Features of the gut microbiota in the pathogenesis and clinical course of diverticular disease (review)

AIM: to assess the most promising areas in the field of studying the microbiome of the colon in patients with complicated forms of diverticular disease, which can be used in clinical practice.
MATERIALS AND METHODS: a systematic literature search of electronic databases (PubMed, EMBASE, Cochrane, Research gate, Scopus) for the past 20 years was done. Initially, 14 meta-analyses, 342 reviews, 116 clinical studies, and 27 experimental studies were found. After screening and evaluating the summary, 12 meta-analyses, 24 reviews, 22 clinical studies, and 5 experimental studies were selected. This article has been prepared in accordance with PRISMA standards.
RESULTS: there is a decrease in the representation of Bacteroidetes, Fusobacterium, Clostridium clusters IV and IX, Lactobacillaceae, and other microorganisms with anti-inflammatory properties and the ability to synthesize shortchain fatty acids. In addition, in all types of diverticular disease, there is an increase in the population of Roseburia hominis and Akkermansia muciniphila. With a complicated course of diverticular disease, there is an increase in the number of representatives of the Proteobacteria family, and with symptomatically uncomplicated diverticular disease — Firmicutes. According to studies, there is a change in the concentration of specific urinary and fecal biomarkers in the blood — hippurate, kininurenine and short-chain fatty acids, therefore, the assessment of the metabolome may be considered a justified goal in determining and predicting changes in the microbiome in these patients with diverticular disease.
CONCLUSION: there is evidence that an increase in the severity of inflammation in diverticular disease may be associated with an increase in the generic diversity of the fecal microbiota. Other bacterial metabolites can act as diagnostic and prognostic markers of the severity of the disease.

1. Peery AF, Crockett SD, Barritt AS. Burden of Gastrointestinal, Liver, and Pancreatic Diseases in the United States. Gastroenterology. 2015 Dec;149(7):1731–1741.e3.

2. Livzan M.A., Gaus O.V., Lisovsky M.A. Diverticular disease: gut microbiota in the clinician’s practice. RMJ. 2023;5:20– 26.

3. Tursi A, Scarpignato C, Strat, LL, et al. (2020). Author Correction: Colonic diverticular disease. Nature Reviews Disease Primers. 6(1). doi: 10.1038/s41572-020-0192-y

4. Drapkina O.M., Lazebnik L.B., Bakulin I.G., et al. Colonic diverticular disease: clinical presentation, diagnosis, treatment, and prevention Clinical guidelines of the Russian Scientific Medical Society of Internal Medicine, the Gastroenterological Scientific Society of Russia, and the NorthWest Society of Gastroenterologists and Hepatologists. Experimental and Clinical Gastroenterology. 2023;(2):33–69. (In Russ.) doi: 10.31146/1682-8658-ecg-210-2-33-69

5. Clinical recommendations. Diverticular disease 06/25/2021. Approved by the Ministry of Health of the Russian Federation. (in Russ.).

6. Emile SH, Elfeki H, Sakr A, et al. Management of acute uncomplicated diverticulitis without antibiotics: a systematic review, metaanalysis, and meta-regression of predictors of treatment failure. Tech Coloproctol. 2018 Jul;22(7):499–509. doi: 10.1007/s10151-018-1817-y Epub 2018 Jul 6. PMID: 29980885.

7. Sartelli M, Tascini C, Coccolini F, et al. Management of intraabdominal infections: recommendations by the Italian council for the optimization of antimicrobial use. World J Emerg Surg. 2024;19:23. doi: 10.1186/s13017-024-00551-w

8. De Simone B, Coccolini F, Catena F, et al. Benefits of WSES guidelines application for the management of intra-abdominal infections. World J Emerg Surg. 2015;10:18. doi: 10.1186/s13017-015-0013-x

9. Williams S, Bjarnason I, Hayee B, et al. Diverticular disease: update on pathophysiology, classification and management. Frontline Gastroenterology. 2024;15:50–58.

