Gut Microbiota Metabolites Targeting the Immune Response in Sepsis: Me

Introduction

Sepsis, a life-threatening syndrome of organ dysfunction, poses a significant challenge in the field of critical care medicine worldwide. According to statistics, there were 189 hospitalized sepsis cases per 100,000 people annually, with 58 requiring intensive care unit admission due to severe conditions.¹ The mortality rate of sepsis is 10% to 20%, and for septic shock, a subtype of sepsis, the mortality rate is 40% to 50%.² Despite advancements in early diagnosis and treatment of sepsis, such as antimicrobial therapy, fluid resuscitation, vasopressor support, and organ function support, the prognosis remains poor. Coagulase-negative staphylococci account for a significant proportion of early-onset sepsis cases, exhibiting 86% to penicillin resistance in recent retrospective analyses.³

The gut microbiota, often referred to as the “second genome” of the human body, plays a crucial role in maintaining immune homeostasis and health.^4,5 Through the metabolism of dietary components and host-derived substances, gut microbiota produce various metabolites that not only affect the local intestinal environment but also influence systemic organs through the bloodstream.⁶ Studies indicate that metabolites from the gut microbiota, such as short-chain fatty acids, bile acids, and tryptophan metabolites, may have potential protective effects in sepsis.⁷

Imbalances in the gut microbiota, characterized by reduced diversity, decreased commensal bacteria, and overgrowth of pathogenic bacteria, not only serve as triggering factors for sepsis but also exacerbate disease progression.⁸ Conversely, the occurrence of sepsis can disrupt the balance of the gut microbiota, thereby worsening the severity of the condition.⁹ While the association between gut microbiota and the development of sepsis is compelling, our understanding in this field remains largely indirect and speculative, with the exact mechanisms yet to be fully elucidated.¹⁰ Furthermore, effective and mature treatments for sepsis are still lacking. Therapeutic strategies based on modulating the gut microbiota, such as FMT, selective digestive decontamination (SDD), and probiotics, face challenges in clinical application.⁸ Although FMT has potential therapeutic effects, it may cause adverse events such as abdominal pain and infection. The complexity of its operation (such as donor screening and maintaining an anaerobic environment) also limits its clinical application. Studies have found that FMT can lead to varying degrees of adverse events (including severe infections), and strict control of donor microbiota safety and operational conditions is necessary to avoid unpredictable risks.^11,12 SDD has an unclear effect on reducing mortality in sepsis patients, and it may induce the colonization of antibiotic-resistant bacteria.¹³ A randomized clinical trial by the Australian and New Zealand Intensive Care Society showed that SDD did not significantly reduce the in-hospital mortality rate in critically ill patients with mechanical ventilation, and there was a potential risk of promoting the emergence of drug-resistant strains.¹⁴ The efficacy of probiotics, prebiotics, and synbiotics is controversial. Some studies have shown that they can improve immunity and microbiota balance,^15,16 but multicenter trials have not confirmed their preventive effect on infections, and the use of probiotics by immunocompromised individuals may increase the risk of infection.¹⁷

Therefore, a deeper exploration of the role of gut microbiota in the onset and progression of sepsis, along with the identification of microbial metabolite targets that could effectively intervene in sepsis, holds promise for opening new avenues in sepsis treatment. This review summarizes the direct targets of gut microbiota metabolites on sepsis immune responses and explores related strategies in microbiota modulation for sepsis therapy, offering new insights and hope for improving patient outcomes.

The Role of Gut Microbiota in the Development and Progression of Sepsis

The gut microbiota is an essential component in maintaining immune system balance and preventing systemic inflammation.¹⁸ Under healthy conditions, the gut hosts a diverse community of beneficial, neutral, and potentially harmful bacteria, all of which contribute to overall homeostasis.^19,20 A Mendelian randomization study utilizing genetic variation as an instrumental variable has provided valuable insights into the causal relationship between the gut microbiota and sepsis. The results underscore the significant role that different microbial species play in the onset and progression of sepsis.²¹ Certain microbes, such as Lentisphaeria species, demonstrate protective effects, while others, including Clostridiaceae (a family of Clostridia) and Gordonibacter species, have been shown to exert detrimental effects. As shown in Figure 1, disruptions in the composition, abundance, and relative proportions of these microbial communities are strongly associated with the development and worsening of sepsis.^9,22

Figure 1 Drugs, diet, lifestyle, disease, and environmental factors influence the composition of the gut microbiota. Reduced diversity of gut microbiota, decreased commensal bacteria, and overgrowth of pathogenic bacteria are important risk factors for the development of sepsis. Following the beginning of sepsis, worsened bacterial imbalance, intestinal mucosal injury, aberrant microbiota transfer, and the induction of inflammatory storms can all contribute to multiorgan dysfunction.

Dysbiosis of the Gut Microbiota: An Important Risk Factor for the Development of Sepsis

As early as 1999, MacFie et al²³ began investigating the relationship between the gut and postoperative sepsis. Disruption or translocation of the relatively balanced microbial community in the proximal gut has become a significant source of infection in postoperative sepsis. The primary causes of gut microbiota imbalance include antibiotic use, improper dietary patterns, underlying diseases, aging, environmental factors, and more.²⁴

Antibiotics, considered one of the greatest medical advancements of the 20th century, hold an irreplaceable position in controlling infectious systemic diseases, significantly reducing mortality rates and shortening hospital stays.²⁵ Unfortunately, antibiotics have been increasingly overused in the 21st century,^26–28 with the risk of resistance becoming increasingly prominent.²⁹ The empirical use of broad-spectrum antibiotics is a common clinical strategy for treating sepsis, but this approach exacerbates gut dysbiosis.³⁰ A study by Kuppala et al³¹ found that among preterm infants without sepsis during the first week of life, prolonged (≥5 days) empiric antibiotic treatment was associated with an increased risk of late-onset sepsis and adverse outcomes, including mortality. Moreover, a retrospective analysis of hospitalized patients using hospital pharmacy databases assessed the relationship between specific antibiotics and the risk of developing sepsis after hospital discharge. By applying multivariable logistic regression models to control for potential confounders, the study examined the association between the use of specific antibiotics and the risk of sepsis after hospital discharge.³² The analysis of single hospitalization records from randomly selected eligible patients across 516 hospitals revealed that 0.17% of patients developed sepsis within 90 days of discharge. Notably, patients who received antibiotics associated with microbial disruption during hospitalization had a 65% higher risk of developing sepsis compared to those who were not exposed to antimicrobial agents. This further supports the notion that gut dysbiosis is likely a contributing factor to the development of sepsis.

Reduced Diversity of Gut Microbiota

A notable phenomenon observed in intensive care unit (ICU) patients is the dramatic decline in the diversity of their microbiomes, which often occurs even before pathogenic bacteria have entered the body.³³ When the diversity of the intestinal microbiota decreases, its ability to prevent the colonization of foreign microorganisms is compromised, thereby increasing the body’s susceptibility to opportunistic pathogens that would otherwise remain harmless. Lankelma et al³⁴ conducted a study analyzing the fecal microbiomes of 34 ICU patients with sepsis and other critical conditions, as well as 15 healthy individuals. In these patients, 13 had gut microbiotas dominated by a single bacterial genus accounting for more than 50% of the microbiome, and 4 had more than 75% dominance, with half of the patients showing a significant decline in microbial diversity.

