Arthroplasty, Replacement, Hip, Gastrointestinal Microbiome, Hip Osteoarthritis, Postoperative Complications, Surgical Wound Infection
Conditions
Keywords
Therapeutic fasting, Buchinger fasting, Intermittent fasting, Gut microbiome, Immunophenotyping, Continuous glucose monitoring, Total hip arthroplasty, Metabolic syndrome, Preoperative optimization
Brief summary
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
OTHERBuchinger 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.
Sponsors
Charite University, Berlin, Germany
Schulthess Klinik
Buchinger Wilhelmi Clinic
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
NONE
Intervention model description
Two-arm parallel-group design with 1:1 randomization stratified by metabolic status (metabolically healthy vs. metabolically unhealthy according to harmonized metabolic-syndrome criteria). Within each stratum, patients are randomized 1:1 to the structured 20-day preoperative fasting intervention versus standard preoperative care.
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in plasma interleukin-8 (IL-8) concentration from baseline to Day +7 post-operatively | Baseline (Day -21, before start of intervention) and Day +7 post-operatively | IL-8 plasma concentration (pg/mL), measured by validated immunoassay |
| Change in gut microbial alpha-diversity (Shannon index) from baseline to Day +7 post-operatively | Baseline (Day -21, before start of intervention) and Day +7 post-operatively | Shannon diversity index from shotgun-metagenomic stool sequencing |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Perioperative kinetics of plasma cytokines (TNFα, IL-10, IL-6, IL-8) | Baseline (Day -21), Day -1 pre-op, and 6 h, 24 h, 72 h, and Day +7 post-operatively | Serial plasma concentrations of TNFα, IL-10, IL-6, and IL-8 measured by validated immunoassays. |
| Serum C-reactive protein (CRP) | Baseline (Day -21) and Day +7 post-operatively | Serum CRP concentration (mg/L). |
| T-cell subsets (CD3+, CD4+, CD8+) by flow cytometry | Baseline (Day -21) and Day +7 post-operatively | Absolute and relative frequencies of CD3+, CD4+, and CD8+ T cells in whole blood. |
| B-cell frequency (CD19+) | Baseline (Day -21) and Day +7 post-operatively | Frequency of CD19+ B cells. |
| NK-cell frequency (CD16+/CD56+) | Baseline (Day -21) and Day +7 post-operatively | Frequency of CD16+/CD56+ natural killer cells. |
| T-cell activation / exhaustion markers (CD28, CD57, HLA-DR, PD-1) | Baseline (Day -21) and Day +7 post-operatively | Frequencies of CD28-, CD57+, HLA-DR+, and PD-1+ T-cell subpopulations. |
| Monocyte HLA-DR expression (mHLA-DR) | Baseline (Day -21) and Day +7 post-operatively | Median fluorescence intensity of HLA-DR on circulating monocytes. |
| Neutrophil-to-lymphocyte ratio (NLR) | Baseline (Day -21) and Day +7 post-operatively | NLR derived from differential blood count. |
| Gut microbial beta-diversity | Baseline (Day -21) and Day +7 post-operatively | Bray-Curtis and weighted UniFrac dissimilarity between time points, analyzed with PERMANOVA. |
| Differential microbial abundance | Baseline (Day -21) and Day +7 post-operatively | Differential abundance of bacterial taxa at genus and species level between arms (ANCOM/DESeq2 with covariate adjustment). |
| Microbial functional gene profile | Baseline (Day -21) and Day +7 post-operatively | Functional gene profiling (HUMAnN) including CAZyme abundance and SCFA-related pathways. |
| Continuous glucose monitoring (CGM) metrics | Day -21 to day of surgery (continuous) | Mean interstitial glucose, glucose variability (SD, CV), time-in-range (70-180 mg/dL) derived from a continuous glucose monitor worn from Day -21 until surgery, compared between arms. |
| Daily self-monitored ketones (fasting arm) | Day -20 to day of surgery | Daily urinary or capillary ketone measurements during the 20-day fasting window. |
| Daily body weight | Day -20 to day of surgery, then Week 6, Month 3, Month 6 post-operatively | Daily self-measured body weight (kg) during the preoperative window, and at follow-up (Week 6, Month 3, Month 6). |
| Daily waist circumference | Day -20 to day of surgery | Daily self-measured waist circumference (cm) during the preoperative window. |
| Daily blood pressure | Day -20 to day of surgery | Daily self-measured systolic and diastolic blood pressure (mmHg) during the preoperative window. |
| Hip disability and Osteoarthritis Outcome Score (HOOS) | Baseline (Day -21), Week 6, Month 3, Month 6 post-operatively | Validated patient-reported hip-specific outcome score; change from baseline to each follow-up time point. HOOS subscale scores range from 0 to 100, with 0 indicating extreme hip symptoms/worst outcome and 100 indicating no hip symptoms/best outcome. Higher scores indicate a better outcome. |
| Patient-Reported Outcomes Measurement Information System 33-item Profile (PROMIS-33) | Baseline (Day -21), Week 6, Month 3, Month 6 post-operatively | Validated multi-domain patient-reported outcomes (PROMIS-33); change from baseline to each follow-up time point. ROMIS-33 is reported as domain-specific T-scores plus a pain intensity item. Domain T-score ranges are: Physical Function 22.5-57.0; Anxiety 40.3-81.6; Depression 41.0-79.4; Fatigue 33.7-75.8; Sleep Disturbance 32.0-73.3; Ability to Participate in Social Roles and Activities 27.5-64.2; Pain Interference 41.6-75.6; Cognitive Function 25.0-61.1. Pain Intensity ranges from 0 to 10. Higher scores indicate a better outcome for Physical Function, Ability to Participate in Social Roles and Activities, and Cognitive Function, and a worse outcome for Anxiety, Depression, Fatigue, Sleep Disturbance, Pain Interference, and Pain Intensity. |
| Dietary intake (DEGS1 food frequency questionnaire) | Baseline (Day -21) | Habitual dietary intake captured at baseline using the DEGS1 food-frequency questionnaire. |
| Patient-reported postoperative infection symptoms (study-specific questionnaire) | Weekly from Day +1 to Week 6 post-operatively | Study-specific questionnaire on infection-relevant signs and symptoms, completed weekly by the patient during the first 6 weeks post-operatively. |
| Postoperative infectious complications (EBJIS) | Day 0 to Day 90 after surgery | Incidence of periprosthetic joint infection per EBJIS criteria within 90 days post-operatively. |
| Wound healing disorders | Day 0 to Day 90 after surgery | Incidence of any wound healing disorder requiring intervention within 90 days post-operatively. |
| Reoperation rate | Day 0 to Day 90 after surgery | Incidence of reoperation related to the index joint within 90 days post-operatively. |
| Length of hospital stay (LOS) | From day of surgery to day of discharge (assessed up to 30 days) | Length of inpatient stay for the index admission, in days. |
| Metabolic complications | Day 0 to Day 30 after surgery | Incidence of postoperative metabolic complications (hyper-/hypoglycemia, electrolyte imbalance, sarcopenia risk markers). |
Countries
Germany
Contacts
CONTACTNele Wagener, Dr. med.
Outcome results
None listed