Indole-3-carboxyaldehyde Does Not Reverse the Intestinal Effects of Fiber-free Diet in Mice

Overview

Journal Front Endocrinol (Lausanne)

Specialty Endocrinology

Date 2024 Apr 8

PMID 38586454

Authors

Mark M Smits

Serafina I L Dreyer

Jenna E Hunt

Anna K Drzazga

Ida M Modvig

Jens J Holst

Hannelouise Kissow

Affiliations

Soon will be listed here.

Abstract

Objective: Fiber-free diet impairs intestinal and colonic health in mice, in parallel with a reduction in glucagon like peptide-1 (GLP-1) levels. Endogenous GLP-1 is important for intestinal growth and maintenance of the intestinal integrity. We aimed to investigate whether fiber-free diet reduces luminal content of metabolites which, upon supplementation, could increase GLP-1 secretion and restore the adverse effects of fiber-free diet.

Methods: Untargeted metabolomics (LC-MS) was performed on colonic content of mice fed a fiber-free diet, identifying a metabolite of particular interest: indole-3-carboxyaldehyde (I3A). We exposed cultured GLUTag cells to I3A, and measured cumulative GLP-1 secretion. Isolated colon perfusions were performed in male C57BL/6JRj mice and Wistar rats. I3A was administered luminally or vascularly, and GLP-1 was measured in portal vein effluent. Finally, female C57BL/6JRJ mice were fed chow or fiber-free diet, with I3A or vehicle by oral gavage. After 10 days, plasma GLP-1 (ELISA) and intestinal permeability (FITC-dextran) were measured, animals were sacrificed and organs removed for histology.

Results: Mice fed a fiber-free diet had significantly lower I3A in their colonic content compared to a control diet (7883 ± 3375 AU, =0.04). GLP-1 secretion from GLUTag cells was unchanged after five minutes of exposure to I3A. However, GLP-1 levels increased after 120 minutes of exposure to 1 mM (60% increase, =0.016) and 5 mM (89% increase, =0.0025) I3A. In contrast, 48 h exposure to 1 mM decreased GLP-1 secretion (51% decrease, 0.001) and viability. In isolated perfused mouse and rat colon, I3A applied into the luminal or vascular side did not affect GLP-1 secretion. Mice fed a fiber-free diet tended to weigh less compared to chow fed mice; and the small intestine and colon were significantly smaller. No differences were seen in crypt depth, villus length, mucosal area, and intestinal permeability. Supplementing I3A did not affect body weight, morphology or plasma GLP-1 levels.

Conclusions: Fiber-free diet lowered colonic content of I3A in mice. I3A stimulates GLP-1 secretion , but not in animal studies. Moreover, it has no evident beneficial effect on intestinal health when administered .

Citing Articles

The Severity of DSS-Induced Colitis Is Independent of the SCFA-FFAR2/3-GLP-1 Pathway Despite SCFAs Inducing GLP-1 Secretion via FFAR2/3.

Hunt J, Christiansen C, Yassin M, Hartmann B, Offermanns S, Dragsted L Metabolites. 2024; 14(7).

PMID: 39057718 PMC: 11278623. DOI: 10.3390/metabo14070395.

References

Huang Z, Boekhorst J, Fogliano V, Capuano E, Wells J . Distinct effects of fiber and colon segment on microbiota-derived indoles and short-chain fatty acids. Food Chem. 2022; 398:133801. DOI: 10.1016/j.foodchem.2022.133801. View

Tolhurst G, Heffron H, Lam Y, Parker H, Habib A, Diakogiannaki E . Short-chain fatty acids stimulate glucagon-like peptide-1 secretion via the G-protein-coupled receptor FFAR2. Diabetes. 2011; 61(2):364-71. PMC: 3266401. DOI: 10.2337/db11-1019. View

Chimerel C, Emery E, Summers D, Keyser U, Gribble F, Reimann F . Bacterial metabolite indole modulates incretin secretion from intestinal enteroendocrine L cells. Cell Rep. 2014; 9(4):1202-8. PMC: 4308618. DOI: 10.1016/j.celrep.2014.10.032. View

Nozu T, Miyagishi S, Kumei S, Nozu R, Takakusaki K, Okumura T . Glucagon-like peptide-1 analog, liraglutide, improves visceral sensation and gut permeability in rats. J Gastroenterol Hepatol. 2017; 33(1):232-239. DOI: 10.1111/jgh.13808. View

Abdalqadir N, Adeli K . GLP-1 and GLP-2 Orchestrate Intestine Integrity, Gut Microbiota, and Immune System Crosstalk. Microorganisms. 2022; 10(10). PMC: 9610230. DOI: 10.3390/microorganisms10102061. View

Billeschou A, Hunt J, Kissow H . Important Endpoints and Proliferative Markers to Assess Small Intestinal Injury and Adaptation using a Mouse Model of Chemotherapy-Induced Mucositis. J Vis Exp. 2019; (147). DOI: 10.3791/59236. View

