Short-Chain Fatty Acids: A Key Modulator of Sepsis-Associated Acute Respiratory Distress Syndrome

Introduction

Sepsis is a systemic inflammatory response syndrome induced by infection, frequently observed in patients with severe trauma or infectious diseases. The lungs are the primary target organ in sepsis, and Acute respiratory distress syndrome (ARDS) is a prevalent clinical complication characterized by diffuse alveolar damage, hypoxemia, and respiratory distress.¹ Approximately 32% of ARDS cases are attributed to sepsis, with sepsis-associated ARDS exhibiting a poorer prognosis and higher mortality rate.² The hyperactivated immune system in sepsis release substantial amount of proinflammatory factors, triggering a “cytokine storm” that significantly compromises the integrity of the intestinal barrier. This disruption facilitates the proliferation and translocation of intestinal microorganisms and endogenous bacteria to the lungs via the portal circulation and mesenteric lymphatic vessels.³ Subsequently, the excessive secretion of anti-inflammatory factors results in immune paralysis, diminishes the capacity for pathogen clearance, exacerbates damage to the alveolar-capillary barrier, and ultimately worsens the lesions associated with ARDS.

The human gastrointestinal tract hosts a large and unevenly distributed microbial community, with the highest microbial density found in the colon.⁴ The predominant microbial phyla include Proteobacteria, Firmicutes, Clostridia, Actinobacteria, and Bacteroides.⁵ Among these, Bacteroidetes and Firmicutes primarily constitute the adult gut microbiota, accounting for more than 90% of the population.⁶ Although potential pathogens such as Helicobacter pylori and Escherichia coli may be present in healthy individuals, the intestinal microbiota is generally considered to be composed of “commensal” microbes. However, during sepsis, factors such as hypoxic injury, impaired intestinal epithelial barrier function, the use of antibiotics, mechanical ventilation, and vasopressors can lead to disruptions in the intestinal microecology. Critically ill ICU patients with severe respiratory failure frequently exhibit sepsis, prolonged invasive mechanical ventilation, and secondary infections, all of which may contribute to microbiota disruption and gut-lung axis dysregulation.⁷ This results in a reduction of beneficial bacteria, such as those producing short-chain fatty acids (SCFAs), and an overgrowth of pathogenic bacteria, including Fusobacteria and Proteus.⁸ The intestinal microecology is intricately linked to sepsis-associated ARDS.² An imbalance in the intestinal microbiota in affected patients results in a decreased production of SCFAs, a diminished anti-inflammatory response, and compromised intestinal epithelial barrier function. These alterations exacerbate immune dysregulation and further damage the intestinal barrier, thereby accelerating the progression of ARDS. In individuals with sepsis-associated ARDS, a significant presence of intestinal-origin bacteria, such as Bacteroides and Enterococcus, has been identified within the pulmonary microbiota.⁶ This observation suggests that dysbiosis of the intestinal microbiota plays a role in the pathogenesis of sepsis-associated ARDS. A critical metabolic function of gut microbes is the fermentation of dietary fiber or starch into SCFAs.⁹ Despite the anatomical independence of the gut and lungs, intestinal microbiota and their metabolites, including SCFAs, are transported to the lungs through the circulatory system, where they modulate immune responses and inflammatory processes.¹⁰ In sepsis, the rapid depletion of SCFA-producing commensals, particularly Faecalibacterium and Bifidobacterium represents a critical feature of dysbiosis that directly undermines these protective mechanisms. This review focuses on the mechanism of intestinal dysbiosis in sepsis-associated ARDS, the research progress of SCFAs intervention, and potential therapeutic strategies targeting intestinal microorganisms.

Mechanism of Intestinal Dysbiosis in Sepsis-Associated ARDS

Gut microbiota metabolites, as signaling molecules and substrates in host metabolic reactions, are involved in the production or transformation of SCFAs, bile acids, endocannabinoids, trimethylamine-N-oxide (TMAO), and lipopolysaccharide (LPS), all of which influence host physiological and pathological processes. The fundamental mechanism underlying Sepsis-associated ARDS involves the interplay between intestinal barrier disruption, inflammatory cascades, and the structure and metabolites of the intestinal microbiota (refer to Figure 1).

