In recent years, with the outbreak of novel epidemic respiratory viruses, the deaths caused by the acute lung injury (ALI) has significantly increased, posing a substantial threat to human health (1, 2). ALI is a serious disease characterized by excessive inflammatory responses, usually triggered by various direct or indirect factors, including pneumonia, sepsis, trauma, and blood transfusions (3, 4). During the acute exudative phase of ALI, a large number of immune cells accumulate at the site of injury, initiating a series of inflammatory signaling pathways and releasing a range of pro-inflammatory cytokines (5). Subsequently, the inflammation disrupts the barrier function of the alveolar epithelium and endothelium, leading to increased permeability of the alveolar-capillary membrane (6). As a consequence of this persistent acute inflammatory process, the majority of patients with ALI will rapidly experience a deterioration in their respiratory function, which will eventually progress to the more severe form of and acute respiratory distress syndrome (ARDS) (7). Despite some advancements in the scientific understanding of the pathophysiological mechanisms underlying ALI, current treatment approaches still mainly depend on supportive therapies, including mechanical ventilation (8). ALI/ARDS remains one of the most fatal clinical syndromes in intensive care (4, 9). In light of these developments, researchers engaged in both clinical and preclinical studies are directing their attention toward the creation of novel treatments and medications, with the objective of providing patients with ALI/ARDS more efficacious therapeutic alternatives.

The emerging theory of the gut-lung axis elucidates a robust interconnection between the gut and the lungs (10). The gut microbiota and their metabolites have been demonstrated to play a role in the pathogenesis of various lung diseases, including asthma and respiratory infections, by regulating both innate and adaptive immunity (11). A substantial body of research indicates that the release of short-chain fatty acids (SCFAs) represents a pivotal mechanism through which the gut microbiota maintains host health and gut homeostasis (12). SCFAs are a type of fatty acid produced by beneficial bacteria in the gut through the fermentation of dietary fiber (13). In the intestines, the primary SCFAs include acetate, propionate, and butyrate (12). SCFAs can be absorbed and utilized by intestinal epithelial cells, with a portion serving as an energy source for cellular metabolic activities, while another portion enters the peripheral circulation to function as signaling molecules that regulate the host’s biological responses (14). They play an important role in regulating gut microbiota balance, maintaining intestinal barrier function, suppressing inflammation, and improving immune system function (15). The relationship between elevated levels of SCFAs in the gut and improved lung health is becoming increasingly clear (16). In patients with impaired immune function, an elevated concentration of SCFAs in their feces is associated with a markedly reduced risk of developing lung infections (14, 17). Currently, researchers have begun to explore the effects of exogenous supplementation of SCFAs in the treatment of ALI in animal experiments. For example, some studies have found that supplementing with SCFAs can significantly reduce the lung injury scores, lung wet-to-dry (W/D) ratio, myeloperoxidase (MPO), tumor necrosis factor-alpha (TNF-α), and malondialdehyde (MDA) levels in animal models of ALI (18–20). However, other studies have reached contradictory conclusions (21, 22). Therefore, it is necessary to summarize the results of the relevant publications to more comprehensively assess the impact of SCFAs on ALI.

Although there is currently an absence of clinical evidence regarding the application of SCFAs in patients with ALI/ARDS, the results of preclinical studies in animal experiments are invaluable for clinical practice and provide a crucial foundation for in-depth research into disease pathology and mechanisms (23). Our study aimed to evaluate the efficacy and potential mechanisms of SCFAs in ALI/ARDS animal models through a systematic review and meta-analysis. The findings could provide robust support for future experimental design and clinical application.

As the role of gut microbiota and their metabolites in regulating immunity and inflammatory responses becoming increasingly clear, their relationship with lung disease (also known as gut-lung axis) have attracted significant attention (10). SCFAs, produced by gut microbiota fermentation, are regarded as key molecules in the gut-lung axis, providing a novel therapy to alleviate even reverse the ALI deterioration (44, 45). To the best of our knowledge, this is the first systematic review and meta-analysis exploring the effects of SCFAs supplementation on ALI in animal research. The subgroup analysis results indicated that the therapeutic effects of SCFAs may be closely related to the dosage and duration of treatment, while being less influenced by the modeling method and the type of SCFAs. In particular, when the dosage reached 400 mg/kg/d and was administered continuously for 24 h to 7 days, the SCFAs showed a better efficacy. Despite the high heterogeneity and publication bias, SCFAs still significantly improved the inflammation levels and lung injury severity in ALI animals based on the overall results. Additionally, we obtained similar results through sensitivity analysis and trim-and-fill analysis, which enhanced the robustness of our findings.

