Impact of ICU dietary conditions on the susceptibility to hospital-acquired infections via host-microbiota and innate immune system-epithelial perturbations

Principle Investigator

Scientific interest within the context of the graduate college

Hospital-acquired infections remain one of the most pressing unresolved challenges in critical care, yet the role of nutritional support, ubiquitous in ICU management, in shaping host susceptibility through microbiota and mucosal immune perturbations has been systematically overlooked. This project offers a doctoral candidate the opportunity to investigate this clinically urgent and mechanistically underexplored question using state-of-the-art approaches spanning gnotobiotic mouse models, microbiome profiling, intestinal organoid culture, and transcriptional analyses of epithelial cells.

Project description

Hospital-acquired infections (HAI) are a major cause of death in intensive care units (ICUs). Mucosal barrier disturbances, immunosuppression and systemic lymphopenia have been identified as predisposing factors but the underlying molecular networks causing increased susceptibility to infections remain to be explored. In particular, the effect of exogenous factors, such as diet composition and formulation, on these biological processes in ICU settings has been understudied.

The microbiota has important effects on epithelial barrier function as well as on mucosal and systemic immunity which are collectively shaped by dietary input.^1,2 Conventional diets contain bioactive metabolites (such as ligands for the nutrient sensors AhR, RAR, RORγt and many more) that affect the differentiation and function of immune cells.^3,4 In particular, ILCs have been recently identified as a major checkpoint for immune-epithelial crosstalk and epithelial homeostasis.⁵ We recently demonstrated that an ILC-macrophage module is an important determinant for inflammatory output and epithelial integrity.⁶ We also showed that the microbiota controls steady-state type I IFN (IFN-I) levels required for metabolic fitness of myeloid cells and for effective antibacterial or antiviral immunity.^7,8 Critically ill patients in ICUs often receive broad spectrum antibiotics and enteral or parenteral nutritional support that has been associated with impaired host immune defenses and susceptibility to nosocomial infections.⁹ Recently, we showed that feeding mice with a chemically defined parenteral diet used in ICUs abolished the mucosal germinal center reaction and IgA response when compared to a conventional diet.¹⁰ The presence of bacteria-derived components in the diet, such as lipopolysaccharide (LPS), promoted germinal center activity and dendritic cell trafficking in dietary mucosal immune responses. The effects of LPS were only reproduced when it was presented within colloidal liposomes rather than in dispersed solution. Moreover, it has been shown that exclusive enteral nutrition reduced inflammatory bowel disease (IBD) in mice by increasing the abundance of E. rectale and as consequence the production of isobutyrate.¹¹ These results suggest that both the composition and the formulation of the diet affect the host immune system and potentially also the susceptibility to infections. We hypothesize that enteral diets used in ICU settings alter microbiota composition, epithelial barrier function, and innate immunity, increasing the risk of HAI.

Aim 1: How do feeding conditions mimicking ICU diets affect intestinal dysbiosis?(Ronchi) In animal models, we will analyze intestinal microbiota composition and function, and perform functional and transcriptional analyses of intestinal epithelial cells in animal models fed enteral diets and treated with broad-spectrum antibiotics. We will study the impact of mechanosensing triggered by the physical properties of solid vs. liquid food^12,13 intestinal motility, nutrient absorption, barrier integrity, and food passage. We will reverse these changes through dietary modifications, such as adding bacterial products (e.g., LPS) or metabolites (e.g., AhR, RAR, RORγt ligands).

Aim 2: How do ICU feeding conditions alter the intestinal innate immune system (i.e., myeloid and innate lymphoid cells, ILCs) and the epithelial barrier? (Diefenbach) We will analyze the phenotype of myeloid and innate lymphoid cells (ILCs) in intestinal and respiratory mucosa, as well as in lymphoid organs including gut/lung-draining lymph nodes, spleen, and bone marrow. An important focus will be previously identified immune-epithelial cell and neuro-immune modules informed by cytokines (e.g., IL-22, IFN-I, IFN-III, IL-17) or neuronal factors (e.g., VIP, NMU), respectively. We aim to rescue observed changes via the same dietary modifications as in Aim 1.

Aim 3: How do such alterations of the microbiota-epithelial-immune metasystem of the intestines affect susceptibility to HAI? (joint aim) We will test whether the experimental conditions and resulting microbiota-epithelial-immune changes (Aims 1-2) affect susceptibility to hospital-acquired K. pneumoniae infections. We will also examine whether diets with altered biophysical properties increase resistance to infection.

Complementary expertise of the PIs. Our labs will contribute expertise in innate immunity and epithelial cell biology (Diefenbach) and microbiome research (Ronchi). The successful candidate will focus on Aim 1, taking ownership of how ICU-mimicking dietary conditions reshape intestinal microbiota composition and epithelial barrier integrity, and will be a central contributor to the project’s integrative scientific narrative across all three aims. The position sits at the interface of microbiology, mucosal immunology, and clinical nutrition, embedded in a collaborative environment bridging two complementary laboratories with expertise in microbiome research (Ronchi) and innate immunity and epithelial biology (Diefenbach). We are looking for a medically trained candidate with genuine curiosity about the biology underlying clinical phenomena and the ambition to develop as an independent scientific thinker.

Application details

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