Impact of Probiotics on Gut Microbiome During Antibiotic Prophylaxis in Elective Orthopedic Surgery

Impact of Probiotics Combined with Antibiotic Prophylaxis on Gut Microbiome Balance in Patients Undergoing Elective Orthopedic Surgery, Double-Blinded Randomized Controlled Trial

This study aims to evaluate whether probiotics can help maintain a healthy gut microbiome in patients receiving prophylactic antibiotics during elective orthopedic surgery. Antibiotics, while effective in preventing infections, can disrupt the balance of gut bacteria, leading to dysbiosis. The study hypothesizes that the use of probiotics during the perioperative period can prevent or reduce this disruption, supporting gut health and overall well-being. The research seeks to answer whether combining probiotics with routine antibiotic prophylaxis can preserve gut microbiome balance and improve patient outcomes.

Study Overview

• Status: Not yet recruiting
• Conditions: Dysbiosis; Antibiotic Prophylaxis; Probiotic; Microbiome Analysis; Gut -microbiota
• Intervention / Treatment: Drug: Placebo Capsule; Dietary supplement: Probiotic with Human Milk Oligosaccharides (HMO)

Detailed Description

This double-blinded, randomized controlled trial aims to evaluate the effect of probiotics on maintaining gut microbiome balance in patients undergoing elective orthopedic surgery who receive routine prophylactic antibiotics. Antibiotics, while essential for reducing the risk of surgical site infections, are known to disrupt gut microbiota, leading to dysbiosis, an imbalance in microbial composition. Dysbiosis can compromise gut health, reduce microbial diversity, and impair metabolic functions essential for recovery.

The study explores whether a dual-strain probiotic with Human Milk Oligosaccharides (HMO) can prevent or minimize dysbiosis during the perioperative period. By comparing patients receiving routine antibiotics alone with those receiving antibiotics plus probiotics, this trial seeks to identify if probiotics can preserve gut microbial diversity and function.

To assess the impact, fecal samples collected at specific time points will undergo detailed microbiome analysis, including metrics such as microbial richness, diversity, and such. Secondary measures will evaluate the broader effects on patient well-being during the recovery period.

This study is designed to provide evidence for the potential role of probiotics as an adjunct therapy to maintain gut health during antibiotic use, offering a novel approach to improving post-surgical recovery and patient outcomes.

• Study Type: Interventional
• Enrollment (Estimated): 60
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: İbrahim Tuncay, Prof. Dr.; Phone Number: +90 212 304 43 78; Email: ituncay@gmail.com
• Study Contact Backup: Name: Göksel Dikmen, Assoc. Prof. Dr; Phone Number: +90 505 202 1748; Email: goksel.dikmen@acibadem.com

Study Locations

• Thailand
  • Thailand, Thailand, 40002
    • Thonburi Trang Hastanesi
• Turkey
  • Istanbul, Turkey, 34098
    • İstanbul University Cerrahpaşa
    • Contact: Halil İbrahim Bulut, Medical Student; Phone Number: +90 506 185 4819; Email: halilibrahim.bulut@ogr.iuc.edu.tr
    • Contact: Halil İbrahim Bulut, Medical Student
  • Istanbul, Turkey, 34457
    • Acıbadem International Joint Center
    • Contact: Göksel Dikmen, Assoc. Prof.; Phone Number: +90 505 202 1748; Email: goksel.dikmen@acibadem.com
    • Contact: Vahit Emre Özden, Assoc. Prof.; Phone Number: +90 532 336 1464; Email: emre.ozden@acibadem.com
    • Contact: İbrahim Tuncay, Prof. Dr.
    • Contact: Javad Parvizi, Prof. Dr.
    • Contact: Göksel Dikmen, Assoc. Prof.
    • Contact: Vahit Emre Özden, Assoc. Prof.
    • Contact: Kayahan Karaytuğ, Assoc. Prof.
  • Istanbul, Turkey, 34752
    • Acibadem LABMED Laboratories
    • Contact: Mustafa Serteser, Prof. Dr.; Phone Number: +90 539 515 3115; Email: Mustafa.Serteser@acibadem.edu.tr
    • Contact: Mustafa Serteser, Prof. Dr.
  • Istanbul, Turkey, 34752
    • Acıbadem Mehmet Ali Aydınlar University
    • Contact: Arda Mavi, Intern Dr.; Phone Number: +90 537 852 6215; Email: ardamavimd@gmail.com
    • Contact: Arda Mavi, Intern Dr
• United States
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19107
      • Parvizi Surgical Innovation
      • Contact: Emanuele Chisari, Dr., Ph.D; Phone Number: +1 646 806 8067; Email: chisari.emanuele@gmail.com
      • Contact: Emanuele Chisari, Dr., Ph.D

