAL AND METHODS

This prospective cohort study included 80 patients with inflammatory bowel disease (47 with CD and 33 with UC). Clinical and diagnostic evaluations were conducted at Stage I. At Stage II, stool samples from 60 patients meeting inclusion criteria were analyzed for SCFAs using gas-liquid chromatography. The following were measured: C2 (acetic), C3 (propionic), C4 (butyric), total C4 isomers, C5 (valeric), and C6 (caproic). Calculated parameters included total SCFAs (C2—C6) and the anaerobic index.

RESULTS

EIMs were observed in 53.2% of CD patients and 51.5% of UC patients; clinically active EIMs were found in 34.0% and 42.4%, respectively. Among CD patients, significant differences in SCFAs were found: mean C4 levels were lower in those with EIMs (0.62 vs. 1.41, p=0.008), as was total C2—C6 content (4.04 vs. 6.67, p=0.019). No significant differences were observed among UC patients.

CONCLUSION

Total SCFA concentration (C2—C6) and butyric acid (C4) may serve as potential diagnostic markers for EIMs in patients with CD.

Keywords:

extraintestinal manifestations

Crohn’s disease

ulcerative colitis

short-chain fatty acids

metabolomic profile

Authors:

Bakulin I.G.

Mechnikov North-Western State Medical University Ministry of Health of the Russian Federation

SPIN RSCI: 5283-2032
Scopus AuthorID: 6603812937
ResearcherID: P-4453-2014
ORCID: 0000-0002-6151-2021

Akishina Yu.A.

Mechnikov North-Western State Medical University Ministry of Health of the Russian Federation

ORCID: 0000-0003-4719-3973

Lyamina S.V.

Russian University of Medicine Ministry of Health of the Russian Federation

ORCID: 0000-0001-8300-8988

Maev I.V.

Russian University of Medicine Ministry of Health of the Russian Federation

ORCID: 0000-0001-6114-564X

Received:

02.06.2025

Accepted:

05.07.2025

Close metadata

References:

