Improving the Outcome of Brain-Injured Patients by Non-Continuous Feeding to Prevent Dysbiosis?

1. Introduction

Acute brain injury is common and severe in critical care. It may be primary, as in traumatic brain injury (TBI), aneurysmal subarachnoid hemorrhage, intracerebral hemorrhage and ischemic stroke, or secondary, as in sepsis-associated encephalopathy (SAE) and intensive care unit (ICU) delirium [1]. These patients often need prolonged mechanical ventilation and long ICU and hospital stays, and many are left with cognitive, functional or psychiatric impairment that lasts well beyond discharge [2]. Beyond acute survival, many of these patients develop the post-intensive care syndrome (PICS): new or worsening impairments in physical, cognitive or mental health that persist after critical illness and beyond hospital discharge [3]. These long-term sequelae lower survivors' quality of life and raise health-care costs through prolonged rehabilitation and repeated hospital readmission [4,5]. Brain-injured survivors are among the most affected, so systemic factors that can be modified to limit neuroinflammation and aid recovery are worth targeting. Their course is frequently complicated by secondary insults such as systemic inflammation, nosocomial infection, dysglycemia and organ dysfunction, which aggravate the primary lesion and worsen the outcome [6]. The presence of neuroinflammation has been linked to adverse neurological outcomes, including the development of delirium [7] and SAE, as well as secondary injury following major trauma [8,9]. This connection is thought to be partly mediated by the microbiota-gut-brain axis, a network of immune, neural, endocrine, and metabolic pathways through which intestinal disturbances directly influence central nervous system (CNS) function. Feeding and nutrition significantly influence these pathways, as nutrients, microbial metabolites, and gut-derived immune signals interact with systemic and neural circuits that regulate inflammation and neuro-immune responses [10]. Critical illness itself is a primary driver of CNS dysfunction as it induces gut dysbiosis, a condition in which beneficial commensals are lost, and opportunistic pathogens proliferate. This affects the intestinal barrier function, the production of local metabolites, and triggers systemic inflammation, immune dysregulation, and metabolic dysfunction, affecting distant organs, including the brain [11]. The gut microbiome (GM) and its associated genes configure the gut as both a biomarker and a mediator of pathophysiology in the ICU, leading to immune dysregulation, metabolic disruption, and secondary organ dysfunction [12].

Once injury is established few treatments change its course, so attention has turned to systemic factors that can be modified and that shape neuroinflammation and recovery; nutrition and the GM are two candidate modifiable factors, whose therapeutic potential still requires confirmation in dedicated clinical investigations [13].

2. Dysbiosis

As soon as the patient is admitted into the ICU, the GM undergoes a profound and rapid disruption of its “steady state” i.e. eubiosis, shifting from a microbiota to a “pathobiota”, the so called dysbiosis, which can happen in as little as 6 hours and is increasingly recognized as a key factor in the progression of organ failure and poor outcomes [11].

Specific alterations in the GM have been described as a reduced microbial richness and diversity, marked by increased opportunistic and nosocomial pathogens, such as Enterococcus and Klebsiella, and a depletion of beneficial commensal bacteria, including Lachnospiraceae and Ruminococcaceae [14]. This microbial rearrangement is driven by various agents that typically occur in the ICU, including broad-spectrum antibiotics, especially those that do not spare anaerobic populations, proton pump inhibitors, and different approaches to enteral nutrition (EN) itself [11].

The impairment of this microbial “symphony” [15] probably has significant consequences that extend beyond the gut. Dysbiosis also impairs several metabolic pathways, including primary bile acid synthesis, which in turn exacerbates intestinal barrier dysfunction [16]. Ultimately, the breakdown of the gut barrier worsens the critical illness and sets the premises for a multi-organ dysfunction syndrome (MODS) to take place and develop abruptly [17]. Clinically, this breakdown translates into common ICU complications. For instance, enteral nutrition-related diarrhea (END) is strongly associated with severe dysbiosis, marked by significantly lower bacterial diversity and the overgrowth of specific pathogens [14]. On the contrary, the ability to tolerate enteral feeding appears to be linked to distinct microbiota profiles and SCFA levels early in the course of nutrition therapy [18], which paves the way for research into microbial markers that could predict intolerance [19].

