The cholecystectomy cascade hypothesis of bile acid signaling and metabolic flexibility

Persistent symptoms after cholecystectomy have multiple explanations, and the contribution of altered metabolic regulation remains uncertain. We present the Cholecystectomy Cascade in two parts. Part 1 separates published human and experimental findings from a specific, untested prediction: a smaller postprandial rise in respiratory exchange ratio after surgery in patients with new or worsened persistent fatigue, compared with their preoperative response and changes in postoperative patients without persistent fatigue. Human bile acid findings motivate this test, but metabolic and microbial results are heterogeneous, including improvement and null findings. A prospective study with preoperative measurements, nonsurgical gallstone comparators, standardized meal testing, and prespecified equivalence analyses could evaluate the prediction. Part 2 presents a broader, practice-derived extended hypothesis linking altered bile acid exposure, candidate receptor and microbial pathways, and changes in fuel switching to five clinical domains: fatigue, cognitive complaints, difficulty regulating weight, perceived hormonal disturbances, and mood changes. These domains have not been established as a postoperative syndrome, and the proposed connections are untested. PDH regulation is a conditional candidate mechanism, not a demonstrated cause of energy deprivation. Each symptom branch requires independent definition and testing; a positive fatigue result would not validate the full Cascade. Neither part establishes mitochondrial dysfunction or justifies treatment. The two-tier framework preserves the broader clinical question while distinguishing its evidentiary gaps from an operational first test.