Darkoh C, Chappell C, Gonzales C, Okhuysen P . A rapid and specific method for the detection of indole in complex biological samples. Appl Environ Microbiol. 2015; 81(23):8093-7. PMC: 4651089. DOI: 10.1128/AEM.02787-15. View

Powell D, Swimm A, Sonowal R, Bretin A, Gewirtz A, Jones R . Indoles from the commensal microbiota act via the AHR and IL-10 to tune the cellular composition of the colonic epithelium during aging. Proc Natl Acad Sci U S A. 2020; 117(35):21519-21526. PMC: 7474656. DOI: 10.1073/pnas.2003004117. View

Al-Dwairi A, Alqudah T, Al-Shboul O, Alqudah M, Mustafa A, Alfaqih M . Glucagon-like peptide-1 exerts anti-inflammatory effects on mouse colon smooth muscle cells through the cyclic adenosine monophosphate/nuclear factor-κB pathway in vitro. J Inflamm Res. 2018; 11:95-109. PMC: 5865574. DOI: 10.2147/JIR.S152835. View

10.

Kuhre R, Frost C, Svendsen B, Holst J . Molecular mechanisms of glucose-stimulated GLP-1 secretion from perfused rat small intestine. Diabetes. 2014; 64(2):370-82. DOI: 10.2337/db14-0807. View

11.

Malipatlolla D, Devarakonda S, Patel P, Sjoberg F, Rascon A, Grander R . A Fiber-Rich Diet and Radiation-Induced Injury in the Murine Intestinal Mucosa. Int J Mol Sci. 2022; 23(1). PMC: 8745769. DOI: 10.3390/ijms23010439. View

12.

Gianfredi V, Salvatori T, Villarini M, Moretti M, Nucci D, Realdon S . Is dietary fibre truly protective against colon cancer? A systematic review and meta-analysis. Int J Food Sci Nutr. 2018; 69(8):904-915. DOI: 10.1080/09637486.2018.1446917. View

13.

Kuhre R, Albrechtsen N, Windelov J, Svendsen B, Hartmann B, Holst J . GLP-1 amidation efficiency along the length of the intestine in mice, rats and pigs and in GLP-1 secreting cell lines. Peptides. 2014; 55:52-7. DOI: 10.1016/j.peptides.2014.01.020. View

14.

Bang-Berthelsen C, Holm T, Pyke C, Simonsen L, Sokilde R, Pociot F . GLP-1 Induces Barrier Protective Expression in Brunner's Glands and Regulates Colonic Inflammation. Inflamm Bowel Dis. 2016; 22(9):2078-97. DOI: 10.1097/MIB.0000000000000847. View

15.

Yusta B, Baggio L, Koehler J, Holland D, Cao X, Pinnell L . GLP-1R Agonists Modulate Enteric Immune Responses Through the Intestinal Intraepithelial Lymphocyte GLP-1R. Diabetes. 2015; 64(7):2537-49. DOI: 10.2337/db14-1577. View

16.

Koehler J, Baggio L, Yusta B, Longuet C, Rowland K, Cao X . GLP-1R agonists promote normal and neoplastic intestinal growth through mechanisms requiring Fgf7. Cell Metab. 2015; 21(3):379-91. DOI: 10.1016/j.cmet.2015.02.005. View

17.

Liu M, Wang Y, Xiang H, Guo M, Li S, Liu M . The Tryptophan Metabolite Indole-3-Carboxaldehyde Alleviates Mice with DSS-Induced Ulcerative Colitis by Balancing Amino Acid Metabolism, Inhibiting Intestinal Inflammation, and Improving Intestinal Barrier Function. Molecules. 2023; 28(9). PMC: 10180526. DOI: 10.3390/molecules28093704. View

18.

Gill S, Rossi M, Bajka B, Whelan K . Dietary fibre in gastrointestinal health and disease. Nat Rev Gastroenterol Hepatol. 2020; 18(2):101-116. DOI: 10.1038/s41575-020-00375-4. View

19.

Hunt J, Hartmann B, Schoonjans K, Holst J, Kissow H . Dietary Fiber Is Essential to Maintain Intestinal Size, L-Cell Secretion, and Intestinal Integrity in Mice. Front Endocrinol (Lausanne). 2021; 12:640602. PMC: 7953038. DOI: 10.3389/fendo.2021.640602. View

20.

Ramezani F, Pourghazi F, Eslami M, Gholami M, Mohammadian Khonsari N, Ejtahed H . Dietary fiber intake and all-cause and cause-specific mortality: An updated systematic review and meta-analysis of prospective cohort studies. Clin Nutr. 2023; 43(1):65-83. DOI: 10.1016/j.clnu.2023.11.005. View