3. Neuroinflammation

In critically ill and brain-injured patients, neuroinflammation usually appears as acute brain dysfunction, from mild delirium to sepsis-associated encephalopathy (SAE), and it adds to the cognitive impairment that many survivors carry for months after discharge [20]. The more severe and prolonged this dysfunction is, the longer patients stay in the ICU and the higher their mortality [21]. There is still no specific diagnostic test, but blood and cerebrospinal markers of glial and neuronal injury such as glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL) and S100B, together with pro-inflammatory cytokines, rise as the encephalopathy worsens and predict a poorer neurological outcome [22,23]. These clinical changes reflect the activation of the resident immune cells of the central nervous system, mainly microglia.

Microglial cells in their homeostatic state act as sentinels, eliminating superfluous synapses and supporting neuronal survival. When activated, they polarize into a pro-inflammatory M1 phenotype, releasing cytokines, reactive oxygen species (ROS), and nitric oxide (NO) that drive neuroinflammation, or into an anti-inflammatory M2 phenotype, promoting repair and neuroprotection through interleukin-10 (IL-10), transforming growth factor-beta (TGF-β), and trophic factors. Beyond this M1/M2 dichotomy, disease-, age-, and context-specific phenotypes have emerged, reflecting neuroplasticity [24].

4. Potential Links Between Dysbiosis and Neuroinflammation

The gut-brain axis is a bidirectional communication system that comprises the gut, the central nervous system (CNS), the sympathetic and parasympathetic nervous systems, and the hypothalamic-pituitary-adrenal (HPA) axis [25].

Through this axis, the GM connects to neuroinflammation by immune, metabolic, endocrine and neural routes.

The link between GM composition and neurological outcomes in critical illness have been reported predominantly in cohorts with primary brain injury and in patients with sepsis, rather than in undifferentiated ICU populations. Observational clinical studies of acute neurological injury (TBI, intracerebral hemorrhage and stroke) and of neurologic ICU populations show disease-specific gut signatures (for example, enrichment of Enterobacteriaceae in some TBI cohorts and altered GM composition after intracerebral hemorrhage) and link dysbiosis to worse neuro-inflammation or delayed recovery in exploratory studies [26,27,28]. However, antibiotic exposure, which is highly prevalent in these cohorts and a dominant driver of dysbiosis, is variably reported (class, timing, and cumulative days are often missing or inconsistent), limiting causal inference in human datasets [29]. Translational and animal models point to a causal role for the GM in post-injury neuroinflammation and recovery: antibiotic-induced dysbiosis before or after experimental TBI altered lesion size, microglial activation, and behavioral outcomes, indicating that perturbations of the GM can both worsen and (in some protocols) improve neuroinflammatory injury, depending on timing and method of manipulation [30,31].

4.1. Microbiota–Gut–Brain Signalling Routes

Schematically, the role of dysbiosis in the modulation of neuroinflammation via the gut-brain axis can be exerted via several mechanisms:

SCFA: During critical illness, the production of SCFA by GM is decreased as reflected by low fecal concentrations. SCFA (butyrate, acetate, propionate) produced by saccharolytic commensals from dietary fibres influence neuroimmune processes, ranging from the regulation of microglia to the maintenance of the blood-brain barrier (BBB) integrity and neuroimmune homeostasis [32]. SCFA are involved in the regulation of intestinal motility, immunity, and energy balance, and have receptors in various systems throughout the body, including the central and peripheral nervous systems [18,33,34]. Hence, SCFA can be considered as central mediators linking feeding patterns to brain immune status via energy metabolism, mucus production, tight-junction integrity, and reprogramming the immune system [35], which in turn affects the dynamic spectrum of microglial phenotypes and neurotrophic signaling. More specifically, SCFAs such as butyrate target different host cells by binding to G-protein-coupled receptors (e.g., FFAR2/FFAR3), inhibiting histone deacetylases with related epigenetic effects, interacting with monocarboxylate transporters, which in turn suppress nuclear factor kappa B (NF-κB)and inflammasome signaling in endothelial and myeloid cells, and finally stabilizing BBB function [36] and the production of central cytokines [37].

SCFA supplementation in an experimental model has been shown to improve cognitive outcomes, including spatial learning, following injury [34]. This suggests a potential path from gut dysbiosis to brain dysfunction in sepsis and other ICU syndromes.

Inflammasome activation: dysbiosis-derived danger signals activate the NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome and promote IL-1β and IL-18 release, contributing to neuroinflammation and pyroptosis. GM-derived indole-3-propionic acid can inhibit this pathway, linking microbial composition to neuroimmune modulation [38,39]. More specifically this pathway has been associated with multiple sclerosis, Alzheimer’s disease, Parkinson’s disease, neuropsychiatric diseases, and sepsis [11].