Figure 1 The fundamental mechanisms of intestinal dysbiosis in sepsis-associated ARDS. Intestinal dysbiosis drives disease progression through four interconnected dimensions: structural alteration of microbiota, intestinal barrier injury, immune imbalance, and systemic inflammation.

Intestinal Barrier Dysfunction

The functional integrity of the intestinal barrier, serving as the primary defense line to maintain microbial-host homeostasis, is crucial for preventing microbial translocation. The protection provided by intestinal epithelial cells (IECs) against pathogens is categorized into mechanical and non-mechanical defenses.¹¹ Mechanical protection involves the roles of tight junctions, the epithelial barrier, intestinal peristalsis, and the mucus layer. Non-mechanical protection encompasses microbial colonization, immunoglobulin secretion, and the presence of dendritic cells.¹² In the context of sepsis, proinflammatory mediators such as TNF-α, IL-6, and IL-1β initiate the apoptosis pathway in IECs, a process that is associated with systemic hypotension and intestinal ischemia and hypoxia due to microcirculatory failure. This cascade leads to IEC necrosis, diminished expression of tight junction proteins such as occludin and claudin, and suppression of mucus layer secretion,¹³ ultimately resulting in a marked increase in internal permeability. During this process, hypoxia adversely affects mitochondrial function within the intestinal epithelium, thereby reducing ATP production, impairing mucosal repair capabilities, and facilitating the overgrowth of opportunistic pathogens. The insufficient secretion of antimicrobial peptides (such as Reg3γ) and decreased mucus production (such as MUC2) collectively allow LPS from Gram-negative bacteria to breach the intestinal barrier and enter systemic circulation via the portal vein or lymphatic system. This breach activates the systemic Toll-like receptor 4 (TLR4)/nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway signaling pathway, precipitating a “cytokine storm.” Consequently, a vicious cycle is established, wherein the release of inflammatory mediators and the compromise of the intestinal barrier mutually reinforce each other.¹⁴

Inflammatory Reaction

As the central pathological characteristic of sepsis, the “cytokine storm” exacerbates intestinal barrier damage through the excessive release of pro-inflammatory mediators. This process facilitates the translocation of intestinal microbiota and their harmful metabolites, such as LPS, to the lungs.¹⁵ Upon LPS binding to the TLR4 on alveolar macrophages, the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway is activated, leading to the release of chemokines such as interleukin-8 (IL-8). These chemokines recruit a substantial number of neutrophils to infiltrate lung tissue. The neutrophils subsequently release neutrophil elastase (NE) and reactive oxygen species (ROS), compromising the integrity of the alveolar-capillary barrier and resulting in pulmonary edema and impaired oxygenation. It is noteworthy that the inflammatory microenvironment of the lung is not unidirectional; factors such as interleukin-6 (IL-6) and IL-8 produced by alveolar macrophages can circulate back to the intestinal tract, further exacerbating barrier damage and establishing a feedback loop within the “gut-lung axis” inflammation. Clinical evidence indicates that 40% of the bacterial flora in the bronchoalveolar lavage fluid of septic patients is homologous to the dominant intestinal flora, with its abundance showing a significant positive correlation with serum IL-6 and TNF-α levels.⁶ This suggests that the translocation of intestinal microbiota is a critical factor.

