Preoperative Fasting and the Gut Microbiome Before Hip Replacement

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.

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