Maev IV, Bakulin IG, Skalinskaya MI, Skazyvaeva EV. Inflammatory bowel diseases: Transformation of representations. A review. Terapevticheskij arkhiv. 2023;95(12):1064-1074. (In Russ.). https://doi.org/10.26442/00403660.2023.12.202507
Nikitin AV, Volynets GV, Skvortsova TA, Kapranova MS. Extraintestinal manifestations of inflammatory bowel disease. Russian Journal of Evidence-Based Gastroenterology. 2023;12(1):93-98. (In Russ.). https://doi.org/10.17116/dokgastro20231201193
Hedin CRH, Vavricka SR, Stagg AJ, Schoepfer A, Raine T, Puig L, Pleyer U, Navarini A, van der Meulen-de Jong AE, Maul J, Katsanos K, Kagramanova A, Greuter T, González-Lama Y, van Gaalen F, Ellul P, Burisch J, Bettenworth D, Becker MD, Bamias G, Rieder F. The Pathogenesis of Extraintestinal Manifestations: Implications for IBD Research, Diagnosis, and Therapy. Journal of Crohn’s and Colitis. 2019;13(5):541-554. https://doi.org/10.1093/ecco-jcc/jjy191
Bakulin IG, Skalinskaya MI, Skazyvaeva EV. North-Western register of patients with inflammatory bowel diseases: achievements and lessons learned. Koloproktologia. 2022;21(1):37-49. (In Russ.). https://doi.org/10.33878/2073-7556-2022-21-1-37-49
Walldorf J, Twarz M, Schober C, Michl P, Hammer T. High frequency of secondary, but not primary ocular manifestations of inflammatory bowel disease in patients treated at a tertiary care center. European Journal of Gastroenterology and Hepatology. 2018;30(12):1502-1506. https://doi.org/10.1097/MEG.0000000000001248
Karmiris K, Avgerinos A, Tavernaraki A, Zeglinas C, Karatzas P, Koukouratos T, Oikonomou KA, Kostas A, Zampeli E, Papadopoulos V, Theodoropoulou A, Viazis N, Polymeros D, Michopoulos S, Bamias G, Kapsoritakis A, Karamanolis DG, Mantzaris GJ, Tzathas C, Koutroubakis IE. Prevalence and characteristics of extra-intestinal manifestations in a large cohort of Greek patients with inflammatory bowel disease. Journal of Crohn’s and Colitis. 2016;10(4):429-436. https://doi.org/10.1093/ecco-jcc/jjv232
Gordon H, Burisch J, Ellul P, Karmiris K, Katsanos K, Allocca M, Bamias G, Barreiro-de Acosta M, Braithwaite T, Greuter T, Harwood C, Juillerat P, Lobaton T., Müller-Ladner U, Noor N, Pellino G, Savarino E, Schramm C, Soriano A, Michael Stein J, Uzzan M, van Rheenen PF, Vavricka SR, Vecchi M, Zuily S, Kucharzik T. ECCO Guidelines on Extraintestinal Manifestations in Inflammatory Bowel Disease. Journal of Crohn’s and Colitis. 2024;18(1):1-37. https://doi.org/10.1093/ecco-jcc/jjad108
Vavricka SR, Schoepfer A, Scharl M, Lakatos PL, Navarini A, Rogler G. Extraintestinal Manifestations of Inflammatory Bowel Disease. Inflammatory Bowel Diseases. 2015;21(8):1982-1992. https://doi.org/10.1097/MIB.0000000000000392
Shen Y-H, Zhu H, Zhou L, Zheng Y-Q, Zhang Z, Xie Y, Liu Z-Q, Peng C-Y, Wang L, Zhao C, Zhang X-Q. In inflammatory bowel disease and extraintestinal manifestations: What role does microbiome play? Engineered Regeneration. 2023;4(4):337-348. https://doi.org/10.1016/j.engreg.2023.04.005
Whitfield C, Clarke BR. Lipopolysaccharides (Endotoxins). Encyclopedia of Microbiology. Fourth Edition. 2019:791-802. https://doi.org/10.1016/B978-0-12-801238-3.07799-0
Scher JU, Ubeda C, Artacho A, Attur M, Isaac S, Reddy SM, Marmon S, Neimann A, Brusca S, Patel T, Manasson J, Pamer EG, Littman DR, Abramson SB. Decreased bacterial diversity characterizes the altered gut microbiota in patients with psoriatic arthritis, resembling dysbiosis in inflammatory bowel disease. Arthritis and Rheumatology. 2015;67(1):128-139. https://doi.org/10.1002/art.38892