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Adults aged between 18 and 65 years
• Scheduled for elective low-risk orthopedic surgery (carpal tunnel release, A1 pulley release, knee arthroscopic surgery).

Exclusion Criteria:

• History of infection or antibiotic use within the last 12 weeks.
• Use of routine probiotics, vitamins, or herbal supplements in the last 4 weeks.
• Known allergy to beta-lactam or cephalosporin antibiotics.
• History of autoimmune disease, uncontrolled systemic disease, or chronic inflammatory conditions (e.g., systemic lupus erythematosus, rheumatoid arthritis).
• History of chronic intestinal diseases such as small intestine bacterial overgrowth (SIBO), irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), or celiac disease.
• Increased risk of infection due to medical comorbidities or use of immunosuppressive drugs.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Routine Antibiotic Prophylaxis + Placebo; This arm receives routine antibiotic prophylaxis with a single dose of intravenous Cefazolin and a placebo capsule to match the probiotic intervention.	Drug: Placebo Capsule; Participants will receive an inert placebo capsule that matches the probiotic capsule in size, shape, and color. The placebo will be administered orally twice daily, starting 2 weeks before surgery and continuing for 2 weeks postoperatively.
Experimental: Routine Antibiotic Prophylaxis + Probiotics; This arm receives routine antibiotic prophylaxis with a single dose of intravenous Cefazolin and a dual-strain probiotic containing Human Milk Oligosaccharides (HMO).	Dietary supplement: Probiotic with Human Milk Oligosaccharides (HMO); Participants will receive a dual-strain probiotic containing Human Milk Oligosaccharides (HMO) in capsule form. The probiotic will be administered orally twice daily, starting 2 weeks before surgery and continuing for 2 weeks postoperatively.; Other Names: Dual-Strain Probiotic

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maintenance of Gut Microbiome Balance	Evaluate whether probiotic administration preserves gut microbiome balance during the perioperative period by assessing changes in microbial richness, diversity, and evenness. Shotgun metagenomic sequencing analysis will be used to measure microbial composition and diversity.	2 weeks preoperatively (T0) to 1 month postoperatively (T4).