10. Nikolenko VN, Oganesyan MV, Sankova MV, et al. Paneth cells: Maintaining dynamic microbiome-host homeostasis, protecting against inflammation and cancer. Bioessays. 2021, 43, 2000180

11. Van Rossen TM, Ooijevaar RE, Kuyvenhoven JP, et al. Microbiota composition and mucosal immunity in patients with asymptomatic diverticulosis and controls. PLoS One. 2021;16:e0256657.

12. Alexandersson BT, Hugerth LW, Hedin C, et al. Diverticulosis is not associated with altered gut microbiota nor is it predictive of future diverticulitis: a population-based colonoscopy study. Scand J Gastroenterol. 2023;1-8. doi: 10.1080/00365521.2023.2194010

13. Serek P, Oleksy-Wawrzyniak M. The Effect of Bacterial Infections, Probiotics and Zonulin on Intestinal Barrier Integrity. Int J Mol Sci. 2021;222:1359.

14. Barbara G, Scaioli E, Barbaro MR, et al. Gut microbiota, metabolome and immune signatures in patients with uncomplicated diverticular disease. Gut. 2017 Jul;66(7):1252–1261. doi: 10.1136/gutjnl-2016-312377 Epub 2016 Sep 12. PMID: 27618836.

15. Daniels L, Budding AE, de Korte N, et al. Fecal microbiome analysis as a diagnostic test for diverticulitis. Eur J Clin Microbiol Infect Dis. 2014 Nov;33(11):1927–36. doi: 10.1007/s10096-014-2162-3 Epub 2014 Jun 4. PMID: 24894339.

16. Levchenko S.V. Anti-recurrent treatment of colon diverticulitis. Eksperimental’naya i Klinicheskaya Gastroenterologiya. 2014;107(7):45–54.

17. Kvasnovsky C.L, Leong L.X, Choo J.M, et al. Clinical and symptom scores are significantly correlated with fecal microbiota features in patients with symptomatic uncomplicated diverticular disease: a pilot study. Eur J Gastroenterol Hepatol. 2018 Jan;30(1):107–112. doi: 10.1097/MEG.0000000000000995 PMID: 29084074.

18. Tursi A, Mastromarino P, Capobianco D, et al. Assessment of Fecal Microbiota and Fecal Metabolome in Symptomatic Uncomplicated Diverticular Disease of the Colon. J Clin Gastroenterol. 2016 Oct;50 Suppl 1:S9–S12. doi: 10.1097/MCG.0000000000000626 PMID: 27622378.

19. Linninge C, Roth B, Erlanson-Albertsson C, et al. Abundance of Enterobacteriaceae in the colon mucosa in diverticular disease. World J Gastrointest Pathophysiol. 2018 Feb 15;9(1):18–27. doi: 10.4291/wjgp.v9.i1.18 PMID: 29487763; PMCID: PMC5823699.

20. Mj O, Turner GA, Frizelle FA, et al. Distinct changes in the colonic microbiome associated with acute diverticulitis. Colorectal Dis. 2022 Dec;24(12):1591–1601. doi: 10.1111/codi.16271 Epub 2022 Aug 11. PMID: 35950499; PMCID: PMC10087140.

21. Humes DJ, Simpson J, Smith J, et al. Visceral hypersensitivity in symptomatic diverticular disease and the role of neuropeptides and low grade inflammation. Neurogastroenterol Motil. 2012 Apr;24(4):318–e163. doi: 10.1111/j.1365-2982.2011.01863.x Epub 2012 Jan 25. PMID: 22276853.

22. Schieffer KM, Kline BP, Harris LR, et al. (2018) A differential host response to viral infection defines a subset of earlier-onset diverticulitis patients. J Gastrointestin Liver Dis. 27(3):249–255.