The homeostasis of the gut actually impacts lung health (45). How is this effect mediated by SCFAs? Some studies have explored this in depth.

In fact, there is an immune mechanism regulated by the microbiota that exists between the respiratory and gastrointestinal tracts. The term “gut microbiota” refers to the complex ecological community composed of symbiotic and pathogenic microorganisms residing in the gut, encompassing thousands of species of bacteria, archaea, viruses, fungi, and other microbes (46, 47). These microorganisms maintain a dynamic balance and protect the gut through multifaceted mechanisms, such as synthesizing metabolites and toxins, providing nutrients, regulating the immune system, and preserving the function of the intestinal barrier (48, 49). Once the balance is disrupted, abnormal microorganisms may breach the intestinal barrier, enter the bloodstream, or migrate to the lungs, leading to systemic infections (sepsis) and lung damage (50). Among the various factors influencing gut microbiota, diet is considered one of the most effective interventions (51). Research shows that a high-fiber diet promotes the production of abeneficial metabolites, especially SCFAs (52). SCFAs construct and sustain the host’s intestinal defense system through various mechanisms, including stimulating the expression of intestinal mucins, enhancing the function of tight junction proteins (TJPs), and regulating the survival of intestinal neurons (53–55). In addition, SCFAs can promote the development of B cells and the differentiation and expansion of regulatory T cells (Tregs) (56–58). Subsequently, these lymphocytes migrate from the gut mucosa through the bloodstream and lymphatic system to reach distant effector sites, ultimately eliciting similar immune responses in mucosal areas throughout the body, including the respiratory mucosa (49, 59, 60).

Exceeding 90% of SCFAs are absorbed in the intestines, with a fraction dedicated to sustaining the metabolic functions of intestinal epithelial cells, while the remainder is disseminated through the circulatory system to a variety of organs (61). It has been demonstrated that SCFAs are present in the human respiratory tract, with their levels being closely correlated with the functional integrity of the gut microbiota (44). The capacity of SCFAs to regulate local immune responses is primarily dependent on two mechanisms: firstly, by directly inhibiting histone deacetylases (HDACs) to modulate gene expression, and secondly, by activating G protein-coupled receptors (GPCRs) to transmit signals. The GPCRs that can be activated by SCFAs are GPR41 (also known as FFAR3), GPR43 (also known as FFAR2), and GPR109A (62). These three receptors are widely distributed in various respiratory epithelial cells and immune cells, where they are capable of inhibiting LPS-induced pulmonary inflammatory signaling (63). As a result, they reduce alveolar edema and decrease the production of TNF-α in the ALI model (58, 64). However, different SCFA receptors exhibit varying affinities for different SCFAs. GPR41 displays a greater affinity for butyrate and propionate than for acetate, whereas GPR43 exhibits a higher preference for acetate over butyrate and propionate. GPR109A, on the other hand, is primarily activated by butyrate (44). Furthermore, propionate and butyrate are widely recognized as HDAC inhibitors. HDACs are enzymes that remove acetyl groups from histones, leading to the formation of compact chromatin structures that inhibit transcription (65). Thus, the inhibition of HDAC activity can promote gene transcription by increasing histone acetylation. In a mouse model of lung injury induced by polycyclic aromatic hydrocarbons, the restoration of butyrate levels in the gut has been demonstrated to reduce the HDAC level in the lung tissues, enhancing the expression of the Foxp3 gene and regulating Th17/Treg cell differentiation (66). In addition, other studies have shown that butyrate and propionate may reverse lung inflammation and oxidative stress by inhibiting HDAC activity, blocking the nuclear factor (NF)-kappaB signaling pathway, and suppressing the release of MDA in lung tissue (26, 31, 67). A summary of the role of SCFAs in regulating systemic and pulmonary inflammation is provided in Figure 8.