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Firmicutes/Bacteroidetes Ratio	Determine changes in the Firmicutes/Bacteroidetes ratio, a key marker of dysbiosis, between intervention groups. Using shotgun metagenomic sequencing.	2 weeks preoperatively (T0) to 1 month postoperatively (T4).
Short-Chain Fatty Acid (SCFA) Production	Assess changes in SCFA production (e.g., acetate, butyrate) as indicators of gut health and microbiome function. Using SCFA quantification through microbiome metabolite analysis.	2 weeks preoperatively (T0) to 1 month postoperatively (T4).
Dysbiosis Index	Dysbiosis Index is the ratio of the total number of Proteobacteria strains divided by total overall bacteria strain	2 weeks preoperatively (T0) to 1 month postoperatively (T4).
Microbiome health index ( MHI) OR Microbiome health index for post-antiobiotic (MHI- A)	Microbiome Health Index (MHI-A) calculated via microbiome analysis. MHI-A is a biomarker and a quantitative measure method of post-antibiotic dysbiosis and subsequent restoration. Higher MHI-A means higher healthy microbiome with low antibiotic resistance gene. Lower MHI- A mean dysbiosis, high antiobiotic resistance gene	2 weeks preoperatively (T0) to 1 month postoperatively (T4).
WHO-5 Well-being Index	The WHO-5 Well-Being Index (The World Health Organization-Five Well-Being Index) is a self-report instrument measuring mental well-being. It consists of five statements relating to the past two weeks. Each statement is rated on a 6-point scale (0,1,2,3,4,5), with higher scores indicating better mental well-being. The raw score is calculated by totalling the scores on each of the five questions. Theraw score ranges from zero to 25, zero representing worst possible mental well-beingand 25 representing best possible mental well-being. To get a percentage score ranging from zero to 100, the raw score is multiplied by four. A percentage score of zero represents worst possible mental well-being; a score of 100 represents best possible mental well-being	1 week preoperatively (T1) and 2 weeks postoperatively (T3).
EuroQol 5-Dimension (EQ-5D) score.	EuroQol 5-Dimension (EQ-5D) score (EQ-5D) descriptive system comprises the same five dimensions (MOBILITY, SELF-CARE, USUAL ACTIVITIES, PAIN / DISCOMFORT and ANXIETY / DEPRESSION), beach dimension having five response levels:no problems, slight problems, moderateproblems, severe problems, unable to/extreme problems. The respondent is asked to indicate his/her health state by checking the box next to the most appropriate response level for each of the five dimensions. Responses are coded as single-digit numbers expressing the severity level selected in each dimension. For instance, 'slight problems' (e.g. 'I have slight problems in walking about') is always coded as '2'. The digits for the five dimensions can be combined in a 5-digit code that describes the respondent's health state; for instance, 21111 means slight problems in the mobility dimension and no problems in any of the other dimensions	1 week preoperatively (T1) and 2 weeks postoperatively (T3).

Collaborators and Investigators

• Sponsor: Acibadem Maslak Hospital
• Collaborators: Acibadem University
• Investigators: Study Chair: Javad Parvizi, Prof. Dr., International Joint Center Acibadem, Parvizi Surgical Innovation; Study Director: Emanuele Chisari, Dr., Ph.D., Parvizi Surgical Innovation, University of Groningen