Some studies suggest that higher gut microbiota diversity is associated with a lower risk of sepsis. A prospective cohort study by Graspeuntner et al³⁵ involving more than 200 preterm infants found that when the gut microbiota of preterm infants was more diverse, the risk of developing sepsis was lower. Additionally, the colonization of anaerobic bacteria has been linked to the prevention of sepsis. Anaerobes can inhibit the growth and reproduction of harmful bacteria by competing for nutrients, producing antimicrobial substances, or modulating gut immunity, thus helping to maintain the stability of the gut microbiota and reducing the likelihood of sepsis in newborns. Similarly, Fay et al³⁶ demonstrated that the α-diversity of the gut microbiota was positively correlated with the resistance of mice to sepsis, meaning that higher α-diversity contributed to improved survival rates in sepsis. By altering the living environment of mice to allow them to share microbial communities, researchers were able to regulate the diversity of their gut microbiotas and, in turn, enhance their resistance to sepsis.

Compared with younger populations, sepsis in the elderly is characterized by difficulty in early identification, rapid disease progression, high mortality, and slow recovery.³⁷ With increasing age, certain changes occur in the composition and function of the intestinal microbiota,³⁸ and these differences become more pronounced in the context of sepsis. Compared with healthy elderly individuals, the intestinal microbiota of elderly sepsis patients shows a further reduction in diversity and evenness. A study on sepsis patients with a mean age of 64 years revealed significant differences in fecal bacterial composition between these patients and healthy individuals, with over half of the patients having only one bacterial genus in their feces.³⁴ Animal experiments have also confirmed this conclusion: the intestinal microbial diversity of elderly septic mice is significantly lower than that of adult septic mice, with more severe disruption of the microbiota structure, including an increase in the abundance of inflammation-related microbiota and a decrease in the abundance of microbiota associated with short-chain fatty acid production (such as Mucispirillum and Bacteroides).³⁹ Due to the presence of inflammatory responses and the potential use of antibiotics during treatment, elderly sepsis patients may experience a reduction in beneficial microbiota such as Bifidobacterium and Lactobacillus, along with an increase in potential drug-resistant pathogens such as Enterococcaceae and Klebsiella. These changes in intestinal microbiota diversity are closely associated with the pathogenesis and severity of sepsis.⁴⁰

Reduction of the Symbiotic Microbiota

In cases of reduced gut microbiota diversity, the abundance of symbiotic probiotics, such as Bifidobacterium, tends to decrease. Symbiotic microbial communities are an essential component of the gut microbiota ecosystem. Under certain conditions, symbiotic bacteria like Coprococcus may activate specific signaling pathways, promoting the synthesis and release of interleukin-1β (IL-1β) by immune cells such as macrophages and monocytes. On the other hand, this activation initiates and enhances the acute inflammatory response, which helps to clear pathogens.⁴¹ Moreover, symbiotic microorganisms significantly influence the types, quantities, and functions of immunoglobulin A in serum. The immunoregulatory network formed by symbiotic microbes, serum immunoglobulin A, and T cells plays a protective role against bacterial infections that may lead to bacterial sepsis.⁴² Some researchers have found that Lactobacillus murinus, a beneficial probiotic, has a positive effect in resisting Klebsiella pneumoniae invasion and colonization, helping to protect animals from infections and sepsis caused by Klebsiella pneumoniae.⁴³ These findings highlight the importance of symbiotic microorganisms in defending against bacterial sepsis.

Bifidobacterium, Bacteroides, and other bacteria produce beneficial metabolites, such as short-chain fatty acids (SCFAs).⁴⁴ SCFAs play a crucial role in regulating intestinal immunity, promoting gut barrier function, and maintaining the acid-base balance in the intestines, all of which are essential for gut health and microbiome stability.⁴⁵ When the abundance of SCFA-producing bacteria is insufficient, the risk of developing sepsis increases.⁹ A prospective study showed that compared to full-term infants, preterm infants had lower abundances of Bacteroides, Bifidobacterium, and Lactobacillus in their gut microbiotas, a change that increased the risk of late-onset sepsis in preterm infants.⁴⁶ Mai et al⁴⁷ selected 10 preterm infants with late-onset sepsis as the case group and 18 matched control infants. They collected fecal samples and used the 16S rRNA method to compare microbiome diversity. They found that, in the two weeks prior to onset, the microbial species in late-onset sepsis preterm infants decreased, with a particularly low abundance of Bifidobacterium, which may be associated with the occurrence of late-onset sepsis. These findings support the aforementioned viewpoint. In another study, an increase in the abundance of Megasphaera species, which produce butyrate, may confer protective effects against sepsis, while a lower abundance of butyrate-producing bacteria could be a risk factor for sepsis.⁴⁸

In the elderly population, butyrate-producing gut microbiota are significantly reduced. Through 16S rRNA sequencing, Yatsunenko et al found that the number of Bifidobacteria also decreases with age.⁴⁹ Such changes in the composition of gut microbiota directly affect the production of intestinal metabolites. Studies have shown that compared with younger populations, the concentrations of short-chain fatty acids (SCFAs, particularly acetate, butyrate, and propionate) in the intestines of the elderly are significantly lower. Additionally, as the main butyrate-producing microbiota, the number of Firmicutes also decreases with age.³⁸ This imbalance in the intestinal microecology reduces the gut’s resistance to pathogens, making the elderly more susceptible to developing sepsis when faced with infections. Meanwhile, it may exacerbate intestinal damage and systemic inflammatory responses during the course of sepsis, forming a vicious cycle.

Overgrowth of Pathogenic Bacteria

A decrease in the number of beneficial gut bacteria may promote the overgrowth of pathogenic bacteria.⁵⁰ Pathogenic bacterial overgrowth is a key feature of gut microbiota dysbiosis. An increase in microbiota dominated by Bacillus species and the accumulation of fermentation products have been linked to the occurrence of late-onset sepsis. Moreover, the colonization of Streptococcus pyogenes, a highly virulent pathogen, in the gut may be a contributing factor to the increased risk of late-onset sepsis.³⁵ A large retrospective cohort study involving 10,996 participants examined the relationship between three different types of hospitalization (non-infection-related hospitalization, infection-related hospitalization, and Clostridium difficile infection-related hospitalization) and the risk of developing severe sepsis within 90 days of discharge.⁵¹ The results indicated that the reason for hospitalization was closely associated with the probability of developing severe sepsis. Infection-related hospitalization, particularly Clostridium difficile infection, significantly increased the risk of severe sepsis. Furthermore, the incidence of severe sepsis was 70% higher in patients hospitalized for C. difficile infection compared to those with other infection-related hospitalizations. These findings further emphasize the significant role of C. difficile infection in increasing the risk of sepsis, suggesting that prevention and treatment of C. difficile infections may be crucial in reducing sepsis incidence.

In septic patients, changes in the gut microbiota composition trigger a chain reaction, akin to a domino effect. Dysbiosis promotes damage to the intestinal mucosal barrier.^52,53 When the intestinal mucosal barrier is compromised, its dysfunction triggers pro-inflammatory responses, allowing pathogenic bacteria to traverse the intestinal wall and enter the bloodstream, causing infections.^54,55 In newborn mice treated with broad-spectrum antibiotics, the immune system was affected, making the mice more susceptible to sepsis when challenged with Klebsiella pneumoniae infection.⁵⁶ Similarly, in an experiment involving newborn mice,⁴³ K. pneumoniae was introduced into the gut, where it proliferated and later translocated from the gut to the bloodstream, leading to systemic infection and ultimately late-onset sepsis in the mice.