Crost EH, Tailford LE, Monestier M, Swarbreck D, Henrissat B, Crossman LC, Juge N. The mucin-degradation strategy of Ruminococcus gnavus: The importance of intramolecular trans-sialidases. Gut Microbes. 2016;7(4):302-312. https://doi.org/10.1080/19490976.2016.1186334
Swann JR, Want EJ, Geier FM, Spagou K, Wilson ID, Sidaway JE, Nicholson JK, Holmes E. Systemic gut microbial modulation of bile acid metabolism in host tissue compartments. Proceedings of the National Academy of Sciences of the United States of America. 2011;108(Suppl 1):4523-4530. https://doi.org/10.1073/pnas.1006734107
Wang J, Zhu N, Su X, Gao Y, Yang R. Gut-Microbiota-Derived Metabolites Maintain Gut and Systemic Immune Homeostasis. Cells. 2023;12(5):793. https://doi.org/10.3390/cells12050793
Gallagher K, Catesson A, Griffin JL, Holmes E, Williams HRT. Metabolomic Analysis in Inflammatory Bowel Disease: A Systematic Review. Journal of Crohn’s and Colitis. 2021;15(5):813-826. https://doi.org/10.1093/ecco-jcc/jjaa227
Jagt JZ, Verburgt CM, de Vries R, de Boer NKH, Benninga MA, de Jonge WJ, van Limbergen JE, de Meij TGJ. Faecal Metabolomics in Paediatric Inflammatory Bowel Disease: A Systematic Review. Journal of Crohn’s and Colitis. 2022;16(11):1777-1790. https://doi.org/10.1093/ecco-jcc/jjac079
Wang C, Gu Y, Chu Q, Wang X, Ding Y, Qin X, Liu T, Wang S, Liu X, Wang B, Cao H. Gut microbiota and metabolites as predictors of biologics response in inflammatory bowel disease: A comprehensive systematic review. Microbiological Research. 2024; 282:127660. https://doi.org/10.1016/j.micres.2024.127660
Zhuang X, Li T, Li M, Huang S, Qiu Y, Feng R, Zhang S, Chen M, Xiong L, Zeng Z. Systematic Review and Meta-analysis: Short-Chain Fatty Acid Characterization in Patients With Inflammatory Bowel Disease. Inflammatory Bowel Diseases. 2019;25(11): 1751-1763. https://doi.org/10.1093/ibd/izz188
Wang S, van Schooten FJ, Jin H, Jonkers D, Godschalk R. The Involvement of Intestinal Tryptophan Metabolism in Inflammatory Bowel Disease Identified by a Meta-Analysis of the Transcriptome and a Systematic Review of the Metabolome. Nutrients. 2023;15(13):2886. https://doi.org/10.3390/nu15132886
Vakhitov TYa, Kononova SV, Demyanova EV, Morugina AS, Utsal VA, Sall TS, Skalinskaya MI, Bakulin IG, Khavkin AI, Sitkin SI. Serum metabolomic profile in patients with ulcerative colitis: pathophysiological role, diagnostic and therapeutic implications. Voprosy detskoj dietologii. 2023;21(5):5-15. (In Russ.). https://doi.org/10.20953/1727-5784-2023-5-5-15
Wang J, Sun Q, Gao Y, Xiang H, Zhang C, Ding P, Wu T, Ji G. Metabolomics window into the diagnosis and treatment of inflammatory bowel disease in recent 5 years. International Immunopharmacology. 2022;113(Pt B):109472. https://doi.org/10.1016/j.intimp.2022.109472
Silva YP, Bernardi A, Frozza RL. The Role of Short-Chain Fatty Acids from Gut Microbiota in Gut-Brain Communication. Frontiers in Endocrinology. 2020;11:25. https://doi.org/10.3389/fendo.2020.00025
Fernandes J, Su W, Rahat-Rozenbloom S, Wolever TM, Comelli EM. Adiposity, gut microbiota and faecal short chain fatty acids are linked in adult humans. Nutrition and Diabetes. 2014;4(6):e121. https://doi.org/10.1038/nutd.2014.23
