Antibiotic-associated gut dysbiosis and intestinal failure in critically ill patients: Mechanisms and interventions

Abstract

Antibiotic-associated gut dysbiosis is an important and potentially modifiable driver of intestinal failure in critically ill patients. Critically ill patients in the intensive care unit receive antibiotics in 70%-90% of cases, yet 20%-50% develop acute gastrointestinal injury (AGI). The pathophysiological link between antibiotic exposure and organ failure remains incompletely synthesized. To systematically elucidate the molecular cascade linking antibiotic-induced gut dysbiosis to intestinal failure, and to map current evidence for stage-specific interventions in critically ill patients. PubMed, Web of Science, EMBASE, CNKI, and Wanfang databases were searched from inception to December 31, 2025. Eligible studies included original research, systematic reviews, randomized controlled trials, animal models, and clinical guidelines. Two investigators independently screened 3214 records; 40 studies were included. Antibiotic exposure initiates a four-stage cascade: (1) Gut microbiota dysbiosis - Shannon diversity declines 30%-50% within 7 days; (2) Short-chain fatty acid depletion - butyrate falls 50%-80%; (3) Intestinal barrier injury - tight junction proteins decline 20%-60%, permeability increases 2-3-fold; and (4) Systemic inflammation - plasma lipopolysaccharide rises 1.5-3-fold, activating Toll-like receptor 4/nuclear factor kappa B, driving systemic inflammatory response syndrome and multiple organ dysfunction syndrome. Antimicrobial stewardship programs reduce broad-spectrum antibiotic use by 20%-30% and AGI incidence by 15%-25%. Fecal microbiota transplantation achieves 80%-90% success for Clostridioides difficile-associated disease. Antibiotic-associated gut dysbiosis represents a mechanistically coherent, stage-specific, and clinically modifiable cascade driving intestinal failure in critically ill patients, with stage-targeted interventions offering measurable outcome benefits.

Key Words: Anti-bacterial agents; Gut microbiota dysbiosis; Critically ill patients; Intestinal failure; Short-chain fatty acids; Molecular mechanisms; Antibiotic stewardship

Core Tip: Broad-spectrum antibiotics precipitate a four-stage pathological cascade in critically ill patients: Gut microbiota dysbiosis, short-chain fatty acid depletion, intestinal barrier injury, and systemic inflammatory activation, ultimately driving multiple organ dysfunction syndrome. This review maps each cascade stage to a specific intervention, proposing a stage-based therapeutic framework. Three clinical priorities: Microbiome surveillance after prolonged antibiotic exposure, early enteral nutrition within 48 hours, and integration of days-of-therapy/antibiotic spectrum index metrics into stewardship decisions.

INTRODUCTION

Intestinal failure is a clinically important complication in critically ill patients with profound implications for prognosis, and is increasingly recognized as a systemic pathological process driven by dysregulation of the “gut-immune-metabolic axis”. Patients in the intensive care unit (ICU) are inherently high-risk, often presenting with severe infection, shock, or multiple organ dysfunction (MODS); 70%-90% require antibiotic therapy. While broad-spectrum, prolonged, or combination regimens are often necessary to control infection, they markedly perturb the gut microbiota, and approximately 20%-50% of affected patients progress to acute gastrointestinal injury (AGI) or outright intestinal failure. More than half ultimately develop MODS or die[1].

Although critical illness itself induces gut dysbiosis, multiple prospective studies identify antibiotic exposure as an independent, modifiable iatrogenic factor. Exposure duration is the primary determinant of early microbiota structural change after ICU admission: Within 24-72 hours, gut microbial α-diversity falls by 30%-50%, with depletion of key short-chain fatty acid (SCFA)-producing taxa, overgrowth of opportunistic pathogens, and erosion of colonization resistance[2]. Animal models and healthy-volunteer studies further suggest that broad-spectrum antibiotics alone may induce this structural dysbiosis independently of disease[3]. Although antibiotics are life-saving, their overuse is a critical, potentially reversible factor in the transition from AGI to intestinal failure. Current strategies - antimicrobial stewardship programs (ASPs) and nutritional support - can partially slow disease progression, but the tension between antimicrobial necessity and microbiota preservation remains unresolved. This review integrates molecular biology, microbiomics, and clinical evidence to systematically examine the mechanisms and intervention strategies for antibiotic-associated intestinal failure, with the aim of providing a theoretical basis for precision microbiota-targeted therapy in critically ill patients.

While several reviews have addressed gut dysbiosis in the context of general critical illness, the present narrative review makes four distinct contributions that differentiate it from prior work. First, we focus specifically on antibiotic-associated dysbiosis rather than dysbiosis attributable to critical illness in general, thereby isolating a modifiable iatrogenic variable. Second, we propose a structured “microbiota-metabolism-barrier-inflammation cascade” as a sequential pathophysiological model, providing an integrated mechanistic framework that extends beyond description of individual disrupted pathways. Third, we compile a quantitative evidence body - including effect estimates (odds ratios, adjusted hazard ratios, relative risks) for antibiotic exposure risk factors and percentage decreases in SCFA concentrations - to ground mechanistic claims in measurable clinical data. Fourth, we introduce a stage-based intervention pathway that explicitly aligns therapeutic modalities with the dominant pathological process at each phase of the cascade, offering a practical clinical decision framework. Together, these contributions aim to advance the conceptual and translational understanding of antibiotic-associated intestinal failure in the ICU setting.

LITERATURE REVIEW

A structured literature search was conducted across five databases - PubMed, Web of Science, EMBASE, CNKI, and Wanfang database - from inception through December 31, 2025. Search terms included “antibiotic”, “anti-bacterial agents”, “gut microbiota dysbiosis”, “intestinal dysbiosis”, “intestinal failure”, “gut failure”, “acute gastrointestinal injury”, “critically ill”, “ICU”, “short-chain fatty acids”, “intestinal barrier”, “bacterial translocation”, and related Medical Subject Headings and free-text terms combined with Boolean operators. Reference lists of retrieved articles and key journals - Critical Care, Gut, Nature Medicine, JAMA, and Intensive Care Medicine - were manually searched for additional eligible publications. Eligible study types included original research articles, systematic reviews, meta-analyses, randomized controlled trials (RCTs), observational cohorts, interventional studies, animal experiments, and clinical guidelines addressing antibiotic-related gut dysbiosis, molecular mechanisms of intestinal failure, or microbiome-targeted interventions. Case reports, conference abstracts, duplicate publications, and articles without accessible full text were excluded. Two investigators independently screened titles, abstracts, and full texts; discrepancies were resolved by consensus. Forty high-quality publications were ultimately included (Figure 1).