Certain pathogenic bacteria trigger the onset of sepsis by producing virulence factors. For example, Gram-negative bacteria produce lipopolysaccharides (LPS), some of which are potent endotoxins that damage host tissues and promote the spread of infection. A study analyzed over 100,000 extremely low birth weight infants over 14 years, identifying 1032 cases of early-onset sepsis and 12,204 cases of late-onset sepsis.⁵⁷ It was found that Gram-negative bacteria frequently caused early-onset sepsis, while Gram-positive bacteria were more commonly responsible for late-onset sepsis. Cernada et al⁵⁸ noted that, unlike Gram-negative bacterial infections, sepsis caused by Gram-positive bacteria generally results in a relatively milder inflammatory response and less tissue damage. To further explore the significant changes in the gut microbiota prior to late-onset sepsis, a study involving 753 premature infants analyzed fecal samples from 40 septic infants three days before the onset of clinical symptoms. The study found that these Gram-negative pathogens were already present in the intestines of the premature infants, whereas no such pathogens were detected in the control group of premature infants.⁵⁹ Over time, the population of Gram-negative bacteria continued to grow in the gut, potentially playing a critical role in the onset of sepsis. Among Gram-negative bacteria, Pseudomonas aeruginosa stands out as an opportunistic pathogen with a unique survival strategy in the host. It can adapt to the host’s hostile environment by secreting various virulence factors, including LPS, outer membrane proteins, and flagella,⁶⁰ to enhance its survival.⁶¹ Individuals with compromised immune function or underlying conditions, as well as those who use antibiotics or immunosuppressive drugs long-term, are more susceptible to P. aeruginosa infection and the development of sepsis.⁸

Studies on critically ill patients over 60 years of age have found that the abundance of pathogens such as Escherichia-Shigella (including various pathogenic bacteria) and Hungatella is significantly increased. This intestinal microecological imbalance, characterized by an increase in pathogenic bacteria, is accompanied by a higher incidence of sepsis and more severe conditions in elderly patients.³⁷ In addition, a research team suggests that the increased susceptibility to sepsis in the elderly is not solely due to host factors; it may also be related to the enhanced virulence of intestinal pathogens with advancing age. The team confirmed this view using two complementary models of experimental sepsis induced by intestinal microbiota.⁶² A broader study involving patients aged 16–81 further verified that an imbalanced intestinal microbiota with an increase in pathogenic bacteria raises the risk of sepsis.¹⁵ The clinical significance of these microbiota changes cannot be ignored. Rapid and accurate identification of harmful bacterial groups is crucial for sepsis patients, as it can facilitate the prompt initiation of appropriate treatment. For example, Enterococcus faecium detected in the urine culture during the initial diagnosis of a 69-year-old patient was not taken seriously, and sepsis developed subsequently.⁶³ Enterococcus faecium bacteremia may lead to sepsis in immunocompromised patients with a high mortality rate. Due to its non-specific manifestations, identification is quite challenging. Rapid and accurate identification of this bacterial infection, coupled with early administration of appropriate antibiotic therapy, is key to improving patient survival rates.

In summary, gut microbiota dysbiosis is a key factor in the development of sepsis. While the pathogenesis of sepsis is complex and multifactorial and remains not fully understood, numerous studies indicate that disruptions such as reduced gut microbiota diversity, decreased symbiotic bacteria, and excessive growth of pathogenic bacteria are significant contributors.⁶⁴ These disruptions increase the risk of sepsis by altering gut barriers and immune regulation.³⁰

Involvement of Gut Microbiota in the Development of Sepsis

The gut microbiota plays a crucial role in the progression of sepsis. From a negative perspective, when the gut microbiota becomes dysregulated, it can have a severely destructive effect on the course of sepsis.^50,65 Specifically, an imbalance between beneficial and harmful gut bacteria can impair the integrity of the intestinal barrier, thereby creating conditions for bacteria and their toxins to translocate into the bloodstream. This triggers a systemic inflammatory cascade, which not only exacerbates the severity of sepsis but also significantly increases the risk of multiple organ dysfunction.⁶⁶

In contrast, beneficial metabolites derived from the gut microbiota demonstrate significant potential for improving sepsis outcomes. Take SCFAs, for example; they exert positive effects on multiple levels: locally within the gut, they strengthen the integrity of the intestinal barrier, forming the first line of defense against pathogen invasion; at the systemic level, they regulate immune responses, effectively suppressing excessive inflammation while promoting the release of anti-inflammatory cytokines, thus restoring immune homeostasis.⁶⁷ These mechanisms open new avenues for clinical treatment strategies in septic patients.

Disruption of Sepsis by Disturbed Gut Microbiota

During sepsis, the gut’s microecological environment, including pH and redox potential, undergoes changes, leading to a more pronounced imbalance in the gut microbiota and poorer sepsis prognosis. Sun et al⁷ employed two approaches to investigate this issue. First, they analyzed fecal samples from septic patients and healthy controls to compare differences in gut microbiota between the two groups. Second, they used a cecal ligation and puncture mouse model for microbiome and transcriptome analysis, validating results previously obtained from human samples. The data revealed that during sepsis, the gut’s previously stable and balanced microbial environment is disrupted, with an abnormal increase in Enterococcus species, which may play a role in the pathogenesis or progression of sepsis. The researchers also found a close correlation between high levels of Bacteroides species in the gut and the severity of sepsis. Other studies have reported significant disruption of the gut microbiota in septic patients. When feces from septic patients were transplanted into mice, the mice exhibited more severe liver inflammation and damage compared to the control group that received healthy feces. The primary pathological change in the septic mice was coagulopathy, which can lead to organ damage and is one of the main causes of death in septic patients.⁶⁸ In summary, gut microbiota composition is associated with complications and mortality.

Gut microbiota dysbiosis further deteriorates, not only with a continued decrease in beneficial bacteria but also with the overgrowth of antibiotic-resistant or opportunistic pathogens. These bacteria may produce more toxins and virulence factors, impacting the progression of sepsis. For instance, a reduction in strict anaerobes and an increase in pathogenic bacteria are associated with septic complications.⁶⁹ The decrease in strict anaerobes weakens the intestinal mucosal barrier, making it easier for pathogenic bacteria to translocate across the damaged gut barrier and enter the bloodstream, triggering systemic infection. The overgrowth of pathogenic bacteria leads to the production and release of large amounts of endotoxins, initiating an inflammatory cascade and increasing the risk of sepsis-related complications.⁷⁰ Desulfovibrio can degrade SCFAs and promote the production of more benzoic acid, acting as a pathogen that damages both the intestinal mucosa and the host. In a sepsis mouse model, the proliferation of Desulfovibrio may exacerbate acute gastrointestinal damage during sepsis.⁷¹ Reports have also indicated that Bacteroides species can influence the development and severity of sepsis.⁷ This is mainly due to Bacteroides species affecting the expression of numerous genes, thereby altering the physiological state and function of the gut. Moreover, Yu et al found that a diet high in methyl donors changes the gut microenvironment, reduces beneficial bacteria, and increases sepsis mortality. However, some studies suggest that although microbiome diversity is significant in many contexts, the reduction of gut microbiota diversity does not seem to be associated with mortality in sepsis patients.^34,72