Facchin S, Bertin L, Bonazzi E, Lorenzon G, De Barba C, Barberio B, Zingone F, Maniero D, Scarpa M, Ruffolo C, Angriman I, Savarino EV. Short-Chain Fatty Acids and Human Health: from Metabolic Pathways to Current Therapeutic Implications. Life. 2024;14(5):559. https://doi.org/10.3390/life14050559
National Center for Biotechnology Information. PubChem Compound Summary for CID 175, Acetate. PubChem. 2025. Accessed May 18, 2025. https://pubchem.ncbi.nlm.nih.gov/compound/Acetate
National Center for Biotechnology Information. PubChem Compound Summary for CID 104745, Propionate ion. PubChem. 2025. Accessed May 18, 2025. https://pubchem.ncbi.nlm.nih.gov/compound/Propionate-ion
National Center for Biotechnology Information. PubChem Compound Summary for CID 5222465, Sodium Butyrate. PubChem. 2025. Accessed May 18, 2025. https://pubchem.ncbi.nlm.nih.gov/compound/Sodium-Butyrate
National Center for Biotechnology Information. PubChem Compound Summary for CID 7991, Valeric acid. PubChem. 2025. Accessed May 18, 2025. https://pubchem.ncbi.nlm.nih.gov/compound/Valeric-acid
National Center for Biotechnology Information. PubChem Compound Summary for CID 4398339, Hexanoate. PubChem. 2025. Accessed May 18, 2025. https://pubchem.ncbi.nlm.nih.gov/compound/Hexanoate
International Union of Pure and Applied Chemistry. Compendium of Chemical Terminology (Gold Book). Accessed May 18, 2025. https://goldbook.iupac.org/terms
Cummings JH, Pomare EW, Branch WJ, Naylor CP, Macfarlane GT. Short chain fatty acids in human large intestine, portal, hepatic and venous blood. Gut. 1987;28(10):1221-1227. https://doi.org/10.1136/gut.28.10.1221
Rechkemmer G, von Engelhardt W. Concentration- and pH-dependence of short-chain fatty acid absorption in the proximal and distal colon of guinea pig (Cavia porcellus). Comparative Biochemistry and Physiology. Part A: Comparative Physiology. 1988;91(4):659-663. https://doi.org/10.1016/0300-9629(88)90944-9
Ritzhaupt A, Wood IS, Ellis A, Hosie KB, Shirazi-Beechey SP. Identification and characterization of a monocarboxylate transporter (MCT1) in pig and human colon: its potential to transport l -lactate as well as butyrate. The Journal of Physiology. 1998; 513(Pt 3):719-732. https://doi.org/10.1111/j.1469-7793.1998.719ba.x
Miyauchi S, Gopal E, Fei YJ, Ganapathy V. Functional identification of SLC5A8, a tumor suppressor down-regulated in colon cancer, as a Na+-coupled transporter for short-chain fatty acids. The Journal of Biological Chemistry. 2004;279:13293-13296. https://doi.org/10.1074/jbc.C400059200
Ganapathy V, Thangaraju M, Prasad PD, Martin PM, Singh N. Transporters and receptors for short-chain fatty acids as the molecular link between colonic bacteria and the host. Current Opinion in Pharmacology. 2013;13(6):869-874. https://doi.org/10.1016/j.coph.2013.08.006
Sivaprakasam S, Bhutia YD, Yang S, Ganapathy V. Short-Chain Fatty Acid Transporters: Role in Colonic Homeostasis. Comprehensive Physiology. 2017;8(1):299-314. https://doi.org/10.1002/cphy.c170014
Binder HJ, Mehta P. Short-chain fatty acids stimulate active sodium and chloride absorption in vitro in the rat distal colon. Gastroenterology. 1989;96(4):989-996. https://doi.org/10.1016/0016-5085(89)91614-4
Murase M, Kimura Y, Nagata Y. Determination of portal short-chain fatty acids in rats fed various dietary fibers by capillary gas chromatography. Journal of Chromatography. B: Biomedical Applications. 1995;664(2):415-420. https://doi.org/10.1016/0378-4347(94)00491-m