Intestinal Dysbacteriosis

Intestinal dysbiosis, characterized by an imbalance in the composition and metabolites of the intestinal microbiota,³ represents another fundamental mechanism in the pathogenesis of sepsis-associated ARDS. Specifically, disturbances in the intestinal microbiota structure include a reduction in beneficial bacteria such as Faecalibacterium (a predominant butyrate producer) and Bifidobacterium (a key acetate producer), alongside an increase in opportunistic pathogens like Escherichia coli and Streptococcus.^5,11,16 Sepsis is associated with a marked decrease in both α diversity (species richness) and β diversity (community composition differences) of the intestinal microbiota, evidenced by the depletion of obligate anaerobes that produce SCFAs, such as Bifidobacterium and Lachnospiraceae. Research indicates a positive correlation between decreased alpha diversity of intestinal microbiota and 28-day mortality in critically ill patients.¹⁷ Intestinal-origin bacteria, including Bacteroidales and Lachnospiraceae, have been found to be enriched in lung flora independently of the upper respiratory tract,⁶ directly reflecting gut-lung translocation. This suggests that the gut microbiome plays a crucial role in the pathophysiology of sepsis-associated ARDS. In addition, patients with chronic bowel diseases, such as inflammatory bowel disease, have an increased risk of lung disease,¹⁸ confirming the pathological association of the gut-lung axis. On the other hand, the imbalance of microbial metabolites is mainly manifested by the decrease of beneficial metabolites of SCFAs such as acetate, butyrate and propionate, and the increase of harmful metabolites such as LPS and TMAO, accompanied by the disorder of tryptophan metabolic pathway and the disruption of secondary bile acid homeostasis.^19,20 The reduction in SCFAs compromises their anti-inflammatory and barrier-repair functions through the activation of G-protein-coupled receptor 43 (GPR43) or histone deacetylase (HDAC) inhibitory pathways.²¹ Butyrate serves as the primary energy source for colon epithelial cells, fulfilling approximately 70% of their energy requirements.²² It facilitates the production of Adenosine Triphosphate (ATP) through beta-oxidation and supports the expression of tight junctions (TJs). A deficiency in butyrate leads to the stabilization of hypoxia-inducible factor 1α (HIF-1α), initiates metabolic reprogramming, disrupts barrier function, and directly contributes to energy metabolism disorders within the intestinal epithelium.²² The accumulation of harmful metabolites, such as LPS, activates a systemic inflammatory response via the TLR4 pathway and induces a mitochondrial ROS surge through Succinate Receptor 1 (SUCNR1). This cascade drives the formation of neutrophil extracellular traps (NETosis), promotes the apoptosis of alveolar macrophages, and accelerates the development of pulmonary microthrombosis, ultimately exacerbating hypoxic lung injury and fibrosis. This process promotes platelet activation and endothelial dysfunction, thereby exacerbating hypercoagulability in ARDS.²³ Among the tryptophan metabolites, indole-3-propionic acid decreases while serotonin increases.Indole-3-propionic acid inhibits NLRP3 inflammasome and enhances lung barrier function by activating AhR,²⁴ while serotonin promotesneutrophil NETosis and aggravates lung injury.²⁵ The disruption of secondary bile acid homeostasis weakens its protective effect of inhibiting NF-κB pathway and maintaining alveolar fluid balance, and further aggravates lung injury.²⁶ These metabolic abnormalities act synergistically through the “gut-lung axis” to drive the progression of Sepsis-associated ARDS.

Immune Imbalance

Immune dysregulation is critically involved in the gut-lung axis.²³ An imbalance in the intestinal microbiota disrupts the Th17/Treg immune axis, resulting in an abnormal increase in the proportion of Th17 cells, which subsequently secrete IL-17A. Upon migrating to the lungs via the circulatory system, IL-17A stimulates alveolar epithelial cells to release IL-8, which recruits neutrophils and promotes the release of neutrophil elastase (NE), thereby directly compromising alveolar integrity.²¹ Concurrently, a reduction in Treg cells leads to inadequate secretion of the anti-inflammatory cytokine IL-10, failing to effectively suppress excessive inflammatory responses. The resultant inflammatory milieu within the lungs inhibits the intestinal epithelial Wnt/β-catenin signaling pathway, diminishes the proliferation of leucine-rich repeat-containing G-protein-coupled receptor 5 (Lgr5+) stem cells, and impairs mucosal repair by releasing IL-6, IL-8, and other factors into the circulatory system.²⁷ Furthermore, LPS derived from the intestinal microbiota can exacerbate pulmonary inflammatory damage by activating the Nod-like receptor 3 (NLRP3) inflammasome in alveolar macrophages and enhancing the caspase-1-mediated maturation and release of IL-1β.

In conclusion, intestinal dysbiosis in sepsis-related ARDS represents a dynamic and evolving systemic pathological process. This process encompasses the disruption of physical barriers, dysregulated immune responses, metabolic disturbances of the microbiota, and intricate inter-organ signaling networks. These factors collectively contribute to intestinal permeability, facilitating microbial translocation and exacerbating inflammatory responses, thereby intensifying the cascade of lung injury. Consequently, intestinal dysbiosis has emerged as a critical pathological underpinning of sepsis-associated ARDS, rendering it challenging to reverse.

Causality Between Intestinal Dysbacteriosis and Sepsis-Associated ARDS

Intestinal dysbiosis in sepsis-associated ARDS is a dynamically evolving pathogenic process. Existing pathophysiological evidence reveals a clear pathway from intestinal metabolic disorders to pulmonary immune injury.