In 1966, Wolochow first introduced the term “bacterial translocation”,⁷³ defining it as the phenomenon in which resident bacteria in the gut pass through the mucosal epithelium into the lamina propria, and subsequently enter the mesenteric lymph nodes or even distant organs. In 1979, Berg et al⁷⁴ expanded this definition to include all phenomena in which microorganisms or their products cross the intestinal mucosal barrier. From the 1980s to the 1990s, numerous studies began to focus on the relationship between gut microbiota translocation and various diseases.^75,76 Research found that under pathological conditions such as trauma, burns, shock, and severe infections, the phenomenon of bacterial translocation becomes more pronounced and is closely associated with the development of multiple organ dysfunction syndrome (MODS).⁷⁷ For example, when gut-derived bacteria translocate to the brain in septic patients, they can cause cognitive dysfunction, leading to delirium.⁷⁸ Bacterial translocation via the bloodstream can damage the kidneys, affecting their normal function.⁷⁹ Severe renal ischemia-reperfusion increases intestinal permeability, allowing translocation of bacteria and endotoxins, which activate the renal TLR4 signaling pathway and trigger inflammation leading to severe ischemic acute kidney injury.⁸⁰ Further studies on microbiota translocation or dysbiosis leading to multiple organ dysfunction in septic patients are summarized in Table 1. Extensive microbiota displacement typically leads to multiple organ dysfunction and failure, and in severe cases, can result in death. A recent study revealed that in elderly septic mice, Akkermansia muciniphila (AKK) in the gut was significantly increased. This bacterium disrupts the intestinal barrier, facilitates microbial translocation, and may contribute to the inflammation and mortality observed in elderly septic patients.³⁹

Table 1 Study of Changes in Gut Microbiota and Shifts in the Destruction of Various Complications of Sepsis

Studies have shown that bacteria such as Enterococcus spp. and Parabacteroides distasonis are closely associated with increased mortality risk in septic patients when their abundance in the human body rises.³³ In a prospective cohort study, rectal swabs and gene sequencing were performed on 301 patients to explore whether the characteristics of gut microbiota in critically ill patients upon admission could predict death or infection.⁷² The results indicated that the abundance of Enterococcus was associated with increased mortality and infection in critically ill patients. This suggests that in the complex and specialized ICU environment, an increase in the abundance of these bacteria could significantly influence the progression and prognosis of sepsis. Specifically, by measuring the abundance of specific harmful gut microbiota upon ICU admission, it may be possible to predict the likelihood of sepsis and death, thereby providing valuable reference points for subsequent medical interventions and improving treatment outcomes.

Amelioration of Sepsis by Beneficial Metabolites of Gut Microbiota

The improvement in sepsis associated with the gut microbiota is primarily attributed to the increase in beneficial bacteria and the secretion of beneficial metabolites by the gut microbiota. Agudelo et al³³ reported that when the abundance of microbial species such as Ezakiella, Megasphaera, and Prevotella increased, the severity of sepsis after onset was alleviated. Sun et al⁷ identified certain beneficial bacteria, such as Lachnospiraceae species, that directly or indirectly promote tryptophan metabolism, potentially having a beneficial impact on the progression of sepsis. In animals treated with a GPR109A agonist, the dysbiosis of the gut microbiota and damage to the intestinal epithelial barrier were alleviated, reducing the intensity of the inflammatory response and improving survival in sepsis.⁹⁴

Severe sepsis often causes damage to terminal organs, and the gut microbiota plays a key role in sepsis-induced liver and kidney injury. Reduced gut microbiota levels decrease renal macrophage and monocyte maturation, protecting against kidney damage. However, complete depletion of gut microbiota eliminates this protective effect.⁹⁵ In mouse experiments, microbiota from septic-resistant mice produced more glaricidins than those from septic-sensitive mice, which protected the mice from cecal ligation and puncture-induced mortality and liver injury.⁹⁶ Recent studies have shown that the gut microbiota metabolite D-serine can help improve kidney injury.^97,98 Another study found that beneficial metabolites, such as SCFAs, may offer some protective effects against renal damage induced by sepsis.^99,100 Conversely, a reduction in SCFAs leads to immune dysfunction in the gut, further exacerbating the systemic damage caused by sepsis.¹⁰¹ AKK can produce SCFAs, and its abundance in the body is linked to the progression and ultimate outcome of sepsis.¹⁰² The main producers of SCFAs are Lachnospiraceae and Ruminococcaceae.^103,104 In general, precisely adjusting the quantity and proportion of these bacteria can positively alleviate the effects of sepsis.

The gut microbiota composition has shown great promise in sepsis research and may serve as an effective biomarker. By analyzing the gut microbiota, it is possible to identify patients who are at relatively higher risk of sepsis. For instance, changes in the abundance of certain microbial species or the diversity of microbial communities may indicate an individual’s risk of developing sepsis. In sepsis-related research, neonatal sepsis has been a key area of focus. However, there is currently limited research validating these findings in adults. While theoretically the gut microbiota could play many positive roles, there is insufficient empirical evidence supporting its reliability as a biomarker for accurately identifying high-risk individuals for sepsis in adults or guiding personalized prevention strategies.⁶⁴ Given the complexity of sepsis in adults and its severe impact on health, there is an urgent need for more studies to explore the mechanisms, risk factors, and other issues related to sepsis in this population. Further investigation into the application of the gut microbiota in adult sepsis could provide scientific evidence for the development of effective prevention and treatment strategies.¹⁰

Targets of Gut Microbiota Metabolites Acting on Immune Responses in Sepsis

In the intricate pathophysiology of sepsis, disturbance of the immune system plays a large and damaging role.¹⁰⁵ As the body struggles against overwhelming infection, an uncontrolled inflammatory cascade is generated, often leading to multiple organ failure and a life-threatening conclusion. In recent years, the gut microbiota and its metabolites have emerged as crucial mediators connecting host health and disease vulnerability. These chemicals, produced by the symbiotic microbial community within the gut lumen, have the ability to control the immune response in basic ways.^106–108 Understanding the major targets via which gut microbiota metabolites influence the immune response during sepsis is not only crucial for dissecting the underlying mechanisms but also holds promise for the development of innovative treatment strategies. As shown in Figure 2, the following is a categorical review of the present targets of microbial metabolites in regulating immune responses during sepsis.

Figure 2 A complete overview of the mechanisms by which metabolites of the gut microbiota directly attack the targets of the immune response. This figure systematically demonstrates the target mechanism of gut microbiota metabolites directly acting on immune response. Different kinds of gut microbiota metabolites are clearly presented in the figure, and their interaction pathways with various key targets of immune response, including the effects on immune cell activation and signaling pathways, are visualized by connecting arrows and lines.

Targets for Pattern Recognition Receptors

Toll-Like Receptors (TLRs)