Publications and helpful links

General Publications

• Kullar R, Chisari E, Snyder J, Cooper C, Parvizi J, Sniffen J. Next-Generation Sequencing Supports Targeted Antibiotic Treatment for Culture Negative Orthopedic Infections. Clin Infect Dis. 2023 Jan 13;76(2):359-364. doi: 10.1093/cid/ciac733.
• Anthony WE, Wang B, Sukhum KV, D'Souza AW, Hink T, Cass C, Seiler S, Reske KA, Coon C, Dubberke ER, Burnham CD, Dantas G, Kwon JH. Acute and persistent effects of commonly used antibiotics on the gut microbiome and resistome in healthy adults. Cell Rep. 2022 Apr 12;39(2):110649. doi: 10.1016/j.celrep.2022.110649.
• Rios JL, Bomhof MR, Reimer RA, Hart DA, Collins KH, Herzog W. Protective effect of prebiotic and exercise intervention on knee health in a rat model of diet-induced obesity. Sci Rep. 2019 Mar 7;9(1):3893. doi: 10.1038/s41598-019-40601-x.
• Akagawa Y, Kimata T, Akagawa S, Yamaguchi T, Kato S, Yamanouchi S, Hashiyada M, Akane A, Kino M, Tsuji S, Kaneko K. Impact of Long-Term Low Dose Antibiotic Prophylaxis on Gut Microbiota in Children. J Urol. 2020 Dec;204(6):1320-1325. doi: 10.1097/JU.0000000000001227. Epub 2020 Jul 2.
• Huang Z, Chen J, Li B, Zeng B, Chou CH, Zheng X, Xie J, Li H, Hao Y, Chen G, Pei F, Shen B, Kraus VB, Wei H, Zhou X, Cheng L. Faecal microbiota transplantation from metabolically compromised human donors accelerates osteoarthritis in mice. Ann Rheum Dis. 2020 May;79(5):646-656. doi: 10.1136/annrheumdis-2019-216471. Epub 2020 Mar 23.
• Coulson S, Butt H, Vecchio P, Gramotnev H, Vitetta L. Green-lipped mussel extract (Perna canaliculus) and glucosamine sulphate in patients with knee osteoarthritis: therapeutic efficacy and effects on gastrointestinal microbiota profiles. Inflammopharmacology. 2013 Feb;21(1):79-90. doi: 10.1007/s10787-012-0146-4. Epub 2012 Jul 22.
• Ramires LC, Santos GS, Ramires RP, da Fonseca LF, Jeyaraman M, Muthu S, Lana AV, Azzini G, Smith CS, Lana JF. The Association between Gut Microbiota and Osteoarthritis: Does the Disease Begin in the Gut? Int J Mol Sci. 2022 Jan 27;23(3):1494. doi: 10.3390/ijms23031494.
• Chisari E, Wouthuyzen-Bakker M, Friedrich AW, Parvizi J. The relation between the gut microbiome and osteoarthritis: A systematic review of literature. PLoS One. 2021 Dec 16;16(12):e0261353. doi: 10.1371/journal.pone.0261353. eCollection 2021.
• Favazzo LJ, Hendesi H, Villani DA, Soniwala S, Dar QA, Schott EM, Gill SR, Zuscik MJ. The gut microbiome-joint connection: implications in osteoarthritis. Curr Opin Rheumatol. 2020 Jan;32(1):92-101. doi: 10.1097/BOR.0000000000000681.
• Boer CG, Radjabzadeh D, Medina-Gomez C, Garmaeva S, Schiphof D, Arp P, Koet T, Kurilshikov A, Fu J, Ikram MA, Bierma-Zeinstra S, Uitterlinden AG, Kraaij R, Zhernakova A, van Meurs JBJ. Intestinal microbiome composition and its relation to joint pain and inflammation. Nat Commun. 2019 Oct 25;10(1):4881. doi: 10.1038/s41467-019-12873-4.

Helpful Links

• Related Info

Study record dates

Study Major Dates

• Study Start (Estimated): February 1, 2025
• Primary Completion (Estimated): August 1, 2025
• Study Completion (Estimated): October 1, 2025

Study Registration Dates

• First Submitted: December 23, 2024
• First Submitted That Met QC Criteria: January 18, 2025
• First Posted (Actual): March 25, 2025

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: January 18, 2025
• Last Verified: January 1, 2025

More Information

Terms related to this study

• Keywords: Probiotics; Surgical Site Infection; Gut Microbiome; Antibiotic Prophylaxis; Intestinal Dysbiosis; Human Milk Oligosaccharides (HMO); Shotgun Metagenomic Sequencing; Short-Chain Fatty Acids (SCFAs)
• Additional Relevant MeSH Terms: Pathologic Processes; Dysbiosis
• Other Study ID Numbers: 2024-KAEK-03

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Individual participant data that underlie the results reported in this article, after deidentification (text, tables, figures, and appendices).
• IPD Sharing Time Frame: Beginning 3 months and ending 5 years following article publication
• IPD Sharing Access Criteria: Data access will be granted to researchers who provide a methodologically sound proposal. Proposals should be directed to goksel.dikmen@acibadem.com To gain access, data requestors will need to sign a data access agreement.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP

Study Data/Documents

1. Individual Participant Data Set
   Information comments: https://drive.google.com/drive/folders/1C-CfBwEXCHEXl86ePRO4o4opAShsa9Op

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No