Preoperative Fasting and the Gut Microbiome Before Hip Replacement

Official title

Preoperative Metabolic Optimization: Influence of Intermittent and Buchinger-Type Fasting on the Gut Microbiome, Immune Profile, and Postoperative Complications in Patients Undergoing Primary Total Hip Arthroplasty - A Randomized Controlled Trial

Overview

Postoperative complications occur in 5-15% of patients undergoing elective primary total hip arthroplasty (THA), including periprosthetic joint infection (PJI), thrombosis, wound healing disorders, and metabolic dysregulation. The gut microbiome and the systemic immune profile have both been implicated as modifiable contributors to perioperative complication risk. Preoperative therapeutic fasting has been shown to remodel the gut microbiome, lower proinflammatory cytokines, and improve metabolic parameters. This single-center, prospective, randomized, two-arm controlled trial at Charité - Universitätsmedizin Berlin investigates whether a structured 20-day preoperative fasting intervention (alternating cycles of the Buchinger Fastenbox and intermittent fasting) modulates two co-primary endpoints - plasma IL-8 (a central proinflammatory marker) and gut microbial alpha-diversity (Shannon index) - compared with standard preoperative care. Secondary endpoints include further immune markers (TNFα, IL-10, T-/B-/NK-cell subsets, activation/exhaustion markers, monocyte HLA-DR), microbiome composition and function, continuous glucose-monitoring and daily metabolic measures, patient-reported outcomes (HOOS, PROMIS-33, infection self-report), and clinical outcomes (postoperative complications per EBJIS criteria, length of stay). Adults aged 18-75 undergoing elective primary THA are stratified by metabolic status (metabolically healthy vs. metabolically unhealthy according to harmonized metabolic-syndrome criteria) and randomized 1:1 to the fasting intervention versus standard care. Stool and whole-blood samples are collected at baseline (Day -21), and at Day +7 post-operatively for shotgun-metagenomic sequencing and multiparameter flow cytometry, with additional cytokine blood samples at Day -1 and 6 h / 24 h / 72 h post-operatively. Continuous glucose monitoring is performed in all participants from Day -21 until surgery. Planned enrollment is 130 participants.

Detailed description

Background. Periprosthetic joint infection (PJI) and other postoperative complications after THA carry substantial clinical and economic costs. Recent evidence links the gut microbiome and systemic immune homeostasis to perioperative complication risk, and preoperative caloric restriction has been shown to lower proinflammatory cytokines and shift gut microbial composition toward a less inflammatory profile.

Hypotheses. Primary: A structured 20-day preoperative fasting intervention reduces plasma IL-8 and increases gut microbial alpha-diversity (Shannon index) at Day +7 post-operatively compared with standard preoperative care.

Secondary (exploratory): Fasting modulates broader immune (TNFα, IL-10, immune-cell subsets, activation/exhaustion markers, HLA-DR) and microbiome (taxonomic, functional) parameters, improves metabolic indicators captured by continuous glucose monitoring and daily measures, and reduces postoperative complications, patient-reported infection symptoms, and length of stay.

Design. Single-center, prospective, two-arm, parallel-group, randomized, open-label controlled trial. Randomization is stratified by metabolic status (metabolically healthy vs. metabolically unhealthy per harmonized metabolic-syndrome criteria, Alberti et al. 2009). Planned enrollment: n = 130 (65 per arm; balanced across metabolic strata).

Intervention (Fasting arm). Structured 20-day preoperative fasting schedule self-administered at home with study-team supervision:

* Day -20 to Day -16 (5 days): Buchinger Fastenbox - ready-to-use organic vegetable broths, low carbohydrate, designed to facilitate ketogenic metabolic switch. * Day -15 to Day -11 (5 days): Intermittent fasting (time-restricted feeding). * Day -10 to Day -6 (5 days): Buchinger Fastenbox (second cycle). * Day -5 to Day -1 (5 days): Intermittent fasting (second cycle). No fasting is performed post-operatively.

Control arm. Standard preoperative care per institutional protocol; no fasting and no probiotic, prebiotic, or symbiotic supplementation as part of the study.

Specimen collection and assessments.