Figure 1 PRISMA 2020 flow diagram - literature search and selection. PRISMA 2020 flow diagram summarizing the literature search and study selection process. Five databases (PubMed, Web of Science, EMBASE, CNKI, Wanfang) were searched from inception to December 31, 2025. Records identified: n = 3214. After removal of duplicates (n = 843), 2371 records were screened by title and abstract. Of these, 2218 were excluded as irrelevant. Full-text assessment was performed for 153 records; 113 were excluded for the following reasons: Not addressing antibiotic-related dysbiosis or intestinal failure mechanisms (n = 48), insufficient methodological quality (n = 31), conference abstracts or inaccessible full text (n = 22), case reports (n = 12). Forty studies were ultimately included in this narrative review.

ANTIBIOTIC EXPOSURE AND DISRUPTION OF GUT HOMEOSTASIS

Systemic consequences of antibiotic overuse

Antibiotic exposure in ICU patients encompasses cumulative dose, treatment duration, spectrum breadth, and combination regimens - collectively representing the degree of iatrogenic gut microbiota injury. Overuse refers specifically to the preferential selection of broad-spectrum agents, prolonged or repeated courses, and multi-drug combinations; in essence, it is associated with disruption of host-microbiome homeostasis, and may directly contribute to dysbiosis and accelerate the progression to intestinal failure. The global EPIC III study reported antibiotic use in 70%-90% of ICU patients[1]; in Chinese sepsis cohorts, carbapenem use exceeds 30%, with combination regimens in up to 72% of cases[4]. No consensus definition of antibiotic overuse currently exists; commonly used quantitative metrics include days of therapy, defined daily dose, and antibiotic spectrum index. Key exposure risk factors and their quantified effect estimates are summarized in Table 1[1,5-12].

Table 1 Risk factors and quantitative effects of antibiotic exposure in critically ill patients.

Category	Risk factor	Metric definition	Effect size (OR/aHR)	P value	Study design	Ref.
Exposure intensity	Elevated ASI	Per 1-unit increase	aHR = 1.14 (1.09-1.19)	< 0.001	Prospective cohort (n = 422)	[5]
	Cumulative DOT	Per 1-day increase	OR = 1.05-1.08	< 0.01	ICU cohort	[6]
	Cumulative DDD	Per 10 DDD	OR = 1.12	0.02	Retrospective study	[7]
Spectrum breadth	Broad-spectrum β-lactams (carbapenems)	Vs non-broad-spectrum	OR = 2.3-3.5	< 0.001	Multicenter cohort	[1]
	Anti-anaerobic coverage (metronidazole/piperacillin-tazobactam)	Present vs absent	OR = 1.8-2.6	< 0.01	ICU microbiome study	[8]
Prescribing pattern	Combination therapy (≥ 2 agents)	Vs monotherapy	OR = 1.9-2.7	< 0.01	Retrospective study	[9]
	≥ 3 antibiotics combined	Vs monotherapy	OR = 3.1	< 0.001	Retrospective study	[10]
Exposure duration	Prolonged course (> 7 days)	Vs ≤ 7 days	OR = 2.0-2.8	< 0.01	Follow-up study	[11]
	Repeated exposure (≥ 2 courses)	Yes vs no	OR = 2.5	0.003	ICU study	[12]
Disease severity	Elevated SOFA score	Per 1-point increase	OR = 1.12-1.18	< 0.001	Multicenter study	[1]

Data were derived from the included cohort studies and meta-analyses. Risk-stratification thresholds: Antibiotic spectrum index > 3.0 = high risk (operational threshold, no universal consensus); cumulative days of therapy > 7 days associated with sustained dysbiosis (odds ratio = 2.0-2.8); defined daily dose > 30 during admission = high cumulative burden. OR: Odds ratio; aHR: Adjusted hazard ratio; ASI: Antibiotic spectrum index; DOT: Days of therapy; DDD: Defined daily dose; ICU: Intensive care unit; SOFA: Sequential Organ Failure Assessment.

The normal gut microbiota - an integrated functional network

The gut microbiota constitutes the body’s largest commensal microbial community, comprising approximately 10¹³-10¹⁴ microorganisms, with Firmicutes (60%-70%) and Bacteroidetes (20%-30%) predominating. Far from a passive microbial reservoir, it functions as a dynamic network[13] that is integral to host homeostasis: It establishes colonization resistance through competitive exclusion and niche occupation; maintains barrier integrity by regulating tight junction proteins, the mucus layer, and epithelial renewal; promotes regulatory T-cell (Treg) differentiation to sustain immune homeostasis; and produces SCFAs that serve as the primary energy source for colonocytes while modulating inflammation and metabolic stability. The gut microbiota is therefore best understood as a dynamic system that integrates barrier function, immune regulation, and metabolic activity - one whose stability depends on both diversity and functional redundancy. When this equilibrium is disrupted, dysbiosis ensues, leading to barrier breakdown, heightened inflammation.

Antibiotic-induced systemic imbalance

Antibiotic exposure is associated with disruption of gut microbiota homeostasis within 24-72 hours, initiating a sequence of pathological changes. Studies show that microbial diversity falls sharply following exposure, with community restructuring characterized by loss of commensals and relative expansion of opportunistic pathogens; SCFA-producing taxa are selectively depleted while Enterobacteriaceae and Enterococcus proliferate[14]. Concurrently, SCFA production declines, luminal pH rises, and the resulting ecological vacuum may facilitate colonization by resistant organisms. These changes extend beyond community structure and appear to alter host metabolism and immune function, potentially exacerbating intestinal injury and may contribute to sustained inflammation - ultimately suggesting a self-reinforcing cycle of dysbiosis and immune dysregulation[15].