Bile acids and FXR/TGR5 signalling: gut bacteria convert primary bile acids into secondary bile acids that act on the farnesoid X receptor (FXR) and Takeda G-protein receptor 5 (TGR5) and help regulate systemic and central immune responses; when dysbiosis depletes these bacteria the signal is lost, which can worsen neuroinflammation [40].

Tryptophan–indole–kynurenine metabolism: bacterial indoles and kynurenine-pathway metabolites bind the aryl hydrocarbon receptor and influence how reactive microglia become and whether the mediators they produce protect or harm neurons [40].

Vagal (cholinergic) anti-inflammatory reflex: microbial signals act on vagal afferents and the cholinergic anti-inflammatory pathway, a direct neural route through which the gut can dampen or amplify brain inflammation [40].

Gut barrier integrity and endotoxin translocation: increased intestinal permeability allows the translocation of endotoxins such as lipopolysaccharide (LPS), which then enter the systemic circulation and reach the brain, where they activate microglia and the cerebral endothelium mainly through Toll-like receptor 4 (TLR4); in this way gut-derived LPS becomes a direct trigger of blood–brain barrier breakdown and central inflammation [41].

HPA axis and systemic stress response: GM-derived signals also modulate the hypothalamic–pituitary–adrenal (HPA) axis and systemic stress responses, contributing to neuroimmune homeostasis [24,42].

Through these mechanisms, the GM shapes the core features of neuroinflammation: it regulates microglial activation, driving microglia towards a pro- or an anti-inflammatory phenotype, and it changes cerebral gene expression in key regions such as the hippocampus and prefrontal cortex.

The downstream consequences of ICU-associated dysbiosis on gut barrier integrity, systemic inflammation, and the gut-brain axis are illustrated in Figure 1.

4.2. Feeding–Fasting Cycles: Mechanistic Links

The timing of feeding and the composition of nutrients regulate a complex network connecting the GM metabolites, immune system, and neural pathways between the gut and the brain. These factors impact microbial metabolism (including the synthesis of SCFAs, indoles, bile acids, and ketones), gut barrier integrity, systemic inflammation, and neurological function.

Ultimately, it appears that feeding fasting cycles are one of the key factors that can significantly influence SCFAs production, as the timing and composition of the feeding are crucial [16]. This is because it feeds the GM the substrates for fermentation and regulates diurnal microbial activity. In fact, a daytime feeding cycle or intermittent feeding cycle preserves the fermentation rhythm and SCFAs production. On the contrary, a continuous feeding cycle or a total lack of fermentable substrates halts this production and disrupts the beneficial flow of mediators to the host [16,43]. The shift is even more evident, as a brief 12-hour nutrient interruption [44] triggers an immediate immunometabolic fasting signal: the body increases ketones and bilirubin, while lowering insulin and IGF-1; the combined effect results in an enhanced cellular repair program. Harnessing this balance between preserving SCFA production and safely controlling fasting harmful mediators could therefore reduce systemic and CNS inflammation [45].

Brief macronutrient interruption triggers ketogenesis within hours; the resulting rise in β-hydroxybutyrate (BHB) acts as a metabolic switch that simultaneously blunts early catabolism and activates cellular repair programs [46,47], and as a signalling metabolite it also inhibits NLRP3 inflammasome activation, improves redox balance and helps protect neurons and glia. This is in contrast to what would happen with continuous nutrition, which sustains insulin and IGF-1 signalling, suppressing ketone utilization and potentially delaying adaptive stress responses [48]. However, its implementation in standard ICU practice requires careful evaluation of risks (such as underfeeding, glycemic variability, and tolerance) against potential benefits of autophagy and immunometabolic reprogramming [44].

This feeding-fasting cycle has a “double-edged sword” effect on the gut-brain axis and neuroinflammation. Short-term, regulated fasting can increase microbial diversity, promote autophagy, and reduce systemic inflammation [49]. During fasting, the scarcity of nutrients favors bacteria that use substrates directly from the host, such as mucin and epithelial glycans, resulting in a thinning of the mucus layer, diminished barrier function, and reduced colonization resistance [50]. As soon as feeding is reestablished, this abrupt influx of new substrate can facilitate the proliferation of opportunistic proteobacteria and enterobacteria, with the release of LPS and other pro-inflammatory mediators. These mediators can translocate into the systemic circulation, triggering the immune system, even within the nervous system, as microglial activity is upregulated and cytokine release in the brain is increased [51]. Consequently, although moderate fasting may temporarily enhance neuroimmune equilibrium, excessive or prolonged fasting, particularly in metabolically vulnerable or critically ill patients, may disrupt the gut ecosystem and exacerbate neuroinflammatory processes due to this rebound “risk”.