Bloemen JG, Venema K, van de Poll MC, Olde Damink SW, Buurman WA, Dejong CH. Short chain fatty acids exchange across the gut and liver in humans measured at surgery. Clinical Nutrition. 2009;28(6):657-661. https://doi.org/10.1016/j.clnu.2009.05.011
Canfora EE, Jocken JW, Blaak EE. Short-chain fatty acids in control of body weight and insulin sensitivity. Nature Reviews Endocrinology. 2015;11(10):577-591. https://doi.org/10.1038/nrendo.2015.128
Kim M, Qie Y, Park J, Kim CH. Gut microbial metabolites fuel host antibody responses. Cell Host and Microbe. 2016;20(2):202-214. https://doi.org/10.1016/j.chom.2016.07.001
Wang CC, Wu H, Lin FH, Gong R, Xie F, Peng Y, Feng J, Hu CH. Sodium butyrate enhances intestinal integrity, inhibits mast cell activation, inflammatory mediator production and JNK signaling pathway in weaned pigs. Innate Immunity. 2018;24:40-46. https://doi.org/10.1177/1753425917741970
Kim CH. Microbiota or short-chain fatty acids: which regulates diabetes? Cellular and Molecular Immunology. 2018;15:88-91. https://doi.org/10.1038/cmi.2017.57
D’Souza WN, Douangpanya J, Mu S, Jaeckel P, Zhang M, Maxwell JR, Rottman JB, Labitzke K, Willee A, Beckmann H, Wang Y, Li Y, Schwandner R, Johnston JA, Towne JE, Hsu H. Differing roles for short chain fatty acids and GPR43 agonism in the regulation of intestinal barrier function and immune responses. PLoS One. 2017;12(7):e0180190. https://doi.org/10.1371/journal.pone.0180190
Thangaraju M, Cresci GA, Liu K, Ananth S, Gnanaprakasam JP, Browning DD, Mellinger JD, Smith SB, Digby GJ, Lambert NA, Prasad PD, Ganapathy V. GPR109A is a G-protein-coupled receptor for the bacterial fermentation product butyrate and functions as a tumor suppressor in colon. Cancer Research. 2009;69(7): 2826-2832. https://doi.org/10.1158/0008-5472.CAN-08-4466
Li M, van Esch B, Wagenaar GTM, Garssen J, Folkerts G, Henricks PAJ. Pro- and anti-inflammatory effects of short chain fatty acids on immune and endothelial cells. European Journal of Pharmacology. 2018;831:52-59. https://doi.org/10.1016/j.ejphar.2018.05.003
Rooks MG, Garrett WS. Gut microbiota, metabolites and host immunity. Nature Reviews Immunology. 2016;16:341-352. https://doi.org/10.1038/nri.2016.42
Wen ZS, Lu JJ, Zou XT. Effects of sodium butyrate on the intestinal morphology and dna-binding activity of intestinal nuclear factor-kappa b in weanling pigs. Journal of Animal and Veterinary Advances. 2012;11:814-821. https://doi.org/10.3923/javaa.2012.814.821
Hayashi A, Sato T, Kamada N, Mikami Y, Matsuoka K, Hisamatsu T. A single strain of Clostridium butyricum induces intestinal IL-10-producing macrophages to suppress acute experimental colitis in mice. Cell Host and Microbe. 2013;13:711-722. https://doi.org/10.1016/j.chom.2013.05.013
Wu JL, Zou JY, Hu ED, Chen DZ, Chen L, Lu FB. Sodium butyrate ameliorates S100/FCA-induced autoimmune hepatitis through regulation of intestinal tight junction and toll-like receptor 4 signaling pathway. Immunology Letters. 2017;190:169-176. https://doi.org/10.1016/j.imlet.2017.08.005
Kelly CJ, Zheng L, Campbell EL, Saeedi B, Scholz CC, Bayless AJ, Wilson KE, Glover LE, Kominsky DJ, Magnuson A, Weir TL, Ehrentraut SF, Pickel C, Kuhn KA, Lanis JM, Nguyen V, Taylor CT, Colgan SP. Crosstalk between Microbiota-Derived Short-Chain Fatty Acids and Intestinal Epithelial HIF Augments Tissue Barrier Function. Cell Host and Microbe. 2015;17(5):662-671. https://doi.org/10.1016/j.chom.2015.03.005