MOLECULAR NETWORK MECHANISMS OF ANTIBIOTIC-ASSOCIATED INTESTINAL FAILURE

To contextualize the detailed mechanistic sections that follow, we first outline the stepwise pathological sequence through which antibiotic exposure is hypothesized to mediate intestinal failure and ultimately MODS. Understanding each transition point clarifies why a multi-level therapeutic approach is necessary: (1) Antibiotic exposure → microbial diversity loss. Broad-spectrum antibiotics non-selectively suppress susceptible commensals; Shannon diversity indices decline by 30%-50% within 24-72 hours of exposure, with loss of SCFA-producing Firmicutes and Bacteroidetes being particularly consistent across studies[16]; (2) Microbial diversity loss → SCFA depletion. Butyrate-producing taxa are disproportionately depleted; fecal and serum butyrate concentrations may fall by 50%-80%, and total SCFA concentrations by 40%-70%[17]. This appears to shift the luminal metabolic environment from homeostatic to proinflammatory; (3) SCFA depletion → hypoxia-inducible factor-1α (HIF-1α) downregulation. Butyrate stabilizes HIF-1α under physiological oxygen gradients; its depletion is linked to reduced HIF-1α transcriptional activity, which in turn is associated with impaired expression of tight junction proteins and mucin 2 (MUC2); (4) HIF-1α downregulation → Tight junction disruption and barrier permeability increase. Protein levels of occludin, claudin-5, and zonula occludens-1 (ZO-1) fall by 20%-60% in experimental models; in vitro transepithelial electrical resistance decreases by 30%-50%, suggesting increased paracellular flux[18,19]; (5) Increased barrier permeability → lipopolysaccharide (LPS) translocation. LPS and bacterial products cross the compromised epithelium; plasma LPS-binding protein (LBP) and soluble CD14 (sCD14) are elevated 1.5- to 3-fold in critically ill patients relative to controls[20]; (6) LPS translocation → Toll-like receptor 4 (TLR4)/nuclear factor kappa B (NF-κB) activation. Translocated LPS engages TLR4, activating downstream NF-κB and mitogen-activated protein kinase (MAPK) signaling cascades, with consequent upregulation of tumor necrosis factor (TNF)-α, interleukin (IL)-6, and IL-1β (serum levels rising 2- to 5-fold)[21]; and (7) TLR4/NF-κB activation → systemic inflammation → MODS. Sustained cytokine release is associated with immune dysregulation, distant organ injury via portal and systemic circulation, and ultimately MODS. Each transition point represents a potential node for targeted therapeutic intervention, as elaborated in section “Clinical Evidence and Intervention Strategies”.

Microbiota collapse and loss of colonization resistance - the initiating event

Declining microbial diversity is the earliest and most direct consequence of antibiotic exposure, rapidly followed by niche vacancy and weakened colonization resistance. Broad-spectrum, prolonged, or combination regimens are associated with disruption of the structural equilibrium of the gut microbiota by eliminating susceptible commensals. Shannon, Simpson, and Chao1 indices fall measurably within 24-72 hours; total diversity declines by 30%-50% within 7 days, with marked shifts in β-diversity[16]. Importantly, the duration of antibiotic exposure is the primary driver of microbiota compositional change after ICU admission, independently of disease severity. As diversity wanes, community structure shifts: Butyrate-producing Firmicutes and Bacteroidetes contract while Proteobacteria - particularly Enterobacteriaceae - and Enterococcus expand[22]. Broad-spectrum antibiotics and illness severity appear to act jointly to skew the Firmicutes-to-Bacteroidetes (F/B) ratio beyond the normal range within the first 7 days of admission, a finding closely associated with adverse outcomes. Multi-drug combinations may compound diversity loss, affording opportunistic pathogens a further competitive advantage[23].

The consequences for colonization resistance are immediate. Under normal conditions, commensals suppress pathogen growth by competing for nutrients, secreting antimicrobial substances, and maintaining a low luminal pH through SCFA production. Antibiotic exposure is associated with erosion of this defense: SCFA generation falls, pH rises, the mucus layer thins, and pathogens such as Clostridioides difficile and carbapenem-resistant Enterobacteriaceae may colonize more readily[24]. Microbiota disruption is also linked to increased intestinal permeability, potential LPS translocation, and impaired immune function - a self-reinforcing pathological cycle that may contribute to AGI progression toward intestinal failure and heightened nosocomial infection risk[25].

Multi-omics analyses further illuminate the systemic nature of microbiota collapse. Integrating metagenomic and metabolomic data, studies document a 40%-70% reduction in SCFA biosynthetic gene cluster abundance following antibiotic exposure, concurrent with marked upregulation of LPS biosynthesis gene clusters; both correlate with plasma inflammatory markers (IL-6, TNF-α; r = 0.62-0.78, P < 0.001), suggesting a regulatory association between microbiota disruption and host immune activation[26,27]. This functional network restructuring not only may amplify colonization resistance failure but appears to provide a molecular substrate for the subsequent metabolic and inflammatory cascade.

Metabolic disruption - SCFA depletion as the central mediator

Microbiota collapse is followed by marked changes in gut metabolic function, foremost among which is impaired SCFA production. SCFAs - particularly butyrate - are the primary energy substrate for colonocytes, modulate intestinal inflammation, and are linked to epithelial barrier homeostasis; they may be understood as the “metabolic hub” connecting microbiota changes to host responses. Under normal conditions, butyrate-producing Firmicutes ferment dietary fiber to generate abundant SCFAs, principally butyrate, propionate, and acetate. After antibiotic overuse, these taxa plummet and fecal and serum SCFA concentrations fall substantially: Butyrate levels may decline by 50%-80%, total SCFAs by 40%-70%[17]. Shimizu et al[13] identify SCFA depletion as one of the most fundamental metabolic consequences of antibiotic-induced intestinal injury.