23. Scarpignato C, Barbara G, Lanas A, et al. Management of colonic diverticular disease in the third millennium: Highlights from a symposium held during the United European Gastroenterology Week 2017. Therap Adv Gastroenterol. 2018;11:1756284818771305. doi: 10.1177/1756284818771305

24. Schieffer KM, Kline BP, Harris LR, et al. (2018) A differential host response to viral infection defines a subset of earlier-onset diverticulitis patients. J Gastrointestin Liver Dis. 27(3):249–255.

25. Jones RB, Fodor AA, Peery AF, et al. An Aberrant Microbiota is not Strongly Associated with Incidental Colonic Diverticulosis. Sci Rep. 2018 Mar 21;8(1):4951. doi: 10.1038/s41598-018-23023-z PMID: 29563543; PMCID: PMC5862835.

26. Mj O, Turner GA, Frizelle FA, et al. Distinct changes in the colonic microbiome associated with acute diverticulitis. Colorectal Dis. 2022 Dec;24(12):1591–1601. doi: 10.1111/codi.16271 Epub 2022 Aug 11. PMID: 35950499; PMCID: PMC10087140.

27. Lopetuso LR, Petito V, Graziani C, et al. Gut Microbiota in Health, Diverticular Disease, Irritable Bowel Syndrome, and Inflammatory Bowel Diseases: Time for Microbial Marker of Gastrointestinal Disorders. Dig Dis. 2018;36(1):56–65. doi: 10.1159/000477205 Epub 2017 Jul 7. PMID: 28683448.

28. Schieffer KM, Sabey K, Wright JR, et al. The Microbial Ecosystem Distinguishes Chronically Diseased Tissue from Adjacent Tissue in the Sigmoid Colon of Chronic, Recurrent Diverticulitis Patients. Sci Rep. 2017 Aug 16;7(1):8467. doi: 10.1038/s41598-017-06787-8 PMID: 28814777; PMCID: PMC5559482.

29. Zitomersky NL, Atkinson BJ, Franklin SW, et al. Characterization of adherent bacteroidales from intestinal biopsies of children and young adults with inflammatory bowel disease. PLoS One. 2013 Jun 11;8(6):e63686. doi: 10.1371/journal.pone.0063686 PMID: 23776434; PMCID: PMC3679120

30. Peterson DA, McNulty NP, Guruge JL, et al. IgA response to symbiotic bacteria as a mediator of gut homeostasis. Cell Host Microbe. 2007 Nov 15;2(5):328–39. doi: 10.1016/j.chom.2007.09.013 PMID: 18005754.

31. Stumpf M, Cao W, Klinge U, et al. Increased distribution of collagen type III and reduced expression of matrix metalloproteinase 1 in patients with diverticular disease. Int J Color Dis. 2001;16(5):271– 275

32. Kauppila JH, Karttunen TJ, Saarnio J, et al. Short DNA sequences and bacterial DNA induce esophageal, gastric, and colorectal cancer cell invasion. APMIS. 2013 Jun;121(6):511–22. doi: 10.1111/apm.12016 Epub 2012 Oct 22. PMID: 23082743.

33. Rosemar A, Ivarsson ML, Börjesson L, et al. Increased concentration of tissue-degrading matrix metalloproteinases and their inhibitor in complicated diverticular disease. Scand J Gastroenterol. 2007 Feb;42(2):215–20. doi: 10.1080/00365520600960104 PMID: 17327941.

34. Ulmer TF, Rosch R, Mossdorf A, et al. Colonic wall changes in patients with diverticular disease — is there a predisposition for a complicated course? Int J Surg. 2014;12(5):426–31. doi: 10.1016/j.ijsu.2014.03.014 Epub 2014 Mar 25. PMID: 24681094.

35. Mimura T, Bateman AC, Lee RL, et al. Up-regulation of collagen and tissue inhibitors of matrix metalloproteinase in colonic diverticular disease. Dis Colon Rectum. 2004 Mar;47(3):371–8; discussion 378-9. doi: 10.1007/s10350-003-0050-5 PMID: 14991500.