Despite variations in receptor selectivity among different SCFAs that could influence their mechanisms, our findings showed that there are no significant differences in their effectiveness in alleviating ALI. We hypothesized that short-chain fatty acids (SCFAs) may provide a lung-protective effect by activating and integrating various biological signaling pathways, rather than depending solely on the selective activation of a specific receptor. This multi-pathway, cross-receptor mechanism elucidates the synergistic effects of different SCFAs in the body, emphasizing their potential as novel therapeutic strategies for ALI. Nevertheless, further in-depth research is still needed to fully elucidate the mechanisms of action of SCFAs and establish clear causal relationships.

Subgroup analysis indicated that higher dosages of SCFAs and longer treatment durations appeared to be more effective in alleviating pulmonary edema in ALI animal models. SCFAs, as HDAC inhibitors, can silence the transcription of specific inflammatory genes. Previous study reported that SCFAs can only effectively reduce HDAC activity at higher millimolar concentrations (68). High concentrations of butyrate (0.5 mM) directly inhibited the activation, proliferation, and production of cytokines (IFNγ, IL-17) in CD4 T cells by increasing histone acetylation, while low concentrations (0.065 mM) did not exhibit these effects. In comparison, acetate and propionate required higher concentrations (10 mM and 1 mM, respectively) to achieve similar inhibitory effects (22). Similarly, propionate could reshape the metabolic stress and immune function of alveolar macrophages following LPS exposure, contingent on its concentration and timing of administration (44). These findings were consistent with our previous observations and further supported the hypothesis that SCFAs may have a dose-dependent effect. However, the specific dose–response relationship has not yet been clearly defined, which provides important evidence and direction for future studies on the optimal administration of SCFAs.

From the perspective of microbial ecology, SCFAs are primarily produced by the fermentation of dietary fiber and complex carbohydrates by gut bacteria, with Firmicutes and Bacteroidetes playing particularly important roles in this process (69). The two studies by Hildebrand (26) and Xiong (34) collectively revealed key changes in the gut microbiome during lung injury: significant decreases in Lactobacillus, Bacteroides, and Bifidobacterium, which were positively correlated with SCFAs concentrations, providing potential microbiological markers for ALI. It is noteworthy that the interactions between different microorganisms (including bacteria, archaea, and fungi) and their metabolic products also influence the production and diversity of SCFAs (70). For instance, lactic acid can help create an acidic intestinal environment suitable for butyrate-producing bacteria, while pentanoate in feces may originate from symbiotic relationships between archaea and other intestinal bacteria (71, 72). Moreover, SCFAs themselves can feedback-regulate the microbial community, promoting the growth of beneficial bacteria while inhibiting the virulence of intestinal pathogens (73). The interaction between the gut microbiome and SCFAs is a multilayered and complex system. Its mechanisms extend beyond nutrition and metabolism to include immune regulation, interactions among microbial lineages, and ultimately influence gut barrier function and the homeostasis of the gut-lung axis (74–76). However, there is currently no research that can provide a systematic and comprehensive elucidation of the specific processes and interrelationships of these mechanisms. Therefore, it is still necessary to explore strategies for targeting the regulation of the gut microbiome and SCFAs as potential treatments for ALI.

This study still has some limitations that warrant attention in future research. First, the quality scores of the included articles were relatively low, which may have resulted in selection bias, implementation bias, and measurement bias. Although we have taken measures to control these biases, they may still affect the reliability of the study results to some extent. Secondly, following the subgroup analysis, there was no significant improvement in heterogeneity within each subgroup. This may be related to the limited number of studies and insufficient variable information in the literature, which could have led to the omission of some potential factors. To more accurately determine the optimal treatment strategy, we recommend conducting more high-quality, multidimensional studies in the future to extensively investigate relevant variables and thoroughly analyze the dose-dependent efficacy of SCFAs. Additionally, we expect subsequent research to employ more standardized experimental designs and evaluation indicators to enhance the overall quality of animal experiments, thereby providing reliable scientific evidence for clinical applications.

This meta-analysis highlights the therapeutic potential of SCFAs in animal models of ALI. The overall evidence supports that SCFAs can alleviate the severity of ALI, suppress inflammatory responses, and reduce oxidative stress levels. Subgroup analyses further suggest that SCFAs may have a dose-dependent effect. These findings will provide important directions for further research and clinical applications in this field.