Broad-spectrum antibiotic exposure is associated with systematic remodeling of the microbiota’s metabolic network - downregulating the SCFA synthesis module while upregulating LPS biosynthesis[28]. This imbalance appears to impair epithelial energy supply and may shift the intestinal milieu from homeostatic to proinflammatory, potentially functioning as the “metabolic switch” linking AGI to intestinal failure. Specifically, SCFA depletion may precipitate multiple pathological effects: Butyrate deficiency is linked to destabilization of HIF-1α, potentially impairing transcription of tight junction proteins (occludin) and MUC2 and contributing to barrier injury; attenuated HDAC inhibition is associated with upregulation of proinflammatory genes (TNF-α, IL-6, IL-1β); colonocyte energy metabolism may be impaired (butyrate supplies > 70% of colonocyte energy needs), potentially accelerating apoptosis and suppressing proliferation; and LPS/endotoxemia may worsen, with plasma LBP rising 1.5- to 3-fold, further supporting TLR4/NF-κB signaling and amplifying systemic inflammation.

Soranno et al[29] found that fecal butyrate concentration in ICU patients correlates inversely with AGI scores (r = -0.62 to -0.75, P < 0.001) and is an independent prognostic biomarker beyond Sequential Organ Failure Assessment (SOFA) score, supporting the hypothesis that microbiota metabolite imbalance may function as the “metabolic switch” linking AGI to intestinal failure and is closely associated with MODS. Restoring SCFA levels has thus emerged as an important therapeutic target in antibiotic-associated intestinal failure.

Barrier dysfunction - from metabolic imbalance to structural injury

Metabolic disruption is associated with intestinal barrier failure through concurrent damage to the physical, chemical, and immunological barriers. The normal intestinal barrier comprises tight junction complexes, the mucus layer, and antimicrobial peptides[30]. Following antibiotic exposure, occludin, claudin-5, and ZO-1 protein levels fall by 20%-60%, while claudin-2 is upregulated - collectively appearing to increase paracellular permeability[18]. In vitro Caco-2 and HT-29 monolayer models treated with antibiotic-conditioned serum show a 30%-50% reduction in transepithelial electrical resistance and a 2- to 3-fold increase in FITC-dextran (4 kDa) flux[19]. Animal models further demonstrate increased colonocyte apoptosis (enhanced caspase-3 activation, 40%-70% more TUNEL-positive cells), suppressed proliferation (Ki-67 positivity reduced by > 30%), mucus layer thinning (Alcian blue staining and MUC2 mRNA/protein both declining by > 50%), and reduced secretion of antimicrobial peptides (Reg3γ, α-defensins)[31,32].

This transition from “selective permeability” to “pathological leakage” is associated with progression from AGI grade III-IV to intestinal failure, and correlates with MODS incidence and mortality. Clinical cohort data combining 16S rRNA sequencing with plasma LBP and intestinal fatty acid-binding protein (I-FABP) levels suggest that dysbiosis severity correlates positively with barrier permeability markers (r = 0.68, P < 0.001), independently of SOFA score[33]. This shift from functional imbalance to structural injury may provide a conduit for microbial products to enter the systemic circulation - a pivotal turning point in the cascade.

Microbial product translocation and immune activation

Bacteria and their products crossing the disrupted barrier into the bloodstream are linked to systemic inflammatory response syndrome (SIRS), which may represent a key amplifying event in the transition from intestinal failure to MODS. Antibiotic-driven dysbiosis and increased barrier permeability appear to allow viable bacteria, bacterial fragments, and LPS to traverse the injured epithelium into mesenteric lymph nodes, the portal vein, and the systemic circulation. Clinical evidence shows that plasma LPS and sCD14 are elevated 1.5- to 3-fold in critically ill patients relative to controls, and increased bacterial 16S rDNA copy numbers in blood support widespread enteric bacterial translocation[20]. Translocated bacterial products are associated with TLR4 signaling activation, engagement of NF-κB and related inflammatory cascades, and massive cytokine release - suggesting a vicious cycle of “gut injury → bacterial translocation → systemic inflammation → further gut injury” that may underlie the gut’s role as a “driver” of critical illness. Shimizu et al[13] report that Enterobacteriaceae and Enterococcus are the predominant translocating organisms in critically ill patients, and their presence is independently associated with nosocomial infection and organ failure beyond SOFA score. This process may inflict hepatic injury via the portal system and damage distant organs through the systemic circulation, supporting a gut-centric model of multiorgan failure.

Inflammatory amplification and systemic dysregulation

Under persistent inflammatory stimulation, the host may enter a state of amplified inflammation marked by sustained cytokine elevation and immune dysregulation. Antibiotic exposure appears to promote LPS-TLR4 binding, potentially activating downstream NF-κB and MAPK pathways: IκBα phosphorylation and degradation, NF-κB p65 nuclear translocation, and upregulation of TNF-α, IL-6, and IL-1β mRNA and protein (serum levels increasing 2- to 5-fold, P < 0.001) have been reported in experimental models. MAPK pathway activity (p38, Jun N-terminal kinase, extracellular signal-regulated kinase) is concurrently enhanced, potentially further amplifying the inflammatory response. At the innate immune level, dysbiosis is associated with a shift of monocytes and macrophages toward a proinflammatory phenotype, evidenced by upregulation of M1 markers (inducible nitric oxide synthase, CD86) and relative downregulation of M2 markers (Arg1, CD206)[21]. Single-cell transcriptomic studies suggest that this immunophenotypic shift is closely linked to gut microbiota disruption, is associated with risk of nosocomial infection and progressive organ dysfunction[34].

Adaptive immune changes are equally notable: CD4+ T-cell frequency declines, the CD4+/CD8+ ratio falls, Treg numbers decrease, and T helper 17 (Th17) cells are relatively expanded - suggesting a disrupted Th17/Treg balance that may sustain local intestinal and systemic inflammation. Clinically, peripheral CD4+/CD8+ ratio correlates positively with Shannon diversity index, suggesting that immune status and microbiota perturbation are functionally associated[35].

Multi-omics data provide further insight into the system-level architecture of inflammatory amplification. Integrating metagenomic, metabolomic, and host signaling pathway data reveals a regulatory network centered on IL-6, TNF, and protein kinase B 1 (AKT1), encompassing phosphoinositide 3-kinase (PI3K)/Akt, NF-κB, MAPK, and AMPK signaling. In cecal ligation and puncture (CLP) animal models, proteomic analysis after broad-spectrum antibiotic intervention suggests reduced PI3K/Akt phosphorylation and increased NF-κB nuclear translocation, with amplification of systemic inflammatory networks; targeted knockdown of AKT1 or TLR4 appears to substantially reduce organ injury scores, suggesting that antibiotics may amplify damage through a multi-target network[28]. Human longitudinal studies and in vitro cell experiments further suggest that antibiotic-conditioned serum is associated with a 40%-60% increase in NF-κB-driven proinflammatory cytokine release, while exogenous SCFA supplementation appears to restore PI3K/Akt phosphorylation - supporting the hypothesis that antibiotics exert their injurious effects primarily by disrupting the microbiota-host metabolic-inflammatory network[36]. Together, these findings - spanning network prediction, animal validation, human correlation, and cellular mechanistic studies - suggest a comprehensive molecular regulatory network for antibiotic-associated intestinal failure (Figure 2), providing a framework for targeted intervention.