36. Floch MH. A hypothesis: is diverticulitis a type of inflammatory bowel disease? J Clin Gastroenterol. 2006 Aug;40 Suppl 3:S121–5. doi: 10.1097/01.mcg.0000225502.29498.ba PMID: 16885694

37. Brennan CA, Clay SL, Lavoie SL, et al. Fusobacterium nucleatum drives a pro-inflammatory intestinal microenvironment through metabolite receptor-dependent modulation of IL-17 expression. Gut Microbes. 2021 Jan-Dec;13(1):1987780. doi: 10.1080/19490976.2021.1987780

38. Jang C, Hui S, Lu W, et al. The Small Intestine Converts Dietary Fructose into Glucose and Organic Acids. Cell Metab. 2018 Feb 6;27(2):351–361.e3. doi: 10.1016/j.cmet.2017.12.016 PMID: 29414685; PMCID: PMC6032988.

39. Marchesi JR, Adams DH, Fava F, et al. The gut microbiota and host health: a new clinical frontier. Gut. 2016 Feb;65(2):330–9. doi: 10.1136/gutjnl-2015-309990 Epub 2015 Sep 2. PMID: 26338727; PMCID: PMC4752653.

40. Sun M, Wu W, Liu Z, et al. Microbiota metabolite short chain fatty acids, GPCR, and inflammatory bowel diseases. J Gastroenterol. 2017 Jan;52(1):1–8. doi: 10.1007/s00535-016-1242-9 Epub 2016 Jul 23. PMID: 27448578; PMCID: PMC5215992.

41. Pomare EW, Branch WJ, Cummings JH. Carbohydrate fermentation in the human colon and its relation to acetate concentrations in venous blood. J Clin Invest. 1985 May;75(5):1448–54. doi: 10.1172/JCI111847 PMID: 3998144; PMCID: PMC425482.

42. Jung TH, Park JH, Jeon WM, et al. Butyrate modulates bacterial adherence on LS174T human colorectal cells by stimulating mucin secretion and MAPK signaling pathway. Nutr Res Pract. 2015 Aug;9(4):343–9. doi: 10.4162/nrp.2015.9.4.343 Epub 2015 Jul 17. PMID: 26244071; PMCID: PMC4523476.

43. Schilderink R, Verseijden C, Seppen J, et al. The SCFA butyrate stimulates the epithelial production of retinoic acid via inhibition of epithelial HDAC. Am J Physiol Gastrointest Liver Physiol. 2016 Jun 1;310(11):G1138-46. doi: 10.1152/ajpgi.00411.2015 Epub 2016 May 5. PMID: 27151945.

44. Schulthess J, Pandey S, Capitani M, et al. The Short Chain Fatty Acid Butyrate Imprints an Antimicrobial Program in Macrophages. Immunity. 2019 Feb 19;50(2):432–445.e7. doi: 10.1016/j.immuni.2018.12.018 Epub 2019 Jan 23. PMID: 30683619; PMCID: PMC6382411.

45. Smith PM, Howitt MR, Panikov N, et al. The Microbial Metabolites, Short-Chain Fatty Acids, Regulate Colonic Treg Cell Homeostasis. Science. 2013;341 (6145) (July 4): 569–573. doi: 10.1126/science.1241165

46. Gonçalves P, Araújo JR, Di Santo JP. A cross-talk between microbiota-derived short-chain fatty acids and the host mucosal immune system regulates intestinal homeostasis and inflammatory bowel disease. Inflamm Bowel Dis. 2018;24(3):558–572. doi: 10.1093/ibd/izx029

47. Jacobs DO. Clinical practice. Diverticulitis. N Engl J Med. 2007 Nov 15;357(20):2057–66. doi: 10.1056/NEJMcp073228 PMID: 18003962.