* Day -21 (baseline / T0): stool + whole-blood sampling for shotgun-metagenomic sequencing, FACS immunophenotyping, and cytokine panel. Start of continuous glucose monitoring (CGM, all participants). Baseline questionnaires: DEGS1 food frequency questionnaire, HOOS, PROMIS-33, and a study-specific infection-baseline questionnaire. * Day -20 onward (fasting arm only): daily self-monitored urinary or capillary ketones. * Day -20 to surgery (all participants): daily body weight, waist circumference, blood pressure. * Day -1 (immediately pre-op): blood sample for cytokine panel. * 6 h, 24 h, and 72 h post-operatively: blood samples for cytokine panel. * Day +7 post-operatively: stool + whole-blood sampling for shotgun metagenomics, FACS immunophenotyping, and cytokine panel (primary endpoint readout). * Weekly to Week 6 post-operatively: study-specific patient-reported infection questionnaire. * Week 6, Month 3, Month 6 post-operatively: HOOS, PROMIS-33, body weight.

Analyses. Stool: shotgun metagenomic sequencing (Illumina NovaSeq 6000) with bioinformatic processing (Trimmomatic, DIAMOND, QIIME, Centrifuge, MetaPhlAn/HUMAnN, LEfSe). Blood: multiparameter flow cytometry (CD3, CD4, CD8, CD16/56, CD19, plus CD28, CD57, HLA-DR, PD-1) and standard inflammatory chemistry (CRP, IL-6, IL-8, IL-10, TNFα).

Statistics. Two co-primary endpoints (IL-8, alpha-diversity) tested with a fixed-sequence (gatekeeping) procedure: IL-8 first at α=0.05 two-sided; if significant, alpha-diversity is then tested at α=0.05. Linear mixed models or generalized estimating equations are used to model time × group interactions for repeated measures. Microbiome differential abundance: ANCOM/DESeq2 with covariate adjustment (BMI, age, sex). Multiple testing controlled with FDR. Clinical secondary endpoints are analyzed descriptively.

Interventions

• Other Buchinger Fastenbox + intermittent fasting (20-day preoperative schedule)
  Two 5-day cycles of the Buchinger Wilhelmi Fastenbox (hypocaloric, low-carbohydrate, plant-based vegetable broths) alternating with two 5-day cycles of intermittent fasting (time-restricted feeding), totaling 20 days immediately preceding surgery. Self-administered at home; participants receive structured instructions, daily symptom and metabolic logs, and contact options with the study team for the duration of each cycle.

Primary outcome measures

• Change in plasma interleukin-8 (IL-8) concentration from baseline to Day +7 post-operatively [Time frame: Baseline (Day -21, before start of intervention) and Day +7 post-operatively]
• Change in gut microbial alpha-diversity (Shannon index) from baseline to Day +7 post-operatively [Time frame: Baseline (Day -21, before start of intervention) and Day +7 post-operatively]

Secondary outcome measures (12)

• Perioperative kinetics of plasma cytokines (TNFα, IL-10, IL-6, IL-8) [Time frame: Baseline (Day -21), Day -1 pre-op, and 6 h, 24 h, 72 h, and Day +7 post-operatively]
• Serum C-reactive protein (CRP) [Time frame: Baseline (Day -21) and Day +7 post-operatively]
• T-cell subsets (CD3+, CD4+, CD8+) by flow cytometry [Time frame: Baseline (Day -21) and Day +7 post-operatively]
• B-cell frequency (CD19+) [Time frame: Baseline (Day -21) and Day +7 post-operatively]
• NK-cell frequency (CD16+/CD56+) [Time frame: Baseline (Day -21) and Day +7 post-operatively]
• T-cell activation / exhaustion markers (CD28, CD57, HLA-DR, PD-1) [Time frame: Baseline (Day -21) and Day +7 post-operatively]
• Monocyte HLA-DR expression (mHLA-DR) [Time frame: Baseline (Day -21) and Day +7 post-operatively]
• Neutrophil-to-lymphocyte ratio (NLR) [Time frame: Baseline (Day -21) and Day +7 post-operatively]
• Gut microbial beta-diversity [Time frame: Baseline (Day -21) and Day +7 post-operatively]
• Differential microbial abundance [Time frame: Baseline (Day -21) and Day +7 post-operatively]
• Microbial functional gene profile [Time frame: Baseline (Day -21) and Day +7 post-operatively]
• Continuous glucose monitoring (CGM) metrics [Time frame: Day -21 to day of surgery (continuous)]