Figure 2 Mechanistic cascade of antibiotic-associated intestinal failure & stage-based intervention pathway. A: Schematic representation of the “microbiota-metabolism-barrier-inflammation cascade” hypothesized to link antibiotic exposure to multiple organ dysfunction syndrome (MODS) in critically ill patients. Antibiotic exposure is associated with rapid microbial diversity loss, depletion of short-chain fatty acid (SCFA)-producing taxa, and reduced SCFA concentrations. SCFA depletion is linked to downregulation of hypoxia-inducible factor-1α and impaired transcription of tight junction proteins, leading to increased intestinal barrier permeability. The disrupted barrier may allow translocation of lipopolysaccharide and microbial products, engaging pattern recognition receptors including Toll-like receptor 4, activating nuclear factor kappa B signaling, and promoting release of proinflammatory cytokines [tumor necrosis factor-α, interleukin (IL)-6, IL-1β]. Sustained innate immune activation involves polymorphonuclear leukocytes and macrophage polarization toward proinflammatory phenotypes. Microbe-associated molecular patterns and damage-associated molecular patterns further amplify the inflammatory response. These events are collectively associated with systemic inflammatory response syndrome and, in severe cases, MODS. Arrows indicate postulated directional associations based on available experimental and clinical evidence; causal relationships in humans require further validation through prospective longitudinal studies; B: Stage-based intervention pathway aligned with the mechanistic cascade depicted in Figure 2A. Five sequential pathological stages are shown, with corresponding therapeutic strategies mapped to each stage. Stage 1 (dysbiosis): Primary intervention is antibiotic stewardship program implementation to minimize microbiota disruption. Stage 2 (metabolic dysfunction/SCFA depletion): Dietary fiber supplementation and prebiotic use to support SCFA-producing bacterial taxa. Stage 3 (barrier injury): Early enteral nutrition to support epithelial renewal, mucus production, and barrier integrity. Stage 4 (inflammatory activation): Immunomodulatory strategies (low-dose corticosteroids, cytokine modulation) combined with upstream microbiota and metabolic interventions. Stage 5 (MODS): Organ support measures including hemodynamic optimization, continuous renal replacement therapy, and mechanical ventilation. The principle underlying this framework is that early upstream intervention offers greater potential for disease modification than late-stage organ support alone. This framework is proposed as a conceptual guide and requires validation in prospective clinical trials. SCFA: Short-chain fatty acid; MODS: Multiple organ dysfunction syndrome; ZO-1: Zonula occludens-1; PRR: Pattern recognition receptor; TLR4: Toll-like receptor 4; NF-κB: Nuclear factor kappa B; PMNs: Polymorphonuclear leukocytes; M1: Proinflammatory macrophages; SIRS: Systemic inflammatory response syndrome; ASP: Antibiotic stewardship program; PN: Parenteral nutrition; IL-6: Interleukin-6; CRRT: Continuous renal replacement therapy; EN: Enteral nutrition; HIF-1α: Hypoxia-inducible factor-1α; LPS: Lipopolysaccharide; MAMPs: Microbe-associated molecular patterns; TNF: Tumor necrosis factor; Treg: Regulatory T cell; Th17: T helper 17.

CLINICAL EVIDENCE AND INTERVENTION STRATEGIES

Grounded in the “dysbiosis → metabolic disruption → barrier breakdown → inflammatory activation → systemic amplification” cascade, current interventions are shifting from infection control alone toward integrated, multi-level strategies. Different therapeutic modalities target distinct nodes along this pathway, and their clinical efficacy reflects this mechanistic specificity.

Targeting the microbiota - antibiotic stewardship and microbial reconstitution

As the initiating event of the cascade, gut dysbiosis is addressed primarily through ASPs and microbiota reconstitution. ASPs reduce the microbiota insult at its source by optimizing antibiotic selection, shortening treatment duration, and curtailing unnecessary broad-spectrum coverage. Clinical data from Micek et al[37] guideline update and multiple ICU cohorts show that ASP implementation reduces broad-spectrum antibiotic use by 20%-30% and AGI incidence by 15%-25%, without increasing the risk of treatment failure. A comprehensive review by Cho et al[38] in Gut Microbes concludes that narrow-spectrum, short-course, precision antibiotic strategies can meaningfully preserve microbiota diversity and reduce dysbiosis-related nosocomial infection rates.

Probiotics and fecal microbiota transplantation (FMT) are used to restore microbial diversity and colonization resistance. Multiple meta-analyses[39-41] show that probiotics reduce the incidence of antibiotic-associated diarrhea to some extent, though their effects on major clinical endpoints in critically ill patients remain inconsistent. FMT demonstrates robust microbiota reconstitution capacity in refractory dysbiosis; the 2024 American Gastroenterological Association (AGA) clinical practice guideline recommends FMT for antibiotic-refractory severe Clostridioides difficile-associated disease (CDAD), with success rates of 80%-90% and a significant reduction in 30-day mortality[42]. A clinical trial by Cibulkova et al[43] showed that FMT is associated with effective treatment of antibiotic-associated diarrhea in ICU patients, reduced multidrug-resistant organism colonization, improved intestinal barrier function and immune status, rapid restoration of microbial diversity, and lower risk of secondary infection; adverse event rates are low in immunocompetent patients, though rigorous donor screening is essential. Overall, restoration of microbiota structure alone can improve some outcomes but has limited impact on established systemic inflammation, underscoring the marked disease-stage dependence of these interventions.