48. Byndloss MX, Olsan EE, Rivera-Chávez F, et al. Microbiotaactivated PPAR-γ signaling inhibits dysbiotic Enterobacteriaceae expansion. Science. 2017;357(6351):570–575. doi: 10.1126/science.aam9949

49. Gonçalves P, Araújo JR, Di Santo JP. A cross-talk between microbiota-derived short-chain fatty acids and the host mucosal immune system regulates intestinal homeostasis and inflammatory bowel disease. Inflamm Bowel Dis. 2018;24(3):558–572. doi: 10.1093/ibd/izx029

50. Barbara G, Cremon C, Barbaro MR, et al. Treatment of Diverticular Disease With Aminosalicylates: The Evidence. J Clin Gastroenterol. 2016;50 Suppl 1:S60–S63. doi: 10.1097/MCG.0000000000000611

51. Ivashkin V.T., Mayev I.V., et al. Practical Recommendations of Scientific Society for the Study of Human Microbiome and the Russian Gastroenterological Association on Use of Probiotics, Prebiotics, Synbiotics and Functional Foods in Treatment and Prevention of Gastroenterological Diseases in Children and Adults. Russian Journal of Gastroenterology, Hepatology, Coloproctology. 2021;31(2):65–91. (In Russ.) doi: 10.22416/1382-4376-2021-31-2-65-91

52. Quigley EM. Gut microbiota, inflammation and symptomatic diverticular disease. New insights into an old and neglected disorder. J Gastrointestin Liver Dis. 2010 Jun;19(2):127–9. PMID: 20593043.

53. Takehiro H, Hiroshi N. The Multifaceted Effects of Gut Microbiota on the Immune System of the Intestinal Mucosa. Immuno. 2021, 1(4), 583-594.

54. Carvalho AL, Fonseca S, Miquel-Clopés A, et al. Bioengineering commensal bacteria-derived outer membrane vesicles for delivery of biologics to the gastrointestinal and respiratory tract. Journal of Extracellular Vesicles. 2019;8(1):1632100. doi: 10.1080/20013078.2019.1632100

55. Miyamoto J, Mizukure T, Park SB, et al. A gut microbial metabolite of linoleic acid, 10-hydroxy-cis-12-octadecenoic acid, ameliorates intestinal epithelial barrier impairment partially via GPR40- MEK-ERK pathway. J Biol Chem. 2015 Jan 30;290(5):2902–18. doi: 10.1074/jbc.M114.610733 Epub 2014 Dec 10. PMID: 25505251; PMCID: PMC4317025.

56. Foligne B, Nutten S, Grangette C, et al. Correlation between in vitro and in vivo immunomodulatory properties of lactic acid bacteria. World J Gastroenterol. 2007 Jan 14;13(2):236–43. doi: 10.3748/wjg.v13.i2.236 PMID: 17226902; PMCID: PMC4065951.

57. Floch MH. A hypothesis: is diverticulitis a type of inflammatory bowel disease? J Clin Gastroenterol. 2006 Aug;40 Suppl 3:S121–5. doi: 10.1097/01.mcg.0000225502.29498.ba PMID: 16885694.

58. Peran L, Camuesco D, Comalada M, et al. Preventative effects of a probiotic, Lactobacillus salivarius ssp. salivarius, in the TNBS model of rat colitis. World J Gastroenterol. 2005 Sep 7;11(33):5185– 92. doi: 10.3748/wjg.v11.i33.5185 PMID: 16127750; PMCID: PMC4320393.

59. Suez J, Zmora N, Zilberman-Schapira G, et al. Post-Antibiotic Gut Mucosal Microbiome Reconstitution Is Impaired by Probiotics and Improved by Autologous FMT. Cell. 2018 Sep 6;174(6):1406–1423. e16. doi: 10.1016/j.cell.2018.08.047 PMID: 30193113.

60. Andrea Piccioni, Laura Franza, Mattia Brigida, et al. Gut Microbiota and Acute Diverticulitis: Role of Probiotics in Management of This Delicate Pathophysiological Balance J Pers Med. 2021, 11(4), 298

61. Ramezani Ahmadi A, Sadeghian M, Alipour M, et al. The Effects of Probiotic/Synbiotic on Serum Level of Zonulin as a Biomarker of Intestinal Permeability: A Systematic Review and Meta-Analysis. Iran J Public Health. 2020 Jul;49(7):1222–1231. doi: 10.18502/ijph.v49i7.3575 PMID: 33083288; PMCID: PMC7548501.