Eligibility criteria

Inclusion criteria

• Adults aged 18-75 years (inclusive)
• Scheduled for elective primary total hip arthroplasty (THA)
• Able and willing to provide written informed consent
• Able to follow the 20-day preoperative fasting protocol independently at home (if randomized to the fasting arm) or willing to be randomized to either arm

Exclusion criteria

• Resorption disorder due to bowel disease (e.g. inflammatory bowel disease, short-bowel syndrome, active celiac disease)
• Antibiotic therapy within the last 2 months before baseline (T0)
• Probiotic, prebiotic, or symbiotic supplementation within the last 2 months before baseline (T0)
• Inability or unwillingness to provide informed consent
• Severe comorbidity precluding fasting (e.g. ASA ≥ IV, advanced renal/hepatic impairment, eating disorder)
• BMI < 18.5 kg/m² (underweight)
• Concurrent participation in another interventional drug or device trial
• Pregnancy or breastfeeding

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Prevention

Study locations

Germany · 1 center

• Centrum für Muskuloskeletale Chirurgie (CMSC), Charité - Universitätsmedizin Berlin — Berlin

Publications

• Cella D, Riley W, Stone A, Rothrock N, Reeve B, Yount S, Amtmann D, Bode R, Buysse D, Choi S, Cook K, Devellis R, DeWalt D, Fries JF, Gershon R, Hahn EA, Lai JS, Pilkonis P, Revicki D, Rose M, Weinfurt K, Hays R; PROMIS Cooperative Group. The Patient-Reported Outcomes Measurement Information System (PROMIS) developed and tested its first wave of adult self-reported health outcome item banks: 2005- PMID 20685078
• Nilsdotter AK, Lohmander LS, Klassbo M, Roos EM. Hip disability and osteoarthritis outcome score (HOOS)--validity and responsiveness in total hip replacement. BMC Musculoskelet Disord. 2003 May 30;4:10. doi: 10.1186/1471-2474-4-10. Epub 2003 May 30. PMID 12777182
• Delconte RB, Owyong M, Santosa EK, Srpan K, Sheppard S, McGuire TJ, Abbasi A, Diaz-Salazar C, Chun J, Rogatsky I, Hsu KC, Jordan S, Merad M, Sun JC. Fasting reshapes tissue-specific niches to improve NK cell-mediated anti-tumor immunity. Immunity. 2024 Aug 13;57(8):1923-1938.e7. doi: 10.1016/j.immuni.2024.05.021. Epub 2024 Jun 14. PMID 38878769
• Kong L, Cao J, Zhang Y, Ding W, Shen Y. Risk factors for periprosthetic joint infection following primary total hip or knee arthroplasty: a meta-analysis. Int Wound J. 2017 Jun;14(3):529-536. doi: 10.1111/iwj.12640. Epub 2016 Jul 10. PMID 27397553
• Alberti KG, Eckel RH, Grundy SM, Zimmet PZ, Cleeman JI, Donato KA, Fruchart JC, James WP, Loria CM, Smith SC Jr; International Diabetes Federation Task Force on Epidemiology and Prevention; Hational Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; International Association for the Study of Obesity. Harmonizing the metaboli PMID 19805654
• Casals-Pascual C, Gonzalez A, Vazquez-Baeza Y, Song SJ, Jiang L, Knight R. Microbial Diversity in Clinical Microbiome Studies: Sample Size and Statistical Power Considerations. Gastroenterology. 2020 May;158(6):1524-1528. doi: 10.1053/j.gastro.2019.11.305. Epub 2020 Jan 10. No abstract available. PMID 31930986
• Valtetsiotis K, Di Martino A, Brunello M, Tassinari L, D'Agostino C, Traina F, Faldini C. The Potential Role of Gut Bacteriome Dysbiosis as a Leading Cause of Periprosthetic Infection: A Comprehensive Literature Review. Microorganisms. 2023 Jul 9;11(7):1778. doi: 10.3390/microorganisms11071778. PMID 37512950
• Salimi M, Karam JA, Willman M, Willman J, Lucke-Wold B, Khanzadeh S, Mirghaderi P, Parvizi J. Neutrophil to Lymphocyte Ratio and Periprosthetic Joint Infection: A Systematic Review and Meta-Analysis. J Arthroplasty. 2024 Mar;39(3):831-838. doi: 10.1016/j.arth.2023.08.067. Epub 2023 Aug 24. PMID 37633509

Identifiers

NCT: NCT07651462 · EA1/279/24

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