In the early stages of sepsis, pathogen infiltration or tissue injury leads to the release of considerable amounts of PAMPs and DAMPs.¹⁰⁹ TLRs act as key sensors for immune cells, enabling the identification of PAMPs.¹¹⁰ For example, LPS, a component of the outer membrane of Gram-negative bacteria, activates TLR4, while peptidoglycan from Gram-positive bacteria activates TLR2.^111,112 These connections initiate either the MyD88-dependent or MyD88-independent signaling pathways, leading to the activation of downstream cascades such as nuclear factor-κB (NF-κB) and mitogen-activated protein kinases.^113,114 Subsequently, the production and secretion of pro-inflammatory cytokines, including tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), are stimulated, culminating in a systemic inflammatory response.¹¹⁵ Activated TLRs not only initiate the main inflammatory response but also perpetuate and enhance inflammation through positive feedback mechanisms. For instance, NF-κB activation leads to an increase in TLR expression and the recruitment of related adaptor molecules that sensitize immune cells. This hypersensitive condition results in prolonged inflammatory activation, further contributing to the pathogenesis of sepsis and implicating various organ systems.¹¹⁶ Studies have indicated that SCFAs, notably butyric and propionic acids, can reduce LPS-induced TLR4-NF-κB activation. In a mouse model of sepsis, exogenous injection of butyric acid markedly lowered serum inflammatory markers and improved survival rates, emphasizing its anti-inflammatory effects via precise targeting of TLR4.¹¹⁷ Bile acids activate nuclear receptors such as the farnesoid X receptor (FXR) and pregnane X receptor (PXR). In hepatic Kupffer cells, active FXR suppresses TLR4 gene transcription, ultimately lowering TLR4 surface expression.¹¹⁸ This lowers susceptibility to LPS, decreases TNF-α production, and alleviates liver inflammatory damage during sepsis. Concurrently, bile acids control TLR2/TLR4 expression in intestinal epithelial cells via PXR, supporting intestinal immunological homeostasis and limiting the worsening of systemic illness induced by bacterial translocation from the gut.¹¹⁹ Recent investigations have demonstrated that plasma levels of hyodeoxycholic acid (HDCA) in septic patients are considerably lower than those in age- and gender-matched healthy controls. Furthermore, HDCA plasma levels exhibit a negative connection with various indications of sepsis development. Supplementation with HDCA has been observed to decrease inflammatory damage associated with sepsis. Investigations into the underlying mechanisms of HDCA’s anti-inflammatory activities have indicated that HDCA prevents the excessive activation of inflammatory macrophages by competitively preventing the binding of LPS to the TLR4/MD2 complex.¹²⁰ Tryptophan metabolites, especially indole-3-propionic acid, activate the aryl hydrocarbon receptor (AhR). Upon activation, AhR translocates to the nucleus and regulates the expression of different genes.¹²¹ In immune cells, AhR activation inhibits the TLR2/TLR4 signaling pathway, lowering the release of pro-inflammatory cytokines such as IL-6 and IL-12. Additionally, AhR stimulates the development of dendritic cells into tolerogenic dendritic cells, thereby fine-tuning the immune response during sepsis. Metabolites of the kynurenine pathway exhibit diverse immunological actions. On one side, they can activate immune cells and boost anti-infective properties. On the other side, during sepsis-induced immunological imbalance, high kynurenine can upregulate TLR4 expression via an unknown mechanism, hence worsening inflammation.¹²² This shows that tryptophan metabolites may bidirectionally influence TLRs and the immunological response in sepsis through the kynurenine pathway, a concept warranting further exploration. During the microbial metabolic process, numerous bacteria create different peptide metabolites. These peptide metabolites can serve as signaling molecules, antimicrobial compounds, or hold other physiological activities. A study, through fecal metagenomic sequencing, demonstrated that the quantity of AKK in the intestines of septic patients is much lower than that in non-septic individuals. Further metabolomics investigation indicated that AKK bacteria can create a new tripeptide, Arg-Lys-His (RKH). RKH directly binds to TLR4, suppresses the inflammatory signaling pathways in immune cells, and ameliorates sepsis.¹²³

Nod-Like Receptors (NLRs)

Members of the NLR family are ubiquitously dispersed across the surfaces of immune cells and epithelial cells. They exhibit the amazing capacity to PAMPs, DAMPs, as well as endogenous danger signals, hence playing a vital role in both beginning and increasing the immune responses during sepsis.

Extensive research has established that SCFAs, with butyric acid being particularly prominent, can directly target the NLRP3 inflammasome.¹²⁴ By perturbing the recruitment pathway of the ASC protein, it effectively thwarts the assembly of the inflammasome complex. In vitro cell-based experiments have shown that upon the addition of butyric acid to macrophages, a conspicuous reduction in the development of ASC speckles is observable, concomitantly leading to the suppression of NLRP3 inflammasome complex formation. As a result, the development and release of IL-1β and interleukin-18 are limited, considerably attenuating the inflammatory reaction.¹²⁵

Within the liver domain, the FXR, once activated by bile acids, can exert transcriptional regulatory control to decrease the expression of the NLRP3 gene, therefore reducing the formation of NLRP3 inflammasomes.¹²⁶ Concurrently, certain bile acids are capable of interacting with the membrane receptor TGR5.¹²⁷ Upon activation, this connection produces an elevation in intracellular cyclic adenosine monophosphate levels, which in turn suppresses the activity of kinases fundamental to the NLRP3 inflammasome activation pathway, such as the inhibitor of NF-κB kinase subunit beta. By inhibiting the action of these kinases, the construction and activation of the NLRP3 inflammasome are successfully avoided, minimizing the inflammatory damage associated with sepsis. Notably, in the setting of intestinal inflammation models, TGR5 agonists have demonstrated efficiency in relieving intestinal inflammation and curbing the intestinal damage mediated by the NLRP3 inflammasome.¹²⁸

Targeting Cytokines and Immune Cells

Recent breakthroughs in gut microbiome research have identified complicated linkages between microbial metabolites, cytokines, and immune cells, demonstrating their critical function in modulating immune responses during sepsis. These metabolites operate as regulatory “keys”, influencing immune cell differentiation, polarization, and cytokine release to restore equilibrium in the dysregulated immunological milieu.

Several essential microbial metabolites with immunomodulatory activities have been identified: SCFAs, such as butyrate, are fermentation products of dietary fiber. Acting as histone deacetylase inhibitors, SCFAs promote regulatory T cell differentiation, suppress pro-inflammatory cytokines, and enhance IL-10 secretion, achieving immune balance,^129,130 acetate has shown promise in sepsis-associated AKI by inhibiting histone deacetylase activity, suppressing the NOX2/ROS pathway, and mitigating oxidative stress to protect against AKI.⁹⁹ Taurodeoxycholate (TDCA), modulates chromatin silencing, alternative splicing, and translation of the myeloid-derived suppressor cells immunoproteome, boosting anti-inflammatory molecule production while reducing pro-inflammatory mediators.¹³¹ Indole (IND), generated from tryptophan metabolism, stimulates the 5-hydroxytryptamine receptor HTR2B, blocking the NF-κB signaling pathway. This alters macrophage polarization from the pro-inflammatory M1 type, lowering cytokines including IL-1β and TNF-α, and relieving gut inflammation.¹³² 3-Indoleacetic acid (IAA), produced from gut microbiota, activates AHR in microglia, enhancing neuronal function and lowering cognitive impairment associated with sepsis.¹³³ Indole-propionic acid (IPA), improves macrophage phagocytosis, assisting in infection management and giving a unique therapeutic pathway for sepsis.¹³⁴ Phenylpyruvate (PPA), a metabolite of Candida albicans, interacts with SIRT2, promoting SIRT2-dependent reactive oxygen species generation. This improves macrophage phagocytosis and bactericidal activity, mitigates organ damage, and reshapes cytokine secretion patterns.¹³⁵ Minacipran activates the AHR in group 3 innate lymphoid cells, promoting IL-22 release and mitigating intestinal ischemia/reperfusion injury.¹³⁶ Polysaccharide A (PSA), which from Bacteroides fragilis induces regulatory T cells and IL-10 secretion, maintaining immune balance and reducing inflammation.¹³⁷

Despite these discoveries, many mechanisms remain unexplained. For instance, how metabolites interact with immune cells and cytokines during the tissue repair phase of sepsis, or their roles within specific tissue microenvironments, are still to be explained. Furthermore, the complicated relationship between metabolites and host signaling pathways merits further research. Looking forward, the merging of multi-omics technology and clinical research shows potential for revealing these pathways. This insight could lead to the development of targeted medicines for sepsis, which would enhance patient survival and long-term results.

Exploration of Sepsis Treatment Strategies Based on Gut Microbiota Regulation

Around the 1980s, it was standard practice in surgical care to provide at least five days of antibiotics to reduce infection rates. In a review of a 1986 report that included 81 hepatectomies, it was found that only 57 of the 81 patients received prophylactic antibiotics and 24 did not. Unexpectedly, no cases of sepsis were reported in patients who did not receive prophylactic antibiotics, and all manifestations of sepsis occurred in patients who received antibiotics.¹³⁸ This phenomenon triggered deeper thinking about the importance of the microbiota, and as its understanding deepened, attention was drawn to the possibility of repairing the gut and improving its function through probiotics, fecal transplants, and other therapeutic approaches.^9,64 Currently, regulating the gut microbiota has become an important direction in the treatment of sepsis.