Zheng L, Kelly CJ, Battista KD, Schaefer R, Lanis JM, Alexeev EE, Onyiah JC, Kominsky DJ, Colgan SP. Microbial-derived butyrate promotes epithelial barrier function through IL-10 receptor-dependent repression of claudin-2. The Journal of Immunology. 2017;199(8):2976-2984. https://doi.org/10.4049/jimmunol.1700105
Wang HB, Wang PY, Wang X, Wan YL, Liu YC. Butyrate enhances intestinal epithelial barrier function via up-regulation of tight junction protein claudin-1 transcription. Digestive Diseases and Sciences. 2012;57:3126-3135. https://doi.org/10.1007/s10620-012-2259-4
Zhao Y, Chen F, Wu W, Sun M, Bilotta AJ, Yao S, Kominsky DJ, Colgan SP. GPR43 mediates microbiota metabolite SCFA regulation of antimicrobial peptide expression in intestinal epithelial cells via activation of mTOR and STAT3. Mucosal Immunology. 2018;11(3):752-762. https://doi.org/10.1038/mi.2017.118
Shin Y, Han S, Kwon J, Ju S, Choi TG, Kang I, Kim SS. Roles of Short-Chain Fatty Acids in Inflammatory Bowel Disease. Nutrients. 2023;15(20):4466. https://doi.org/10.3390/nu15204466
Marchesi JR, Holmes E, Khan F, Kochhar S, Scanlan P, Shanahan F, Wilson ID, Wang Y. Rapid and noninvasive metabonomic characterization of inflammatory bowel disease. Journal of Proteome Research. 2007;6(2):546-551. https://doi.org/10.1021/pr060470d
Parada Venegas D, De la Fuente MK, Landskron G, González M., Quera R, Dijkstra G, Harmsen HJM, Faber KN, Hermoso MA. Short Chain Fatty Acids (SCFAs)-Mediated Gut Epithelial and Immune Regulation and Its Relevance for Inflammatory Bowel Diseases. Frontiers in Immunology. 2019;10:277. https://doi.org/10.3389/fimmu.2019.00277
Camilleri M. Leaky gut: mechanisms, measurement and clinical implications in humans. Gut. 2019;68:1516-1526. https://doi.org/10.1136/gutjnl-2019-318427
Fakhoury HMA, Kvietys PR, AlKattan W, Anouti FA, Elahi MA, Karras SN, Grant WB. Vitamin D and intestinal homeostasis: barrier, microbiota, and immune modulation. Journal of Steroid Biochemistry and Molecular Biology. 2020;200:105663. https://doi.org/10.1016/j.jsbmb.2020.105663
Zeissig S, Bürgel N, Günzel D, Richter J, Mankertz J, Wahnschaffe U, Kroesen AJ, Zeitz M, Fromm M, Schulzke JD. Changes in expression and distribution of claudin 2, 5 and 8 lead to discontinuous tight junctions and barrier dysfunction in active Crohn’s disease. Gut. 2007;56(1):61-72. https://doi.org/10.1136/gut.2006.094375
Dignass AU, Podolsky DK. Cytokine modulation of intestinal epithelial cell restitution: central role of transforming growth factor beta. Gastroenterology. 1993;105(5):1323-1332. https://doi.org/10.1016/0016-5085(93)90136-z
Heller F, Florian P, Bojarski C, Richter J, Christ M, Hillenbrand B, Mankertz J, Gitter AH, Bürgel N, Fromm M, Zeitz M, Fuss I, Strober W, Schulzke JD. Interleukin-13 is the key effector Th2 cytokine in ulcerative colitis that affects epithelial tight junctions, apoptosis, and cell restitution. Gastroenterology. 2005;129(2):550-564. https://doi.org/10.1016/j.gastro.2005.05.002
Gitter AH, Wullstein F, Fromm M, Schulzke JD. Epithelial barrier defects in ulcerative colitis: characterization and quantification by electrophysiological imaging. Gastroenterology. 2001;121(6): 1320-1328. https://doi.org/10.1053/gast.2001.29694
Nakamura YK, Janowitz C, Metea C, Asquith M, Karstens L, Rosenbaum JT, Lin P. Short chain fatty acids ameliorate immune-mediated uveitis partially by altering migration of lymphocytes from the intestine. Scientific Reports. 2017;7:11745. https://doi.org/10.1038/s41598-017-12163-3