First of all, systemic hypotension and visceral vasoconstriction caused by sepsis lead to severe hypoxia of intestinal mucosa, which not only directly damages the mitochondrial function of intestinal epithelial cells, but also destroys the living environment of obligate anaerobes. As a result, the key beneficial bacteria that produce SCFAs (such as Bifidobacterium, Clostridium tenella, and Faecalis praecox) are rapidly depleted, while oxygen-tolerant opportunistic pathogens (such as Enterobacteriaceae and Enterococcus) take advantage of the situation to proliferate.²⁸ This structural dysbiosis directly leads to a sharp decline in the synthesis of protective metabolites SCFAs. Because butyrate is the main energy source of colonic epithelial cells, its deficiency leads to energy metabolism disorders of epithelial cells, down-regulation of tight junction proteins (Occludin, Claudin), and ultimately leads to the collapse of physical barriers. This “leaky gut” condition opens the floodgate for distal metastasis of the causative agent: bacterial debris and damaging metabolites of intestinal origin (eg., endotoxin LPS, trimethylamine-N-oxide TMAO) break through the mucosal barrier, bypassing the “first-pass effect” of the liver not only through the portal system, but also through the mesenteric lymphatic vessels. It flows directly through the thoracic duct into the superior vena cava and back into the pulmonary circulation. These translocated bacterial products act as potent pathogen-associated molecular patterns (PAMPs) and serve as “core initiating factors” for lung inflammation. They specifically activate the TLR4/NF-κB and NLRP3 inflammasome pathways on the surface of alveolar macrophages in lung tissue, leading to the explosive release of proinflammatory cytokines (IL-6, TNF-α) and the chemotactic aggregation of neutrophil, triggering a cascade of amplified cytokine storms.^29,30 At the same time, the systemic deficiency of SCFAs leads to the failure of immune regulation, which is manifested by the imbalance of Th17/Treg cells and the persistent polarization of M1 macrophages, which hinders the timely resolution of inflammation and aggravates diffuse alveolar injury.

Clinical evidence shows that bronchoalveolar lavage fluid of ARDS patients is highly enriched in gut-derived flora, which is strongly correlated with the severity of the disease,⁶ strongly confirming that intestinal dysbiosis is a key upstream factor driving the progression of ARDS.

Types and Core Characteristics of SCFAs

SCFAs are the main end products of undigested carbohydrates fermented by intestinal flora, in which acetate, propionate and butyrate account for more than 95% of the total. Although they share some anti-inflammatory properties, they are significantly specific in terms of microbial origin, tissue distribution and utilization preferences (Table 1), which determines their different roles in the prevention and treatment of ARDS.

Table 1 Properties of Major Short-Chain Fatty Acids

Mechanism of SCFAs Acting on Sepsis-Associated ARDS

Clinical studies have shown that the levels of SCFAs in patients with sepsis-associated ARDS are significantly lower than those in healthy individuals, and their concentrations are negatively correlated with the severity of ARDS.SCFAs play a protective role through the “gut-lung axis”. The core mechanism is around the bidirectional regulation of anti-inflammatory and pro-inflammatory, the remodeling of immune cell function and the protection of gut-lung barrier, which are all achieved by inhibiting histone deacetylase (HDACs) or activating two key pathways of G protein-coupled receptors (GPCRs, mainly GPR41/43, GPR109a) (See, Figure 2). Host protective crosstalk is supported by the “gut-lung axis”.^21,40,43

Figure 2 Molecular mechanisms of SCFAs modulating the gut-lung axis in sepsis-associated ARDS. Gut-derived SCFAs exert pulmonary protective effects by regulating multiple signaling pathways (including AhR, TLR4/NF-κB, GPCRs, and HDAC), thereby mitigating inflammation, modulating immune cells, and promoting autophagy.

Regulation of Inflammatory Response

ARDS is characterized by inflammatory injury of alveoli and capillaries, and infection and inflammation are the core drivers of ARDS. Intestinal dysbacteriosis resulting from critical illness severely reduces SCFAs, exacerbating the inflammatory response triggered by pathogens such as Gram-negative bacteria through TLR4 activation of the NF-κB/IRF3 pathway. The regulation of SCFAs on inflammation is not a one-way inhibition, but a dynamic balance between pro-inflammation and anti-inflammatory,⁴⁴ and its effect depends on the type, concentration, target cell type and inflammatory response stage of SCFA. It inhibits inflammation mainly through two mechanisms.

