Harley Reynolds

 Introduction: Inflammatory Bowel Disease (IBD) and Irritable Bowel Syndrome (IBS) are two distinct dysregulations of the human gastrointestinal (GI) tract. IBD is characterized by marked inflammation of the intestinal epithelium and is subdivided into Crohn’s disease (CD), or ulcerative colitis (UC) based on the relative location of inflammation. Symptoms include abdominal pain, diarrhea, and rectal bleeding. Patients with IBS may have similar symptoms of abdominal pain and diarrhea but lack the inflammatory state present in IBD. Studies have posited that dysbiosis of the human gut may lead to these symptoms ^[1-3]. While it is unclear whether gut dysbiosis is the cause of these disorders or an effect, a link between the two is well documented ^{[1, 3, 4]}. Furthermore, an association between long-term doxycycline use and gastrointestinal issues in deployed populations has been theorized ^[5-7]. This study underscores a possible link between the use of doxycycline as antimalarial prophylaxis and a resulting gut dysbiosis that is found in IBD/IBS patients. Additionally, a mechanistic approach to linking gut dysbiosis with inflammation is also explored. Methods: Minimum Inhibitory Concentrations (MIC) of various antibiotics were tested in vitro against different bacterial gut species to determine their impact on the gut microbiome ^[8]. Mouse models were utilized to investigate the effects of short-chain fatty acid (SCFA) depletion via antibiotic use on pro-inflammatory macrophage activity ^[9]. Additionally, dextran sulphate sodium (DSS) was used to induce a colitis-like state of dysregulation in mouse models while triggering receptor expressed on myeloid cells 1 (TREM-1) was inhibited via gene knockout or pharmacotherapy to study its role in inflammation. Results: Doxycycline was shown to inhibit all gut bacterial species that were tested including many known commensal bacteria that produce SCFA’s such as Bifidobacterium. SCFA depletion led to an increase in the amount of pro-inflammatory cytokines produced by intestinal macrophages and monocytes ^[9]. Inhibiting TREM-1, a receptor known to increase the pro-inflammatory effects of macrophages, resulted in a marked decrease in the amount of inflamed gut tissue within mouse models ^[10]. Conclusions: A causal relationship between doxycycline use, gut dysbiosis, and IBD/IBS has been explored and warrants further testing. The mechanism by which intestinal macrophage activation is shifted towards a pro-inflammatory state by SCFA depletion highlights both an avenue for further experimentation as well as a method for treating or preventing gut dysbiosis in those on long-term doxycycline through supplementation with SCFA’s.

1. Jackson MA, Verdi S, Maxan ME, et al. Gut microbiota associations with common diseases and prescription medications in a population-based cohort. Nat Commun. Jul 9 2018;9(1):2655. doi:10.1038/s41467-018-05184-7
2. Botschuijver S, Roeselers G, Levin E, et al. Intestinal Fungal Dysbiosis Is Associated With Visceral Hypersensitivity in Patients With Irritable Bowel Syndrome and Rats. Gastroenterology. Oct 2017;153(4):1026-1039. doi:10.1053/j.gastro.2017.06.004
3. Shukla R, Ghoshal U, Dhole TN, Ghoshal UC. Fecal Microbiota in Patients with Irritable Bowel Syndrome Compared with Healthy Controls Using Real-Time Polymerase Chain Reaction: An Evidence of Dysbiosis. Dig Dis Sci. Oct 2015;60(10):2953-62. doi:10.1007/s10620-015-3607-y
4. Seelbinder B, Chen J, Brunke S, et al. Antibiotics create a shift from mutualism to competition in human gut communities with a longer-lasting impact on fungi than bacteria. Microbiome. Sep 12 2020;8(1):133. doi:10.1186/s40168-020-00899-6
5. Lee TW, Russell L, Deng M, Gibson PR. Association of doxycycline use with the development of gastroenteritis, irritable bowel syndrome and inflammatory bowel disease in Australians deployed abroad. Intern Med J. Aug 2013;43(8):919-26. doi:10.1111/imj.12179
6. Hickey PW, Mitra I, Fraser J, Brett-Major D, Riddle MS, Tribble DR. Deployment and Travel Medicine Knowledge, Attitudes, Practices, and Outcomes Study (KAPOS): Malaria Chemoprophylaxis
7. Prescription Patterns in the Military Health System. Am J Trop Med Hyg. Jul 2020;103(1):334-343. doi:10.4269/ajtmh.19-0938
8. Maier L, Goemans CV, Pruteanu M, et al. Dissecting the collateral damage of antibiotics on gut microbes. bioRxiv. 2020:2020.01.09.893560. doi:10.1101/2020.01.09.893560
9. Scott NA, Andrusaite A, Andersen P, et al. Antibiotics induce sustained dysregulation of intestinal T cell immunity by perturbing macrophage homeostasis. Sci Transl Med. 2018;10(464):eaao4755. doi:10.1126/scitranslmed.aao4755
10. Kökten T, Gibot S, Lepage P, et al. TREM-1 Inhibition Restores Impaired Autophagy Activity and Reduces Colitis in Mice. J Crohns Colitis. 2018;12(2):230-244. doi:10.1093/ecco-jcc/jjx129
11. Sairenji T, Collins KL, Evans DV. An Update on Inflammatory Bowel Disease. Primary Care: Clinics in Office Practice. https://www.sciencedirect.com/science/article/pii/S0095454317301045?via%3Dihub. Published October 5, 2017. Accessed May 24, 2021.