The dual nature of these interactions -- beneficial when feeding is moderate and timed, harmful when fasting is excessive -- is illustrated in Figure 2, and the full set of mechanistic pathways is summarized in Table 1.

5. Ways to Interfere with the Gut–Brain Axis

From the pathways described above, the concept “microbiota-sparing feeding” could characterize feeding patterns and substrates that preserve saccharolytic commensals and their SCFA output. SCFAs come from the fermentation of dietary fibres and are the main fuel for colonocytes; they also influence microglial tone and the production of neuroactive metabolites and neurotransmitters such as serotonin and GABA-related mediators that signal to the brain [25,55].

5.1. Changing the diet: Fibre And Ketogenic Strategies

Diet composition, even before feeding timing, can shape the GM and its metabolic output. Fermentable fibres and prebiotic substrates give saccharolytic commensals more substrate and raise luminal SCFA production, which supports colonocyte metabolism, the mucosal barrier and a more regulatory immune tone [8,55]. However, fibre enrichment is not uniformly beneficial in the critically ill: a recent pilot randomised trial in critically ill trauma patients found that enteral supplementation with fermentable fibre (short-chain fructo-oligosaccharides) accelerated the loss of beneficial Bifidobacterium and Firmicutes and favoured the expansion of pathogenic Enterobacteriaceae, with the microbial response shifting from beneficial to detrimental according to prior exposure to anaerobic antibiotics, underscoring that composition-based interventions are context-dependent [56]. Ketogenic diets work differently: they shift energy provision toward fat and sustain ketogenesis, reproducing some anti-inflammatory effects of fasting, including β-hydroxybutyrate-mediated inhibition of the NLRP3 inflammasome [48,57]. Both act through nutrient composition rather than timing, and are covered only briefly here because this review focuses on the temporal pattern of feeding (Section 5.2).

5.2. Non-Continuous, Time-Patterned Enteral Feeding

In the ICU, “fasting” is not a single intervention but a spectrum of intentional feeding modifications, from standard 24-hour continuous EN to scheduled intermittent feeding pathways, to a complete halt of all nutrition support for a defined period; each carries distinct metabolic and microbiological implications, and operational definitions are summarized in Table 2. The default gold standard has been, and remains, continuous feeding, where a 24-hour infusion is maintained via a pump with no fasting interval [53]. The logic is simple, as it keeps the fuel coming.

Important boundaries and limitations that define the scope include exclusion criteria used in randomized controlled trials (RCTs) (e.g., those studies not including total parenteral nutrition, recent GI surgery, or severe motility disorders), variation in fasting duration and position, some intermittent regimens having greater glycemic variability, and existing trials being underpowered for patient-centered outcomes [58].

Continuous EN is frequently interrupted in routine ICU care for procedures, airway management, medication administration, and gastrointestinal events, resulting in measurable caloric deficits (median three interruption episodes per patient; median interruption 5.5 h; interruptions accounted for ≈19% of designated EN time) [59]. Meal timing is a significant non-photic zeitgeber (a time cue that sets the body’s internal clock through eating patterns rather than light) for peripheral circadian clocks and directly influences metabolism and inflammation. Continuous 24-hour enteral feeding in the ICU disrupts the body’s natural daytime-feeding/nighttime-fasting rhythm [60,61]. By contrast, intermittent or daytime-restricted feeding better mimics normal eating patterns and may preserve circadian alignment, hormonal rhythms, and metabolic functions that support recovery [62].

In addition to circadian effects, intermittent feeding activates fasting-type metabolic pathways -- ketogenesis, reduced insulin/insulin-like growth factor-1 (IGF-1), and autophagy induction -- that can reshape the gut ecosystem and its metabolome [16,44]. Importantly, during short nutrient interruptions, the brain can rapidly use ketone bodies and lactate as alternative substrates to glucose, underscoring the importance of cerebral substrate safety when designing fasting schedules [63].

5.3. Other Approaches to Microbiota Modulation

Beyond the timing of nutrient delivery, several other strategies can modulate the GM in critically ill and brain-injured patients. Probiotics and synbiotics aim to reintroduce beneficial commensals and have been associated with fewer episodes of ventilator-associated pneumonia and infection in a recent meta-analysis, although individual trials vary [71]. Prebiotic fibers and postbiotics, especially SCFAs, aim to restore microbial metabolites directly rather than the bacteria that make them [55]. Fecal microbiota transplantation works in refractory Clostridioides difficile infection and is being tested in ICU dysbiosis, but concerns about safety and standardization still limit its routine use [72]. Antibiotic stewardship and avoiding unnecessary microbiota-disrupting drugs are simpler, lower-risk measures [73]. All of these act on microbiota composition and complement feeding-pattern interventions rather than replace them; feeding pattern is the focus of this review.