First, gene expression is regulated by inhibition of HDACs activity. HDACs can bind an acyl group to chromatin and inhibit gene expression. As HDAC inhibitors, SCFAs can regulate the degree of acetylation and deacetylation of chromatin, and regulate the balance between pro-inflammatory factors (TNF-α, IL-6) and anti-inflammatory factors (IL-10).^45,46 Butyrate attenuates oxidative stress in septic lung injury byinhibition of HMGB1/TLR4/NF-κB pathway through inhibition of HDAC activity.²⁴ Propionic acid can also inhibit HDAC, affect energy metabolism, reduce neutrophil ROS production and NETosis.⁴⁷ Secondly, anti-inflammatory signals are transmitted through the activation of GPCRs. The free fatty acid receptors GPR41, GPR43, and GPR109A are the major receptors for SCFAs.Butyrate ameliorates ARDS by activating GPR43 to promote autophagy through a HIF-1α-dependent mechanism, reducing alveolar epithelial damage.^45,48

It is worth noting that different SCFAs may have different immunomodulatory effects. Under specific conditions, SCFAs may delay neutrophil apoptosis, leading to an increase in inflammatory factors. For instance, Xuan et al demonstrated that gut microbiota-derived acetate promotes sepsis-induced ARDS by delaying neutrophil apoptosis through fatty acid-binding protein 4 (FABP4) signaling,³⁹ while He et al showed that butyrate enhances CD8+ T cell antitumor immunity by sustaining their metabolic fitness through delayed apoptosis.⁴⁸ This seemingly paradoxical effect reflects the bidirectional regulation of inflammation by SCFAs, with anti-inflammatory effects preventing excessive immune injury and modest pro-inflammatory effects ensuring rapid clearance of pathogens.⁴⁹

Immunomodulation

SCFAs regulate macrophage function and inflammatory cytokine secretion through dual mechanisms of HDAC inhibition and GPCRs activation.²²

In the aspect of neutrophil regulation, butyrate inhibits the activation of neutrophil by inhibiting HDAC activity and reducing the expression of glycolysis-related genes. At the same time, butyrate activates the GPR43 receptor and inhibits the migration of neutrophil to the lung and the release of NETosis. Propionic acid reduces neutrophil infiltration in lung tissue through the GPR43 receptor pathway.

In the regulation of macrophage polarization, propionic acid reduces the polarization of proinflammatory M1 macrophages and promotes anti-inflammatory M2 polarization by inhibiting HDAC activity and down-regulating the expression of key glycolytic enzymes such as HK2 and LDHA. Meanwhile, SCFAs regulate macrophage metabolic reprogramming through GPR43, maintaining the Th17/Treg cell balance.

Barrier Protection

Enrichment of gut-derived bacteria in the pulmonary microbiota of ARDS patients is associated with increased intestinal and alveolar capillary permeability.⁵⁰ SCFAs enhance the barrier function through multiple mechanisms: on the one hand, SCFAs activate the GPR43 receptor, up-regulate the expression of antimicrobial peptides, reduce gut leakage and bacterial and endotoxin translocation to the lung.⁵¹ Butyrate, as the main energy source of colonic epithelial cells, accounts for 70% of the energy demand of colonic cells, generates ATP through β-oxidation, and maintains the expression of tight junction-related proteins.^52,53

Butyrate, on the other hand, acts as an aryl hydrocarbon receptor (AhR) ligand and directly activates AhR.⁵⁴ It is worth noting that while butyrate exhibits AhR-binding capacity, tryptophan-derived microbial metabolites—particularly indole-3-aldehyde, indole-3-acetic acid, and indole-3-propionic acid—are more potent and well-characterized endogenous AhR ligands.²⁴ These tryptophan catabolites, produced by commensal bacteria such as Lactobacillus, synergize with SCFAs to fine-tune mucosal immunity. AhR activation, regardless of ligand source, leads to the decrease of pro-inflammatory factors such as IFNγ, IL-6 and TNF, and the increase of regulatory factors such as IL-10 and IL-22, which promotes the production of antimicrobial peptides and epithelial barrier integrity.⁴⁶ Butyrate also reduces the translocation of LPS of intestinal origin to the lungs by supporting the formation of tight junction proteins that maintain the barrier through the synaptopodin mechanism.⁴⁶

In the context of sepsis, intestinal flora imbalance leads to the reduction of SCFAs, weakens the protective mechanism, promotes histone deacetylation, inhibits GPCR activation, induces immune disorders and intestinal barrier dysfunction, and forms a vicious circle of inflammatory response and tissue injury. Therefore, targeted therapy of SCFAs may be an effective way to improve sepsis-associated ARDS.