It is critical to clarify that the strong evidence supporting FMT is restricted to CDAD per the 2024 AGA guideline[42]. For non-CDAD ICU-associated dysbiosis, evidence is limited to small case series and pilot RCTs; FMT should be regarded as investigational and used only within clinical trial frameworks.

Targeting metabolism - nutritional support and SCFA restoration

Given the central role of SCFAs in linking microbiota perturbation to host injury, metabolic-level interventions are receiving increasing attention. Enteral nutrition - particularly fiber-enriched formulas - may improve the intestinal metabolic environment by promoting SCFA production. Early enteral nutrition (initiated within 48 hours) is associated with reduced infection rates and improved clinical outcomes[44,45]. A prospective study by Liu et al[46] in JMDH found that higher dietary fiber intake during the first 3 days of ICU admission was significantly and inversely associated with AGI severity (odds ratio = 0.82-0.86), and that elevated SCFA levels correlated with improved prognosis. Fu et al[47] suggest that dietary fiber supplementation is associated with increased abundance of butyrate-producing bacteria and attenuation of gut dysbiosis[48].

Prebiotic and synbiotic supplementation may indirectly enhance SCFA production, thereby improving epithelial energy supply and reducing inflammation. A meta-analysis by Bagdadi et al[49] encompassing multiple RCTs found that probiotics/synbiotics significantly reduced diarrhea incidence in ICU patients (relative risk = 0.70-0.80) and were associated with decreased risk of ventilator-associated pneumonia and sepsis, while shortening mechanical ventilation duration and ICU length of stay. Lou et al[50] further demonstrated that synbiotic supplementation was associated with improved intestinal barrier markers (reduced I-FABP) and raised SCFA levels. However, a subgroup analysis by Lee et al[51] from a high-quality RCT found that benefits were concentrated in lower-risk patients; the risk-benefit profile in high-acuity ICU patients warrants careful assessment. Direct clinical evidence for exogenous SCFA supplementation in critically ill patients remains limited and requires further investigation.

Targeting the barrier - intestinal barrier protection

When barrier dysfunction is established, interventions shift toward maintaining or restoring epithelial integrity. Enteral nutrition supports this structurally - in addition to its metabolic benefits - by stimulating epithelial renewal and mucus secretion. Compared with parenteral nutrition, enteral nutrition is associated with significantly reduced bloodstream infection incidence (odds ratio = 0.73, 95% confidence interval: 0.57-0.93), shortened ICU stay, and decreased overall infectious complications, while appearing to preserve gut microbial homeostasis and immunomodulatory function[52].

The role of glutamine supplementation in barrier maintenance has been explored, but its clinical benefit remains contested[53,54]. A 2024 meta-analysis found no significant overall improvement in intestinal permeability with glutamine supplementation; a benefit was observed only in high-dose (> 30 g/day), short-duration (< 2 weeks) subgroups, and most high-quality trials have not demonstrated clear gains in infection rates or mortality[55]. The fundamental limitation at this stage is the absence of barrier-specific repair strategies; once structural injury is established, reversibility appears poor - reinforcing the primacy of early intervention.

Targeting inflammation - immunomodulation and anti-inflammatory therapy

Once the cascade has entered the inflammatory activation phase, clinical management typically focuses on controlling excessive inflammation to limit ongoing multiorgan injury. Current strategies encompass three broad approaches: Optimizing infection control to reduce inflammatory triggers; minimizing the input of microbial products such as endotoxin; and modulating the immune response. More precise antibiotic prescribing within an ASP framework reduces bacterial burden; limiting endotoxin translocation depends on upstream barrier protection and microbiota interventions. Immunomodulatory strategies - including low-dose corticosteroids, ulinastatin, thymosin, and cytokine inhibitors - have been explored to reduce proinflammatory cytokine burden, though the evidence is inconsistent. A meta-analysis of over 5000 patients suggested that immunomodulatory therapy reduces mortality risk in sepsis overall (relative risk = 0.87, 95% confidence interval: 0.81-0.93), but effects vary substantially across interventions, and most high-quality trials have not demonstrated durable long-term benefit[56]. It bears emphasis that targeting inflammation in isolation rarely alters the disease trajectory, since upstream drivers - gut dysbiosis and metabolic imbalance - persist and may sustain or rekindle the inflammatory response. Anti-inflammatory therapy is therefore best positioned as one component of a multi-level integrated strategy, delivered in concert with microbiota reconstitution, barrier protection, and metabolic support.

System-level intervention and clinical outcome improvement

In the late stages of the cascade, patients commonly manifest SIRS and MODS. Treatment priorities shift to organ support, including hemodynamic management, continuous renal replacement therapy (CRRT), mechanical ventilation, and enteral or parenteral nutritional support, aiming to preserve vital organ function and stabilize the internal environment. Current guidelines and meta-analyses indicate that standardized implementation of these measures can improve short-term outcomes and reduce acute-phase mortality[57]. However, organ support measures differ substantially in their quality of evidence and in their capacity to address the upstream pathological drivers identified in preceding sections.

High-quality evidence supports hemodynamic optimization (including early goal-directed fluid resuscitation and vasopressor use per surviving sepsis guidelines) as improving short-term survival in septic shock[57]. However, hemodynamic support does not address gut dysbiosis, SCFA depletion, or barrier dysfunction; its benefits are confined to stabilization of macrovascular perfusion. Similarly, lung-protective mechanical ventilation strategies reduce ventilator-induced lung injury and acute-phase mortality, but do not modify intestinal microbiota composition, epithelial integrity, or systemic inflammatory pathway activation; the evidence base is high quality for the pulmonary endpoint but indirect with respect to gut-specific pathology.

Moderate-quality evidence supports CRRT in managing fluid overload, acid-base disturbances, and cytokine clearance in sepsis-associated acute kidney injury. Some studies suggest that CRRT may attenuate circulating inflammatory mediators; however, whether this translates into meaningful attenuation of microbiota-driven inflammatory amplification remains uncertain, and CRRT does not reverse upstream dysbiosis or barrier injury. Nutritional support - early enteral nutrition in particular - is supported by moderate-to-high quality evidence for reducing infectious complications and preserving gut barrier function[52], and is the only organ support modality with demonstrated mechanistic relevance to the upstream gut-centric cascade.