6. Knowledge Gaps and Unanswered Questions

While these gut-brain interactions operate across all critically ill patients, their neurological consequences are most directly measurable and clinically significant in patients with primary or secondary brain injury. Nonetheless, evidence on how feeding timing affects the GM and host metabolic pathways derives predominantly from general ICU populations on mechanical ventilation, because trials enriched for neurological phenotypes do not yet exist. The following mechanistic and clinical evidence should therefore be read as the biological foundation upon which a dedicated, neurologically focused trial can be built.

Several questions remain unresolved. It is unclear whether the GM changes seen after brain injury cause neuroinflammation or merely follow it, and how much they reflect confounders such as antibiotic exposure [29], sedation and impaired gut motility rather than the injury itself [74]. The best mode, timing and duration of feeding to protect the microbiota in these patients are undefined, and no randomized trial has yet used microbiota-related or neurological endpoints as primary outcomes in brain-injured patients. Whether changing feeding pattern actually improves outcomes such as infection, delirium or neurological recovery is still unknown.

6.1. Aim of this Review

This review brings together two strands of evidence that are usually kept apart: how the timing and pattern of EN affect the GM and host metabolism, studied almost entirely in general, mechanically ventilated ICU patients; and how the microbiota shapes neuroinflammation and recovery, studied mainly in observational and preclinical models of brain injury. No trial has yet tested feeding timing against microbiota or neurological endpoints in brain-injured patients, and closing that gap is the central aim. The general-ICU feeding evidence is therefore used as the biological foundation, read through the lens of the gut-brain axis, to build a prioritized research agenda for the neurologically relevant ICU phenotypes in which a measurable benefit is most plausible.

7. Methods

7.1. Literature Search

A comprehensive search was performed in PubMed, Scopus, and Web of Science up to September 2025. The search combined free text terms and Medical Subject Headings (MeSH). Keywords included: intermittent feeding, intermittent fasting, time-restricted feeding, cyclic enteral nutrition, continuous enteral nutrition, GM, gut microbiome, dysbiosis, neuroinflammation, gut-brain axis, critical illness, intensive care unit, mechanical ventilation, ketogenic diet, ketogenesis, circadian rhythm, sepsis-associated encephalopathy, traumatic brain injury, delirium, and short-chain fatty acids. Boolean operators AND and OR were used to combine terms across domains. Reference lists of relevant articles were also screened to identify additional studies.

7.2. Study Selection

After duplicate removal, titles and abstracts were screened for relevance. Full texts were evaluated when necessary. Eligible articles included peer reviewed studies written in English that investigated intermittent feeding strategies or fasting related mechanisms involving the GM or neuroinflammatory pathways. Both preclinical and clinical studies were considered. Conference abstracts, editorials, and non peer reviewed material were excluded.

7.3. Data extraction and Synthesis

Key information from selected studies included study design, population, experimental model, microbiota related findings, and reported neuroinflammatory mechanisms. Evidence was summarized narratively and organized according to mechanistic pathways linking feeding patterns, microbiota composition, and neuroinflammation. Preclinical evidence is reported before the clinical studies.

7.4. Quality Assessment

Because this work is a narrative review, no formal risk of bias assessment or meta-analysis was conducted. Studies were selected for their conceptual and mechanistic relevance to the topic. As a narrative review, the literature search was not prospectively registered in PROSPERO or equivalent databases.

8. Results

8.1. Study Selection and included Studies

Figure 3 summarises how studies were identified and selected. After screening and full-text assessment, the review drew on five preclinical or translational studies (Table 3) and twelve clinical studies (Table 4), along with supporting pooled analyses. These covered continuous, intermittent, cyclic, bolus, sequential and fasting-mimicking enteral strategies as well as ketogenic and microbiota-targeted interventions. The preclinical evidence is presented first (Section 8.2), then the clinical evidence (Section 8.3).

8.2. Preclinical Evidence

Preclinical experimental work in clinically relevant animal models supports several mechanistic pathways by which non-continuous feeding can alter host pathophysiology relevant to critical illness, including metabolic switching, autophagy induction, enhanced anabolic signaling, and microbiota-mediated organ protection. Key preclinical evidence is summarized in Table 3.

