Gut Failure as a Potential Unmeasured Modifier of Micronutrient Response in Critical Illness: A Structured Narrative Review of Absorption, Metabolism, and Immune Function

Background: Micronutrient abnormalities are frequent in critically ill patients and are associated with organ dysfunction, infection, and adverse outcomes. Yet randomized controlled trials of supplementation have largely failed to demonstrate a consistent mortality or organ-failure benefit. One possible contributor to this translational gap is a systematically under-characterized variable: gut failure. In critical illness, the intestinal barrier is disrupted, epithelial cell mass is depleted, transporter expression is impaired, the intestinal microvasculature exhibits severe dysfunction, and the microbiome undergoes profound dysbiosis. These alterations may collectively impair the absorptive, metabolic, and immunological functions upon which micronutrient homeostasis depends. Purpose: This structured narrative review (SANRA-guided; 202 records) first outlines the epidemiology of micronutrient deficiencies in the ICU and defines gut failure as a biological entity distinct from ileus. It then traces the mechanistic pathways by which a dysfunctional gut disrupts key micronutrients and links this gut–micronutrient axis to immune dysregulation. Overview: We critically appraise landmark ICU supplementation trials and examine whether the absence of gastrointestinal phenotyping, reliance on circulating surrogates of bioavailability, and neglect of microbiome–nutrient interactions may have contributed to heterogeneous or negative findings. Finally, we propose a hypothesis-generating, gut-integrated framework for future studies, comprising gut integrity stratification, microbiome phenotyping, phase-adapted timing and route selection, and microbiome restoration, to realign micronutrient interventions with the biology of the gut–microbiome–immune axis. Direct evidence that gut dysfunction modifies the response to supplementation is lacking.