Low-quality evidence characterizes most other organ support strategies in the context of gut-specific endpoints. No current organ support measure has been shown to restore intestinal microbial diversity, normalize SCFA concentrations, or reverse structural epithelial injury. This underscores the fundamental limitation of late-stage reactive approaches: Organ support is necessary to prevent immediate death but insufficient to alter the gut-driven pathological trajectory. Soranno et al[29] emphasize that positioning the gut as a central driver of critical illness highlights the inadequacy of relying solely on late supportive care to modify the overall disease course. Clinical practice is therefore increasingly emphasizing earlier intervention - optimizing antibiotic use, promoting microbiota recovery, protecting the intestinal barrier, and improving metabolic status - ideally before the cascade becomes self-sustaining. Future studies should evaluate whether combined upstream (microbiota/metabolic) and downstream (organ support) strategies produce additive or synergistic benefits in high-acuity ICU patients.

A mechanism-based clinical decision pathway

Drawing on the mechanistic cascade and available clinical evidence, interventions can be roughly stratified according to disease stage to better match therapeutic strategies to the dominant pathological process at each phase. The overarching principle is to intervene as early as possible in upstream pathology, integrating additional levels of treatment as the disease progresses.

In the early phase, characterized predominantly by gut dysbiosis, the focus is on minimizing unnecessary microbiota disruption - emphasizing ASPs and microbiota-protective strategies, with preference for narrow-spectrum, short-course, targeted antibiotic regimens to preserve commensal diversity and colonization resistance.

As the disease evolves and metabolic abnormalities and barrier dysfunction become apparent, intensified enteral nutritional support is warranted, with supplemental dietary fiber and prebiotics to promote SCFA-producing taxa, thereby potentially improving epithelial energy supply and barrier integrity.

In the inflammation-dominated phase, the priority shifts to balancing infection control with immunomodulation: Standardized antimicrobial therapy is combined with immune regulation and supportive care - including low-dose corticosteroids or other immunomodulatory agents as clinically appropriate - while upstream microbiota stabilization and barrier maintenance remain integral concerns. In the late phase, organ support predominates, and emerging studies are exploring multi-target approaches that combine microbiota and metabolic interventions, though the evidence base remains limited.

In practice, SOFA score can guide stratification: Patients with SOFA score < 6 are managed primarily with optimized antibiotic strategies and early enteral nutrition[57]; patients with SOFA score ≥ 6 may benefit from combined microbiota and metabolic interventions; those with severe AGI (SOFA > 9) warrant individualized multi-level therapeutic planning. The major clinical interventions across levels, along with supporting evidence, are summarized in Table 2.

Table 2 Summary of multi-level clinical interventions for intestinal failure in critically ill patients.

Intervention level	Primary strategy	Key measures	Primary clinical outcomes	Effect size/results	Ref.
Microbiota	ASP	Optimize selection, shorten courses, reduce broad-spectrum coverage	Broad-spectrum antibiotic use rate, AGI incidence	Use rate ↓ 20%-30%; AGI incidence ↓ 15%-25%	[37]
Microbiota	Microbial reconstitution (probiotics/synbiotics)	Probiotic/synbiotic supplementation	Antibiotic-associated diarrhea incidence	RR = 0.70-0.80	[49]
Microbiota	Microbial reconstitution (FMT)	FMT	CDAD success rate, 30-day mortality	Success rate 80%-90%; mortality significantly reduced	[42,43]
Metabolic	Nutritional support and SCFA restoration	Fiber-enriched enteral nutrition	AGI severity, butyrate-producing bacteria abundance	OR = 0.82-0.86	[46]
Metabolic/barrier	Early enteral nutrition	Initiated within 48 hours	Bloodstream infection rate, ICU length of stay	OR = 0.73 (95%CI: 0.57-0.93)	[52]
Barrier	Barrier protection	Glutamine supplementation	Intestinal permeability	Improved in high-dose, short-course subgroup; no significant benefit otherwise	[55]
Inflammatory	Immunomodulation and anti-inflammatory therapy	Low-dose corticosteroids, etc	Mortality in sepsis	RR = 0.87 (95%CI: 0.81-0.93)	[56]
Systemic	Organ support (high-quality evidence)	Hemodynamic management, mechanical ventilation	Short-term prognosis, acute-phase mortality	Standardized implementation improves short-term outcomes; does not address upstream dysbiosis	[57]
Systemic	CRRT (moderate-quality evidence)	Continuous renal replacement therapy	Cytokine clearance, fluid balance	Some attenuation of circulating mediators; effect on gut microbiota unproven	[57]

ASP: Antibiotic stewardship program; AGI: Acute gastrointestinal injury; RR: Relative risk; FMT: Fecal microbiota transplantation; CDAD: Clostridioides difficile-associated disease; SCFA: Short-chain fatty acid; ICU: Intensive care unit; OR: Odds ratio; CI: Confidence interval; CRRT: Continuous renal replacement therapy.

The present review makes several novel contributions relative to prior narrative reviews on gut dysbiosis in critical illness. First, whereas previous reviews have addressed dysbiosis as a consequence of the general critical illness state, we specifically focus on antibiotic-associated dysbiosis as a modifiable iatrogenic exposure, enabling clearer delineation of a potentially reversible causal pathway. Second, the “microbiota-metabolism-barrier-inflammation cascade” framework proposed here offers a sequential pathophysiological model - rather than a descriptive enumeration of individual disrupted pathways - and identifies specific molecular transitions (SCFA depletion → HIF-1α downregulation → tight junction disruption → LPS translocation → TLR4/NF-κB activation) as potential intervention nodes. Third, we compile a quantitative evidence body - including odds ratio, adjusted hazard ratio, relative risk values, and percentage changes in SCFA concentrations - providing a structured, data-anchored mechanistic framework that extends beyond qualitative description. Fourth, the stage-based intervention pathway introduced in Figure 2B explicitly maps therapeutic modalities to dominant pathological processes at each cascade stage, offering a practical clinical decision framework. Together, these contributions are intended to advance both the conceptual understanding of antibiotic-associated intestinal failure and its clinical management in the ICU setting.