8.3. Clinical Evidence

Ketogenic diets (KD) represent a composition-based, rather than timing-based, strategy to sustain endogenous ketogenesis by delivering the majority of calories as fat with minimal carbohydrate intake. In ICU patients with sepsis, a recent open-label RCT (n=40) demonstrated that KD reliably induced stable ketosis, eliminated insulin requirements after Day 4 in all treated patients (vs 35-60% in controls), and was associated with significantly more ventilation-free, vasopressor-free, and ICU-free days, without major metabolic complications [57]. Immunological analyses revealed reduced immune dysregulation with decreased T-cell activation gene expression, consistent with the known anti-inflammatory properties of β-hydroxybutyrate, including NLRP3 inflammasome inhibition [48]. No survival benefit was demonstrated at 30 days. While KD shares the key metabolic effectors of intermittent fasting - ketogenesis, reduced insulin/IGF-1, and NLRP3 inhibition - it operates through sustained metabolic reprogramming rather than cyclic fasting signals, raising distinct concerns about protein catabolism and electrolyte balance in prolonged critical illness. Clinical data in the ICU remain limited to small trials, and no study has yet integrated GM composition or neuroinflammatory endpoints as primary outcomes.

The clinical trials available to date were conducted in general, mechanically ventilated ICU populations rather than in brain-injured cohorts; the findings below should therefore be read as the general-ICU foundation on which a neurologically focused study would build. On the clinical side, intermittent and cyclic feeding reliably induces fasting metabolic signals -- rising β-hydroxybutyrate, declining insulin and IGF-1, and a flatter urea:creatinine ratio trajectory -- without compromising safety, as demonstrated by the ICU-FM-1 pilot crossover [44] and the sequential-feeding RCT [16]. However, these metabolic benefits have not translated into consistent patient-centered improvements. The most recent and largest RCT (n~294) found that intermittent feeding accelerated time to energy targets but increased diarrhea rates (11% vs. 4.7%) and had no effect on mortality, ventilator-associated pneumonia (VAP), or protein delivery [65], consistent with an earlier trial showing no benefit in muscle mass preservation despite higher protein delivery [43]. A pooled analysis of eight RCTs (n~993) confirmed no significant difference in hospital mortality (pooled RR 0.97, 95% CI 0.72-1.32) [82]. Notably, only one RCT to date incorporated GM end-points [16]; it found genus-level shifts and modest improvements in albumin and lymphocyte counts, but no change in alpha-diversity or 90-day survival. These genus-level shifts align with translational data linking dysbiosis and Proteobacteria overgrowth to enteral intolerance and systemic inflammatory signaling [54]. GM and neuroinflammation outcomes remain unmeasured in virtually all existing trials. Full details of individual studies are presented in Table 4.

Consistent with these findings, a systematic review and meta-analysis of nine RCTs comparing bolus versus continuous enteral feeding (n=863) found no statistically significant differences in gastrointestinal outcomes, hospital mortality, or length of stay, further supporting the absence of a consistent benefit from non-continuous feeding strategies in heterogeneous critically ill populations [83].

Despite extensive investigation, no definitive conclusion could be drawn to favour one feeding mode over the other in the general ICU population [84]. This persistent lack of signal in heterogeneous cohorts points to the need to restrict future investigations to biologically informed subgroups, such as patients with neurological injury.

9. Discussion

9.1. Summary of Findings

The clinical and preclinical evidence reviewed here suggests that the timing and pattern of EN can influence the GM, its metabolites and host metabolic signaling in critically ill patients. Clinical studies show that intermittent and cyclic feeding induce a fasting-type metabolic response and reach caloric targets at least as well as continuous feeding, with no consistent effect on mortality; the one trial that included microbiome endpoints found measurable shifts in gut taxa and in the serum metabolome. Preclinical models point in the same direction, connecting feeding-fasting cycles to SCFA production, barrier integrity, immune tone and neuroinflammation. Almost all of this evidence, however, comes from general ICU populations rather than from patients selected for brain injury.

9.2. Promising Preclinical Evidence but Heterogeneous Clinical Results

Direct clinical evidence that feeding timing improves neurological outcomes does not yet exist; the case for targeting brain-injured patients is, for now, mechanistic and observational. ICU populations are heterogeneous, and existing RCTs are underpowered, in part because they do not preselect for neurological phenotypes most likely to respond to GM-targeted interventions [58]. Phenotype-guided enrichment increases signal-to-noise for mechanistic biomarkers and may substantially reduce required sample sizes. The ICU phenotypes with the strongest mechanistic rationale for gut-brain-feeding interactions are summarized in Table 5. The strength of direct clinical evidence linking enteral feeding timing → microbiota/metabolome → objective neuroinflammation or improved neurological outcomes is uneven across these phenotypes, so each phenotype should be treated as a prespecified subgroup or mechanistic substudy in future RCTs rather than assumed to respond identically.