Probiotics, Prebiotics, Synbiotics

Beneficial bacteria or their derivatives, as alternative strategies, can help address the challenges posed by antibiotic resistance while maintaining the composition and function of the gut microbiome. Currently, the most common approaches include the use of probiotics, prebiotics, or synbiotics.⁸

Probiotics are live beneficial microorganisms that can help regulate the balance of the gut microbiome. The consumption of probiotics has shown positive effects in very low birth weight infants, reducing the risk of sepsis-related complications, mortality, and length of hospitalization, while also promoting weight gain. Optimal effects are seen when administered at specific doses and with multi-strain formulations.¹³⁹ A meta-analysis revealed that the incidence of late-onset sepsis in preterm infants treated with probiotics decreased from 16.3% in the placebo group to 13.9%. This difference remained significant across infants treated with lactobacilli, bifidobacteria, or a combination of single and multiple probiotic strains. Additionally, in developing countries, preterm infants treated with probiotics showed a significant reduction in the incidence and mortality of late-onset sepsis.¹⁴⁰ The intestinal microbiota of neonates is in a stage of dynamic colonization, and probiotic intervention at this time can promote the establishment of a healthy microbial community, enhance intestinal barrier function, and facilitate the development of the immune system.¹⁴¹ In the field of adjuvant therapy for adult sepsis, probiotics combined with early enteral nutrition may have a positive impact.¹⁴² However, they also exhibit a more complex efficacy profile and non-negligible safety risks, particularly in immunocompromised patients or those with severe underlying diseases.¹⁴³ This risk may stem from the relatively stable intestinal microbial community in adults, where exogenous probiotics have weak colonization ability and may instead translocate into the bloodstream.¹⁴⁴ Molecular biology studies have shown that after adults take probiotics, most strains only exist temporarily in the intestine (for approximately 2–4 weeks) and disappear rapidly after discontinuation, failing to achieve persistent colonization as in neonates.¹⁴⁵ Based on current evidence, the application of probiotics in the prevention and treatment of sepsis must strictly follow the principles of age stratification and risk assessment.

Prebiotics, such as fructooligosaccharides and fibers, promote the growth and proliferation of beneficial bacteria. Studies have shown that prebiotics also provide significant benefits to preterm infants by reducing the incidence of sepsis and mortality, shortening the duration of total enteral feeding and hospitalization, and increasing bowel movement frequency. Notably, prebiotics are most effective in infants born at 28 weeks gestation or later, and their effects are especially enhanced when combined with breast milk, infant formula, or galactooligosaccharides.¹⁴⁶ Moreover, fiber, as a source of microbial food that produces SCFAs, may have a beneficial role in the prevention and treatment of sepsis.¹⁴⁷

Synbiotics refer to the combination of probiotics and prebiotics in a form that exerts synergistic effects. They have been shown to regulate the gut microbiome, reduce inflammatory responses, decrease the incidence of infections, and lower the rate of sepsis-related complications in sepsis patients.^148,149 However, a comprehensive analysis of 18 randomized controlled trials indicated that there was no significant difference in the incidence of postoperative sepsis between patients receiving synbiotics or probiotics. No clear advantages or positive effects were observed. Subgroup analyses also failed to detect any significant benefits in reducing urinary tract infections, pneumonia, or postoperative wound infections.¹⁴⁶ Table 2 lists additional studies on the impact of probiotics, prebiotics, and synbiotics in sepsis.

Table 2 Published Studies on the Effect of Probiotics/Prebiotics/Synbiotics on Sepsis

Probiotics have demonstrated certain efficacy in the clinical management of preterm infants, showing improvements in specific aspects of sepsis prognosis. However, in some cases, interventions have been ineffective or even led to adverse outcomes. The choice of bacterial strains and the dosage of probiotics are crucial, as certain LAB strains can influence immune functions, and even the same strain may exhibit different effects. Research and reports on the use of probiotics and prebiotics in adult sepsis treatment are relatively limited, and further exploration is urgently needed to fill this knowledge gap. While some successful cases have been reported where synbiotics promote the growth of symbiotic bacteria and regulate the gut microbiome to treat sepsis, it is important to note that their effects are heavily influenced by dietary habits and individual differences. More extensive clinical data are required to substantiate their efficacy.

Fecal Microbial Transplantation (FMT)

FMT is typically performed through methods such as enemas or oral capsules, in which processed fecal suspensions from healthy individuals are transplanted into the patient’s gut to rebuild the intestinal microbiome.¹⁵⁸ Several animal studies have demonstrated that FMT offers numerous benefits for septic mice, including a reduction in incidence and mortality, restoration of the gut microbiome, and improvement in barrier function.^159–161 In a study by Li et al,¹⁶² animal models of SAE were treated with four different interventions—probiotics, prebiotics, synbiotics, and FMT—to modulate the gut microbiome in septic rats. The results showed that FMT was most effective in restoring gut microbial diversity and exhibited strong neuroprotective effects in SAE. Clinical reports also reveal that, over time, most patients who underwent FMT experienced corresponding changes. Specifically, improvements in organ function, regression of sepsis and its complications, and increased survival rates were observed. For example, in one study on septic patients, those who received FMT showed significant improvement in gut microbial communities, which effectively alleviated sepsis-induced MODS and diarrhea symptoms.¹⁶³ A 44-year-old female patient who developed septic shock and severe diarrhea after vagotomy, unresponsive to antibiotic treatment, underwent FMT due to dysbiosis. Post-treatment, the patient’s septic symptoms and diarrhea were controlled, and beneficial changes in the microbiome were noted.¹⁶⁴

When extrapolating animal experimental results to clinical applications, it is essential to maintain a highly cautious approach. This translation process involves numerous complex factors that are difficult to predict with precision, including but not limited to the potential risks of various complications during treatment, the optimal timing for drug interventions, the precise dosing regimen, and the overall safety of the drug in clinical use. Previous mouse models have often failed to translate into effective clinical therapies. For instance, Kim et al¹⁶¹ constructed a mouse model of sepsis induced by human pathogens and subsequently performed FMT. Their study found that FMT restored the microbiome of septic mice, re-established interferon regulatory factor 3 levels, activated the TLR signaling pathway, and promoted the clearance of systemic pathogens, thereby improving the survival rate of septic mice.

FMT appears to be a promising therapeutic strategy. However, there have been reports of adverse outcomes, including death, following FMT treatment,^12,165 and there is a concern that FMT may transfer potential pathogenic bacteria from the donor’s feces to the recipient. Cases of fatal Escherichia coli infections following FMT have already been reported,¹² highlighting the need for thorough donor screening. Additionally, many sepsis patients are treated with broad-spectrum antibiotics, which may influence the effectiveness of FMT. Although FMT has been explored for treating sepsis in humans, most studies remain scattered and case-report-based, without forming a systematic, widely recognized, and routine therapeutic approach. There is an urgent need for large-scale, multi-center, prospective clinical studies to provide robust evidence for the application of FMT in septic patients and to promote the scientific use and development of this therapy in clinical practice.