62. Chabok A, Påhlman L, Hjern F, et al. AVOD Study Group. Randomized clinical trial of antibiotics in acute uncomplicated diverticulitis. Br J Surg. 2012 Apr;99(4):532–9. doi: 10.1002/bjs.8688 Epub 2012 Jan 30. PMID: 22290281.

63. Daniels L, Ünlü Ç, de Korte N, et al. Dutch Diverticular Disease (3D) Collaborative Study Group. Randomized clinical trial of observational versus antibiotic treatment for a first episode of CT-proven uncomplicated acute diverticulitis. Br J Surg. 2017 Jan;104(1):52– 61. doi: 10.1002/bjs.10309 Epub 2016 Sep 30. PMID: 27686365.

64. Tandon A, Fretwell VL, Nunes QM, et al. Antibiotics versus no antibiotics in the treatment of acute uncomplicated diverticulitis — a systematic review and meta-analysis. Colorectal Dis. 2018 Jan 11. doi: 10.1111/codi.14013 Epub ahead of print. PMID: 29323778.

65. van Dijk S.T, Daniels L, Ünlü Ç, et al. Dutch Diverticular Disease (3D) Collaborative Study Group. Long-Term Effects of Omitting Antibiotics in Uncomplicated Acute Diverticulitis. Am J Gastroenterol. 2018 Jul;113(7):1045–1052. doi: 10.1038/s41395-018-0030-y Epub 2018 May 11. PMID: 29700480.

66. Emile S.H, Elfeki H, Sakr A, et al. Management of acute uncomplicated diverticulitis without antibiotics: a systematic review, metaanalysis, and meta-regression of predictors of treatment failure. Tech Coloproctol. 2018 Jul;22(7):499–509. doi: 10.1007/s10151-018-1817-y Epub 2018 Jul 6. PMID: 29980885.

67. Sartelli M, Tascini C, Coccolini F, et al. Management of intraabdominal infections: recommendations by the Italian council for the optimization of antimicrobial use. World J Emerg Surg. 2024;19, 23. doi: 10.1186/s13017-024-00551-w

68. Lahner E, Bellisario C, Hassan C, et al. Probiotics in the Treatment of Diverticular Disease. A Systematic Review. J Gastrointestin Liver Dis. 2016 Mar;25(1):79–86. doi: 10.15403/jgld.2014.1121.251.srw PMID: 27014757.

69. Chey WD, Shah ED, DuPont HL. Mechanism of action and therapeutic benefit of rifaximin in patients with irritable bowel syndrome: A narrative review. Therap Adv Gastroenterol. 2020, 13. doi: 10.1177/1756284819897531

70. Pimentel M, Cash BD, Lembo A, et al. Repeat Rifaximin for Irritable Bowel Syndrome: No Clinically Significant Changes in Stool Microbial Antibiotic Sensitivity. Dig Dis Sci. 2017 Sep;62(9):2455– 2463. doi: 10.1007/s10620-017-4598-7 Epub 2017 Jun 6. Erratum in: Dig Dis Sci. 2017 Oct;62(10):2945. doi: 10.1007/s10620-017-4729-1 PMID: 28589238; PMCID: PMC5561162.

71. Mandalia A, Kraft CS, Dhere T. Diverticulitis after fecal microbiota transplant for C. difficile infection. Am J Gastroenterol. 2014 Dec;109(12):1956–7. doi: 10.1038/ajg.2014.350 PMID: 25470590; PMCID: PMC4795814.

72. Clinical trial NCT05373784: “Outcomes of fecal microbiota transplantation (FMT) in uncomplicated diverticulitis: a pilot study”. https://ichgcp.net/ru/clinicaltrials-registry/NCT05373784