9.3. Strengths

The main strength of this review is that it brings together mechanistic, preclinical and clinical evidence from the nutrition, microbiome and neurocritical care literatures, which are rarely read side by side. Treating feeding pattern as a modifiable determinant of the gut-brain axis gives a target that is biologically plausible and clinically actionable. The operational definitions in Table 2, the evidence tables and the implementation framework are meant to make the idea usable at the bedside and to help design future trials.

9.4. Limitations

This review also has limitations. Being a narrative review, it did not use a prospectively registered search protocol and is therefore open to selection bias. The clinical evidence is heterogeneous in interventions, populations and endpoints, mostly comes from small and underpowered studies, and, most relevant here, was generated in general ICU rather than brain-injured cohorts, so any conclusion about brain-injured patients is at present an extrapolation and remains hypothesis-generating. Antibiotic exposure, a major driver of dysbiosis, is reported inconsistently and limits causal inference. Finally, only one trial so far has included microbiome endpoints, which limits any firm conclusion about microbiota-mediated effects of feeding pattern.

9.5. Perspectives

9.5.1. Microbiota-Sparing Feeding Concepts

“Starving the bad bugs” may be an approach. Still another would be not to starve them at all and feed them from the moment the patient is admitted to the ICU, remembering that among those bugs are also key GM players that provide a formidable, beneficial output for the host.

That’s why a microbiota-maintenance microfed (continuous, ultra-low caloric “prebiotic drip”) could be an interesting concept, an isotonic, very low volume infusion (eg, comparable to trophic EN rates or lower) containing fermentable soluble fibre/oligofructose/inulin and low osmolality to provide substrate for SCFA producers without materially increasing systemic caloric load. The EDEN RCT in 2013 [96] already demonstrated that trophic, hypocaloric enteral feeding can maintain gastrointestinal tolerance and safety in early critical illness, using standard polymeric formulas at minimal rates to protect the gut without delivering significant calories. In contrast, the concept we suggest evolves this approach from a purely metabolic strategy to a microbiota-maintenance strategy. Rather than providing inert calories at low rates, a microfed “prebiotic drip” would supply a minimal, isotonic infusion designed not to feed the host, but to sustain commensal SCFA-producing microbes. The final goal is therefore to preserve commensal fermenters during periods when full EN is unsafe, for instance, during hemodynamic instability when there is a high risk of bowel necrosis and gut ischemia due to compromised splanchnic perfusion [97,98]. This could slow down the otherwise swift transition from GM to Gut “Pathobiota” [11].

A variant of this strategy would be to administer time restricted prebiotic meals, i.e. short small boluses of fermentable glycans (oligosaccharides/resistant starch blends) only during daytime windows to sync the GM’s clock and SCFA’S output steady without altering much the caloric target and especially without “calling “ too much blood into the gut in a moment in which the blood is needed somewhere else.

Beyond prebiotics, postbiotics themselves could be used to replace host-interrupted SCFAs signaling during the fasting phase: a small amount of butyrate/acetate could be delivered enterally or rectally in selected patients to provide energy to the enterocytes, preserve barrier integrity, and modulate immune signals [99].

Enteral strategies (even minimal) should not be used during active gut hypoperfusion or when escalating vasopressor requirements are present without preclinical/early-phase safety data. Evidence linking early full feeding with harm in unstable patients motivated this recommendation [64]. Furthermore, fermentable substrates can induce osmotic diarrhea if osmolality or delivery rate is poorly matched to absorptive capacity [100], so gradual dose escalation and pump control are essential. The prebiotic microfed concept described above is therefore proposed only for the stabilizing or post-acute phase, once vasopressor requirements are decreasing and splanchnic perfusion is being restored — not as a strategy during active hemodynamic compromise.

9.5.2. A proposed Phased Clinical Trial

Based on the mechanistic and clinical evidence reviewed above, a phased RCT is here outlined as a future research priority to test whether daytime timed intermittent or cyclic enteral feeding, compared with standard continuous feeding, modulates GM, its metabolites, and neuroinflammatory responses in neurologically relevant ICU patients.