Selective Digestive Decontamination (SDD)

SDD involves administering non-absorbable antibiotics, such as polymyxin and tobramycin, to the gastrointestinal tract to eliminate potential pathogenic microorganisms while preserving beneficial anaerobic bacteria. This method is used to prevent infections.¹⁶⁶ Several studies have shown that SDD significantly reduces infection rates in critically ill patients, decreases the duration of mechanical ventilation, and shortens hospital stays. For example, SDD effectively inhibits the growth of Gram-negative bacteria in the gut, reducing their colonization in the respiratory tract, and significantly lowers the incidence of respiratory infections in the ICU.¹⁶⁷ A study involving 24,389 ICU patients who required mechanical ventilation showed that, compared to standard care, SDD reduced the mortality rate (RR 0.91), with a 99.3% probability of lowering the risk of death. SDD also reduced the risk of pneumonia and bacteremia.¹⁶⁸ In patients with severe burns, bacterial translocation plays a key role in burn-associated sepsis, and SDD has been shown to reduce this translocation. A study of 30 burn patients found that the treatment group, which received SDD with amikacin, miconazole, and polymyxin sulfate, showed significant effectiveness in controlling infections and multi-organ dysfunction syndrome.¹⁶⁹

Selective Digestive Decontamination (SDD) remains a topic of ongoing debate in clinical research, as opinions diverge on whether its potential risks of inducing antibiotic resistance outweigh its clinical benefits.¹⁷⁰ In terms of benefits, SDD has been reported as an effective strategy for reducing mortality rates in ICU patients and preventing bacterial translocation in sepsis.¹⁷¹ Meta-analyses further support these findings, reporting reduced mortality rates in critically ill patients receiving SDD treatment, particularly in environments with higher baseline infection rates.¹⁷² However, the potential to promote the emergence of antibiotic-resistant pathogens is one of the main concerns in the clinical application of SDD, especially considering that the ICU has become a hotspot for antibiotic use and resistance.¹⁷³ There is a view that SDD has a potential risk of inducing antibiotic resistance, which may lead to the colonization or increased infection of multi-drug resistant strains.¹⁷⁴ A study found that during SDD, the resistance rates of intestinal Gram-negative bacteria to ceftazidime, tobramycin and ciprofloxacin were 5%, 7% and 7% respectively, and after SDD intervention, the corresponding resistance rates increased to 15%, 13% and 13%.¹⁷⁵ However, this study was a point-in-time prevalence survey, and the research subjects included all ICU patients. Therefore, the level of evidence for this study is not high. At present, a growing body of evidence indicates that the use of SDD does not increase the emergence of drug-resistant bacteria. A longitudinal study conducted over 21 years in an ICU that implemented SDD found no increase in the incidence of resistant microorganisms during this period.¹⁷⁶ Recent studies have also shown that in ICUs where SDD is used, antibiotic resistance levels are no higher than those in ICUs that do not use SDD.^166,177 The primary factor influencing resistance rates appears to be patient characteristics, rather than the use of SDD itself.¹⁷⁸

The benefits of SDD in reducing the mortality and infection rates of ICU patients are clear, especially in low antibiotic resistance environments. Although evidence from high-resistance regions still needs to be supplemented, long-term application experience and mechanistic research in Europe suggest that the benefit-risk ratio of SDD is acceptable under reasonable management. In the future, it is necessary to strengthen localized research in high-resistance regions and facilitate the transition of SDD from controversy to precise application.

Exploring Treatment Techniques That Target LPS

LPS, as a fundamental component of the cell wall of Gram-negative bacteria, plays a central driving role in the pathogenesis of sepsis and is a critical trigger for generating uncontrolled inflammatory reactions in the body. In recent years, investigations based around antagonizing LPS for the treatment of sepsis have developed, opening up new options for clinical therapy.

Targeting the LPS transport pathway is a new line of thought for anti-LPS treatments. A novel antibiotic, Zosurabalpin (RG6006), was discovered to prevent the transfer of bacterial LPS from the inner to the outer membrane, and its in vitro antibacterial and pharmacokinetic properties revealed potent in vivo activity in an animal model of infection.¹⁷⁹ Its potential therapeutic efficacy is subject to further validation in clinical trials.

Gut microbial metabolites reveal unique potential in antagonizing LPS. Butyrate is an essential gut microbial metabolite involved in gut-pulmonary interaction and has immunomodulatory effects. In an animal investigation, septic mice receiving sodium butyrate gavage demonstrated a considerable increase in intestinal barrier integrity, a significant decrease in blood LPS levels, and a significant increase in mouse survival. Thus, butyrate supplementation may be a possible method for treating sepsis by maintaining normal function of the lung-gut axis.¹³⁰ In addition, anti-inflammatory LPS produced by some bacteria has been found to aid in the prevention and treatment of LPS-induced inflammatory responses by shifting the balance between anti-inflammatory LPS and pro-inflammatory LPS.¹⁸⁰ A new study has presented an integrated method with both antibacterial and anti-inflammatory actions to reduce sepsis by stopping the cascade of LPS activation. In this work, bacteria were promptly killed and LPS neutralized by bactericidal mucins, and the neutralized LPS was further scavenged by acyl acyl hydrolases, which eliminated secondary fatty chains and detoxified the bacteria in situ. The technique exhibited great therapeutic efficiency in two mouse models of Pseudomonas aeruginosa infection. This technique presents a new intervention strategy for the treatment of sepsis by ameliorating hyperinflammatory-associated infections in the clinic from the standpoint of combination drug delivery.¹⁸¹

LPS within the circulation in sepsis interacts with a range of plasma proteins to create diverse biological consequences. Among these, lipopolysaccharide-binding protein (LBP) and bactericidal permeability increasing protein (BPI) are the two most prevalent plasma proteins.¹⁸² During sepsis, plasma LBP can reach more than seven times the normal levels.¹⁸³ Early removal of LBP from the body can prevent sepsis-induced acute kidney damage and improve the outcome of critically ill patients.¹⁸⁴ However, the positive and negative effects of LBP combined with LPS-mediated inflammatory response during host infection may be related to the bacterial species, the route of infection, and the concentration of LPS, suggesting that the specific conditions and indications for LBP in the treatment of sepsis need to be thoroughly investigated. BPI has a highly essential role in the clearance of LPS, with bactericidal, anti-inflammatory, and phagocytosis-regulating actions. rBPI23 is a recombinant protein of BPI that is more efficient in the treatment of sepsis. rBPI23 can neutralize LPS, drastically lower the release of inflammatory factors, and diminish the activation of fibrinolytic and coagulant systems after small-dose endotoxin infusion.^185,186 However, the short half-life of BPI in vivo limits the clinical applicability of recombinant BPI. However, a chimeric protein comprised of the N-terminal domain of LBP and the C-terminal domain of BPI overcomes the short half-life and enhances the survival rate of rats with sepsis.¹⁸⁷ More scientific and clinical investigations linked to LBP and BPI are needed to advance its vital role in sepsis management.

Treatment of Sepsis from Diets

The pathophysiology of sepsis is exceedingly complex, and a number of processes directly or indirectly impact the balance of the intestinal microbiota, which in turn affects the clinical signs and prognosis of sepsis.