LIMITATIONS AND FUTURE DIRECTIONS

Methodological limitations

The literature is dominated by observational studies and animal experiments; high-quality, large-sample RCTs are scarce, limiting causal inference. Most multi-omics investigations are cross-sectional in design, making it difficult to reconstruct the temporal causal sequence of the “microbiota collapse → SCFA depletion → barrier injury → inflammatory activation” cascade. Inconsistent definitions of “intestinal failure” - with AGI grading systems and intestinal failure criteria used interchangeably across studies - generate substantial heterogeneity and impede cross-study comparisons. ICU cohorts are generally small, and follow-up is typically confined to the inpatient period, leaving the long-term prognostic consequences of gut dysbiosis poorly characterized.

Mechanistic gaps

Research depth is uneven across different nodes of the cascade. The relationship between SCFA depletion and the HIF-1α/tight junction axis is reasonably well established in vitro, but dose-response relationships in ICU patients in vivo remain unclear. The association between bacterial translocation and MODS has been supported in CLP animal models, yet human clinical evidence relies largely on surrogate markers - LBP and I-FABP - with limited specificity. The system-level molecular network proposed in this review is primarily derived from correlative metagenomic-metabolomic analyses, and functional validation of key network nodes (AKT1, TLR4) comes mainly from gene-knockdown animal models, whose applicability to the human critical illness context requires confirmation. The potential contribution of epigenetic regulation to antibiotic-associated dysbiosis remains largely unexplored - a likely key to understanding interindividual variability in response. Specifically, two research directions merit prioritization: (1) DNA methylation at tight junction gene promoters (TJP1, OCLN), constituting a durable epigenetic record of antibiotic-induced barrier injury; and (2) The regulatory roles of non-coding RNAs (miR-21, miR-155, lncRNA H19) in antibiotic-induced epithelial injury and immune dysregulation.

Translational challenges

Multiple challenges complicate the clinical translation of these findings. An inherent tension exists between the clinical necessity of antibiotic use and the imperative to protect the microbiota; while ASPs can reduce broad-spectrum antibiotic exposure, no established metric yet enables real-time quantification of individual microbiota injury risk, leaving precision decision-making largely experience-dependent. The appropriate indications, donor selection criteria, and optimal timing of FMT and probiotic interventions in ICU populations lack consensus; available safety data derive mainly from immunocompetent individuals and cannot be directly extrapolated to critically ill patients. There is also a lack of point-of-care biomarkers for early detection of “metabolic switch” activation - that is, significant SCFA decline - meaning metabolic-level interventions typically lag behind the actual pathological timeline and miss the optimal therapeutic window.

Notwithstanding these limitations, current progress offers important guidance for refining future intervention strategies. Several directions warrant prioritization. First, building longitudinal multi-omics cohort platforms through dynamic sampling from ICU admission to discharge, integrating metagenomics, metabolomics, and host transcriptomics to validate the temporal causal and dose-response relationships among cascade nodes, generating more convincing human mechanistic evidence. Second, developing targeted SCFA-based precision interventions - establishing point-of-care assays for real-time monitoring of fecal and serum butyrate levels, and systematically evaluating the efficacy of butyrate enemas and oral precursor supplementation (e.g., resistant starch, inulin) in early intestinal failure - to define effective intervention windows and dosing thresholds. Third, constructing individualized microbiota intervention decision models by integrating baseline microbial diversity metrics (Shannon index, F/B ratio) with SOFA scores into composite stratification systems, defining candidate populations for FMT and prebiotic therapy and advancing the clinical translation of “microbiota-guided treatment”. Fourth, validating key molecular targets in humans through peripheral blood single-cell transcriptomics and intestinal organoid models to characterize dose-dependent perturbation of TLR4/NF-κB and PI3K/Akt pathways by antibiotic exposure, providing translational evidence for targeted interventions.

CONCLUSION

Antibiotic-associated gut dysbiosis is a core, potentially modifiable pathogenic contributor to intestinal failure in critically ill patients. Through a sequential pathological cascade - microbiota collapse → SCFA depletion → barrier injury → inflammatory amplification → systemic dysregulation - antibiotic overuse appears to amplify the risk of intestinal failure and MODS beyond that attributable to critical illness alone. This mechanistic understanding, grounded in converging evidence from multi-omics studies, animal models, clinical cohorts, and intervention trials, identifies the gut microbiota as a tractable therapeutic target in the ICU setting. Critically, the cascade model underscores that late-stage organ support, while necessary, is insufficient to alter the disease trajectory when upstream pathological drivers remain unaddressed.

Three evidence-supported, clinically actionable recommendations emerge from this analysis. First, antibiotic stewardship should be prioritized from ICU admission: Preference for narrow-spectrum, short-course, targeted regimens can reduce iatrogenic microbiota disruption by 20%-30% and is associated with reduced AGI incidence, without increasing treatment failure risk[37,38]. Second, early enteral nutrition - initiated within 48 hours - combined with dietary fiber supplementation should be implemented as standard practice in eligible critically ill patients, as it is associated with preserved barrier function, promoted SCFA production, reduced infectious complications (odds ratio = 0.73), and attenuated gut dysbiosis[44,46,52]. Third, microbiota monitoring should be integrated into risk stratification for high-risk ICU patients: Baseline microbial diversity metrics (Shannon index, F/B ratio) combined with SOFA score can potentially identify patients at elevated risk of progressive intestinal failure, informing timely decisions regarding FMT or prebiotic therapy. These recommendations are intended as practical clinical guidance while acknowledging that the evidence base for individualized microbiome-targeted interventions remains evolving.

Future research priorities should encompass three interrelated domains. First, the PRISMA-structured evidence base assembled in this review highlights the predominance of observational and cross-sectional data; prospective longitudinal multi-omics cohort studies are urgently needed to validate temporal causal relationships within the cascade and to generate dose-response data applicable to ICU populations. Second, multi-omics validation of the proposed molecular network - particularly the HIF-1α/tight junction axis, TLR4/NF-κB pathway activation, and PI3K/Akt suppression - in human critical illness contexts is essential to move from correlative to mechanistic evidence. Third, the development of precision microbiome medicine strategies - including point-of-care SCFA monitoring, standardized FMT protocols for ICU patients, and biomarker-guided intervention timing - represents the translational frontier. Realizing the clinical potential of microbiome-targeted therapy in critical care will require coordinated investment in mechanistic research, large-scale randomized trials, and implementation science.