The optimal window to assess whether intermittent or cyclic enteral feeding modifies pathogenic mechanisms is after the early, unstable “acute” phase, i.e., in the post-acute/stabilization and early rehabilitation periods, rather than immediately at ICU admission. The optimal mechanistic sampling window is Days 5-14” [16] (commonly Day 7–10) to collect microbiome (stool/rectal swab), metabolomics (serum/urine for ketones, SCFAs, bile acids), insulin/IGF-1, inflammatory cytokines and biomarkers analyses (NfL, GFAP, S100B) [101,102], and markers of autophagy. A baseline (early 4-24h status) would also be pivotal. The samples should be frozen at −80 °C within strict timeframes and should then be analyzed centrally to minimize batch effects.

Assessing effects in the post-acute [103] (days 7–14), at ICU discharge, and during early post-ICU rehabilitation (30–90 days) will capture mechanistic and clinically meaningful outcomes (muscle mass, delirium/neurologic recovery, infection, ventilator-free days, and functional recovery).

The study would enroll adults requiring mechanical ventilation and EN, excluding those with major gastrointestinal diseases or diabetes. Randomization would be stratified by antibiotic exposure and admission category to control key confounders.

Safety monitoring would focus on glycemic control and feeding intolerance [104]. Mechanistic end-points would be linked to clinical outcomes, such as ventilator-free days or ΔSOFA, using mixed-effects and mediation models. A pilot phase would assess feasibility and refine power estimates, paving the way for a larger, fully powered trial integrating multi-omics and clinical data.

9.5.3. Practical Implementation and Safety

Implementing time-restricted or fasting-mimicking feeding strategies in the ICU requires careful patient selection and ongoing physiological assessment. These interventions should be initiated only after metabolic and hemodynamic stability has been achieved and should always be individualized according to the patient’s trajectory, ongoing therapies, and gastrointestinal tolerance; the readiness criteria are detailed in Table 6 and the clinical pathway is illustrated in Figure 4. These criteria align with current American Society for Parenteral and Enteral Nutrition (ASPEN) [105] and European Society of Intensive Care Medicine (ESICM) [106] recommendations for nutritional reintroduction following circulatory instability and ensure that fasting intervals are initiated in a safe and reproducible manner.

Examples of daytime feeding protocols include 10-hour daytime cycles or 07–09, 11–13, and 17–19 h feeding windows, while maintaining the same total 24-h caloric and protein dose. Caloric and protein guidance should follow contemporary ICU nutrition practice: trials and protocols testing cyclic/diurnal strategies commonly used targets near 20 kcal/kg/day and ~0.8 g protein/kg/day in the acute phase [66], but consensus guidance [64,107] support a pragmatic kcal range during the first week of approximately 12.5–25 kcal/kg/day tailored to clinical context and a higher protein prescription (up to ≈1.2–1.5 g/kg/day in some populations such as trauma) when tolerated and indicated.

Additionally, it would be advisable to deliver feeds via pump-controlled, slower infusions rather than rapid gravity/bolus pushes to reduce intolerance and aspiration risk where possible [108].

Intermittent feeding requires careful monitoring to prevent key complications. Diarrhea is a common issue [65] and should be managed with routine stool tracking, review of osmotic medications or antibiotics, and gradual introduction of soluble fiber once the patient is stable. Glycemic variability and hypoglycemia [44] must be prevented through protocolized glucose checks and insulin adjustments during fasting windows. Isotonic formulas should be preferred initially, with fiber [109] added only after tolerance is established, while minimizing drugs or antibiotics that impair motility or disrupt the GM. Aspiration risk remains variable across studies [68], so standard preventive measures, such as head elevation and the use of prokinetics, must be maintained at all times. A structured bedside monitoring plan is summarized in Table 7, outlining key surveillance domains and practical actions for early detection and management.

10. Conclusions

Intermittent or circadian-aligned feeding may open a new frontier in critical care nutrition. By restoring physiological fasting–feeding rhythms, it offers a biologically coherent way to influence metabolism, GM, and brain–immune communication. The concept that short, time-gated nutrient restriction could “starve the bugs” (redirect a dysbiotic microbiota toward a healthier state) and “save the host” (limit neuroinflammation and organ dysfunction) is bold but mechanistically possible. Evidence so far confirms the feasibility and safety of this approach, yet clinical benefits remain unproven because existing trials are small and not designed to capture microbiome or neuroimmune changes. The field is ready to evolve: the next generation of trials should couple metabolic and microbiome end-points with patient-centered outcomes to test whether time-patterned nutrition can truly reshape recovery in critical illness.