Therapeutic Strategies and Clinical Transformation Prospects Based on Intestinal Flora and SCFAs

According to the pathological characteristics of intestinal flora imbalance and SCFAs depletion in Sepsis-associated ARDS, the reconstruction of intestinal microecological balance has become an important treatment entry point. By targeting and regulating the generation, metabolism and signal transduction of SCFAs, a multi-level intervention network is formed, which is expected to provide a new therapeutic scheme with anti-inflammatory, immunomodulatory and barrier repair functions for clinical practice. However, most of the existing studies focus on preclinical models, and the transformation from basic mechanisms to clinical practice still faces multiple challenges, which require the integration of existing interventions and further optimization of future diagnosis and treatment strategies.

Intervention Strategies to Restore Flora Homeostasis

Current interventions primarily aim to restore gut SCFAs levels by introducing beneficial bacteria, providing metabolic substrates, or directly transplanting the flora. Probiotics play a protective role by competitive exclusion of pathogenic bacteria and production of metabolites. For example, Clostridium butyricum directly metabolizes butyric acid, which plays a protective role by inhibiting inflammatory signaling pathways and enhancing intestinal barrier function,⁵⁵ while Lactobacillus rhamnosus improves the prognosis of respiratory tract infections by remodeling the flora balance and regulating the immune response.⁵⁶ Prebiotics such as inulin and fructooligosaccharides are able to selectively stimulate the growth of beneficial bacteria such as Bifidobacteria, providing a fermentation substrate to significantly increase endogenous SCFAs synthesis.⁵⁷ As a scientific combination of probiotics and prebiotics, synbiotics can play a synergistic role, promote the production of propionic acid and butyric acid, and alleviate the inflammatory response through the immunoregulatory pathway mediated by SCFAs.^58,59

In addition, fecal microbial transplantation (FMT), as a more comprehensive reconstitution strategy, aims to introduce the whole lineage flora of healthy donors. FMT can significantly increase the concentration of SCFAs such as propionic acid and butyric acid in the intestine, repair the intestinal mucosal barrier and improve the diversity of flora.^60,61 Although the direct evidence of FMT in the field of ARDS is limited, its successful application in the dysbacteriosis associated with severe infections, such as Clostridium difficile infection,⁶² and its advantages in reconstructing complex microecology and regulating the metabolism of SCFAs make it a potential therapeutic strategy. However, route optimization and safety assessment in critically ill patients require further study.

Core Challenges for Clinical Translation

Although the above strategies have demonstrated significant efficacy in experimental models, clinical translation still faces core bottlenecks, resulting in inconsistencies in the results of existing trials.^63,64 First, patients with sepsis are often in an extremely complex clinical state, with multiple organ failure, intestinal dysfunction, and long-term use of broad-spectrum antibiotics severely disrupting the intestinal microenvironment.⁶⁵ Antibiotics, while treating infections, may inhibit exogenous probiotics supplementation and lead to a significant decline in intestinal flora diversity and slow recovery.⁶⁶ Gastrointestinal motility disorders associated with critical illness may affect the colonization and distribution of oral preparations.⁶⁷ Secondly, there is significant heterogeneity of flora among patients. Critical patient vary widely in baseline microbiota composition and metabolic capability,⁵⁰ and this heterogeneity results in part from differences in disease severity, previous antibiotic exposure history, and host genetic background. Emerging evidence suggests that host genetic polymorphisms, such as single nucleotide polymorphisms (SNPs) in SCFA receptor genes (GPR41, GPR43, GPR109A) and pattern recognition receptors (TLR4, NOD2), may influence individual responsiveness to microbiota-derived metabolites.^44,51 For example, the GPR43 polymorphism rs3742171 has been associated with altered inflammatory responses in metabolic and immune disorders. Although the clinical impact of these polymorphisms on SCFA-based interventions in ARDS remains unexplored, pharmacogenomic profiling may represent a future avenue for precision medicine approaches. Patients lacking specific functional flora may not be able to effectively use prebiotics to synthesize SCFAs, suggesting the need for precise intervention strategies based on individual flora characteristics. Finally, there is still uncertainty about the timing of intervention. During the course of sepsis, dysbacteriosis and inflammatory response show a dynamic evolution, and the composition of intestinal flora shows time-dependent changes in different disease stages.⁶⁸ Therefore, distinguishing between early prevention and late-stage rescue is crucial for bedside clinicians. Early prevention may aim to maintain the intestinal barrier before ARDS onset, while late-stage rescue would focus on mitigating the “cytokine storm” and tissue injury. At present, there is insufficient evidence to determine the optimal intervention window, and future studies need to explore the relative benefits of early preventive intervention versus late-stage rescue, as well as restorative treatment in the remission stage of inflammation.

