Gut Failure as a Potential Unmeasured Modifier of Micronutrient Response in Critical Illness: A Structured Narrative Review of Absorption, Metabolism, and Immune Function
4 affiliations
- 1Neuro Critical Care Unit, ASST Grande Ospedale Metropolitano Niguarda, 20162 Milan, Italy
- 2Department of Anesthesiology and Critical Care Medicine, Ospedale SS. Annunziata, 12038 Savigliano, Italy
- 3SC Anestesia, Rianimazione e Terapia del Dolore, ASST Nord Milano, Via Gorki 50, 20092 Cinisello Balsamo, Italy
- 4Pain Medicine and Intensive Care Unit, Department of Anesthesiology, Policlinico San Pietro, Ponte San Pietro, 24036 Bergamo, Italy
Abstract
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.
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BibTeX
@article{marelli2026failure,
title = {{Gut Failure as a Potential Unmeasured Modifier of Micronutrient Response in Critical Illness: A Structured Narrative Review of Absorption, Metabolism, and Immune Function}},
author = {Stefano Marelli and Alessandro Girombelli and Paolo Formenti and Francesco Vetrone},
journal = {Nutrients},
year = {2026},
month = oct,
doi = {10.3390/nu18213516},
url = {https://www.mdpi.com/2072-6643/18/21/3516},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Gut Failure as a Potential Unmeasured Modifier of Micronutrient Response in Critical Illness: A Structured Narrative Review of Absorption, Metabolism, and Immune Function
AU - Stefano Marelli
AU - Alessandro Girombelli
AU - Paolo Formenti
AU - Francesco Vetrone
PY - 2026
DA - 2026/10/26
JO - Nutrients
DO - 10.3390/nu18213516
UR - https://www.mdpi.com/2072-6643/18/21/3516
AB - 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.
SN - 2072-6643
ER -