Future Directions

In order to overcome the above limitations, the following potential directions can be explored in future research and clinical practice. First, developing a microbiota-metabolite-based stratification and monitoring system. Although SCFAs have been proved to be biologically active in inflammatory bowel disease and other diseases, their value as a prognostic stratification index of sepsis still needs to be validated by prospective studies. In the future, we can explore the establishment of a multi-parameter evaluation system including serum/fecal SCFAs levels, inflammatory factors and intestinal barrier markers, and dynamically track the abundance changes of SCFAs-producing flora through metagenomics technology to assess the response to intervention. Secondly, for the special physiological state of critically ill patients, we need to explore the optimal delivery strategy. In patients with severely impaired bowel function, the traditional oral route may be limited. It is theoretically possible to explore the delivery of prebiotics through enteral nutrition tubes to promote the synthesis of endogenous SCFAs, but the intestinal tolerance, colonization capacity of flora and nutrient absorption status need to be fully evaluated. Although encapsulated FMT has been successful in noncritical recurrent C. difficile infection,⁶⁹ it requires normal gastrointestinal motility and absorptive function and is not appropriate in ICU patients with bowel dysfunction. Alternative routes such as colonoscopic FMT or nasointestinal tube infusion may be considered for these patients, but safety and efficacy data are lacking. Finally, future clinical trial designs should focus more on patient heterogeneity. Trial designs that pre-stratify patients based on microbiome characteristics have been proposed, but practical implementation still faces challenges such as lack of standardized testing methods and long turnaround time. In addition, timing coordination strategies between probiotics/prebiotics and antibiotic management should be explored, and biological outcome indicators including SCFA recovery level and immunophenotypic changes should be included to evaluate the intervention effect more comprehensively and clarify the mechanism of action. It is worth emphasizing that these strategies are still in the exploratory stage, and their clinical feasibility, cost-effectiveness and long-term safety need to be verified by rigorous prospective studies before they can provide a reliable basis for clinical decision-making.

Conclusion

Intestinal dysbacteriosis directly leads to the development of sepsis-associated ARDS by disrupting barrier function, promoting microbial translocation, inducing systemic inflammation and immune disorders. SCFAs, as key protective metabolites, play a complex two-way regulatory role through dual mechanisms of HDAC inhibition and GPCRs activation, which can both prevent excessive immune injury and ensure effective pathogen clearance. The ultimate effect of this action depends on the type, concentration, stage of inflammation, and target cell type of SCFAs. Interventional strategies targeting the intestinal flora, including probiotics, prebiotics, FMT, and direct SCFA supplementation, have demonstrated therapeutic potential in animal models and pilot clinical studies. However, there are still many challenges in clinical translation: interference with antibiotic use, differences in bacterial flora among individuals, and intestinal dysfunction in critically ill patients. In the future, it is necessary to develop reliable biomarkers, design individualized treatment programs and carry out high-quality clinical trials in order to truly apply SCFAs-related therapies to clinical practice.

In conclusion, SCFAs-targeted therapy based on the “gut-lung axis” provides a new treatment paradigm for sepsis-associated ARDS, but it is still necessary to cross multiple challenges from the mechanism to the clinical application. Integration of multi-omics technology, development of new delivery systems and optimization of combination therapy will be the key directions to promote the development of this field.