Available studies have shown that the use of plant-based diets such as the Mediterranean diet, as a therapeutic dietary intervention, can have a beneficial impact on the host’s microbiome, by Shifting the microbiome environment towards the beneficial bacteria Prevotella and Mycobacterium anthropophilum, while away from the thick-walled phylum, helps to reduce inflammation, improve insulin sensitivity and promote optimal energy balance.¹⁸⁸ In patients with sepsis, early enteral nutrition and supplemental parenteral nutrition are beneficial in the presence of intestinal function, while supplementation with pharmacological nutrients such as glutamine, arginine, and omega-3 fatty acids has not been shown to be prognostically beneficial in sepsis.¹⁸⁹

The western diet is defined as a diet high in fat, high in sugar, and low in fiber. In a sepsis model, mice fed a Western diet generate more severe illness and poor prognosis as compared to mice fed a typical fiber-rich diet. Importantly, the Western diet dependent increase in sepsis severity and increased morbidity and mortality were independent of the microbiome, suggesting that food may directly affect the innate immune system through an undiscovered mechanism.¹⁹⁰

Ketogenic diets, with their low-carbohydrate, high-fat characteristics, have shown potential in a range of health areas in recent years. A team of researchers recently randomized septic patients in the ICU to a ketogenic diet or a standard high-carbohydrate diet in a clinical experiment. There was no significant difference in survival between the two groups, but notably, the patients on the ketogenic diet did not experience any side effects. In-depth study found that these patients had lower production of inflammatory chemicals by T cells, suggesting that the ketogenic diet may offset the immunological imbalance in sepsis by modifying the immune system.¹⁹¹ With additional investigations, the ketogenic diet may become an important supplement to enhance the prognosis of sepsis patients, giving fresh inspiration and options to overcome this medical obstacle.¹⁹²

Recently, the SINFONI program evaluated the impact of a multifunctional dietary strategy integrating diverse bioactive components on inflammation, gut microbiota regulation, and cardiometabolic profile. In this randomized crossover controlled study, the multifunctional intervention reduced intestinal inflammation and fasting LPS levels but did not alter systemic inflammation levels compared to controls.¹⁹³ Although this technique was only successful for low-grade inflammation, it may be a useful strategy to learn from in the treatment of sepsis in the future when optimized.

Admittedly, dietary strategies still face challenges in the application of sepsis treatment. Dietary compliance is difficult to control, especially under long-term special dietary patterns, where patients tend to give up halfway. Precise nutritional programs are costly, slow to promote, and hard to reach primary care. Different dietary components are complex with synergistic and dynamic interactions, and their underlying logic needs further exploration. However, looking to the future, with the integration of multiple disciplines, the empowerment of big data, and the improvement of public health awareness, nutrition is expected to become a crucial tool in sepsis treatment, rewriting patients’ prognosis trajectories from the source.

AI-Based Analysis of Gut Microbiota-Related Data for Sepsis Treatment

AI plays a significant role in personalized sepsis management. Recently, a new sepsis screening tool named qSepsis has been reported. This tool is based on machine learning algorithms such as logistic regression, random forest, and extreme gradient boosting, and uses 12 non-laboratory data including patients’ vital signs and symptoms for modeling. It can quickly assess the risk of sepsis without relying on laboratory test results.¹⁹⁴ Additionally, the TOPSIS-based classification fusion model integrates 7 classic machine learning models such as decision tree and random forest, and uses clinical data from 4872 ICU patients with septic shock for modeling and validation. It can effectively predict the 28-day mortality risk of septic shock patients in the ICU, providing a reliable early warning auxiliary tool for clinicians.¹⁹⁵ At present, some models are still in the preclinical or small-sample validation stage and require larger-scale trials for verification.

The integration of multi-omics technologies and AI is reshaping sepsis clinical practice via a comprehensive approach encompassing molecular typing, target identification, and dynamic monitoring. For example, a study based on transcriptomics constructed a “benefit score” model, successfully identifying a subgroup of septic shock that is sensitive to restrictive fluid strategies, providing the first cross-modal clinical decision-making tool for septic shock fluid management.¹⁹⁶ Another study combined serum exosomal miRNA sequencing with single-cell transcriptome analysis, screened out miR-125a-5p and miR-221-3p as therapeutic targets. Through the delivery of miRNA mimics/inhibitors by macrophage membrane biomimetic nanovesicles, it significantly reduced lung injury in mice, providing a new strategy for targeted intervention.¹⁹⁷ Moreover, by systematically integrating multimodal data from mouse models and clinical samples, the research comprehensively revealed the metabolic change characteristics in the early stage of sepsis-induced acute kidney injury (SA-AKI), identified 5 core metabolites, and constructed a diagnostic model IC3, with an early detection efficacy of Area Under the ROC Curve = 0.90 for SA-AKI, providing a foundation for subsequent clinical targeted therapy trials.¹⁹⁸

Understanding alterations in the gut microbiota is a key topic in critical care. One study determined the taxonomic composition of gut microbiota by 16S rRNA gene sequencing and constructed a machine learning classifier for differentiating sepsis with an AUC value of 81.25%; although further validation is needed, it suggests that the composition of gut microbiota has some potential for the diagnosis of sepsis.¹⁹⁹ Antibiotics are currently the mainstay in the treatment of sepsis; however, the timing of antibiotic administration is difficult to accurately manage in the clinic. A recent study has developed a unique approach (named T4) to quantify the influence of time-to-treatment antibiotic administration in sepsis treatment. It was able to accurately determine the appropriate timing of treatment in sepsis patients and explain the expected results by displaying crucial time points and factors, which further lowered patient mortality.²⁰⁰ Fluid treatment is crucial in the management of septic patients. Reinforcement learning has been employed to design a fluid treatment balancing method for patients with viral shock in the ICU. Machine learning and reinforcement learning techniques have the potential to optimize fluid management in sepsis patients, not only to assist in anticipating fluid overload and response but also to improve treatment results through tailored solutions.²⁰¹ In the treatment of sepsis associated with neocoronavirus infection, multi-omics data indicated changes in high-density lipoprotein function, which guided the individualized use of recombinant high-density lipoprotein, considerably improving clinical outcomes for patients.²⁰²

Multi-omics technologies, such as genomics, proteomics and metabolomics, along with combined AI, enable us to develop innovative tools to deeply study the heterogeneity of sepsis and achieve precise treatment. By integrating modern technologies with traditional medicine, the treatment of sepsis is moving towards higher precision and efficiency.

Conclusion

To sum up, this review sheds light on the vital role that gut microbiota and its metabolites play in the pathophysiologic process of sepsis, as well as the various therapeutic approaches that go along with it. A symbiotic microbial ecosystem, the gut microbiota of the human body plays a key regulatory function in the pathophysiology of sepsis and is crucial for maintaining internal environment homeostasis. The development of sepsis is at increased risk due to dysbiosis, which includes decreased diversity, attenuation of beneficial commensal bacteria, and growth of dangerous bacteria. Use of antibiotics, infections, and serious illnesses frequently alter the gut microbiota and cause abnormal immune activation, which leads to unchecked inflammation and immunological imbalance and raises the risk of organ failure and death. Good metabolites, on the other hand, such as RKH peptide, butyrate, and HDCA, can stop the production of inflammatory factors, guide the host immune response correctly, and improve sepsis.

Gut microbiota-targeted therapy has garnered a lot of interest lately. Treatments include FMT, SDD, probiotics, prebiotics, synbiotics, anti-LPS medications, and dietary changes that are anticipated to alter the microbial balance, encourage the synthesis of advantageous metabolites, and reduce sepsis. In the meantime, the use of AI and machine learning in the study of gut microbiota data and in the diagnostic and treatment decision-making of sepsis is starting to yield encouraging results. However, a number of obstacles must be addressed before microbiome therapy may be clinically implemented, including the short-term effects of probiotics, the specificity of patient gut microbiota, and the difficulty of standardizing interventions. FMT has been demonstrated in preclinical studies to reduce the mortality rate in animal models of sepsis. For sepsis caused by antibiotic-resistant bacteria, the combination of FMT and SDD holds promise as a potential breakthrough. Metabolite-based therapies are more likely to be translated into clinical practice due to their clear mechanism of action and favorable safety profiles. Future trials should prioritize FMT protocols and metabolite-based therapies, leveraging AI for patient stratification. With standardized systems and refined personalized strategies, microbiota-targeted therapies will synergize with conventional treatments, significantly reducing sepsis mortality and ushering in a new paradigm of restoring health via microbiota balance.

Further investigation into the role of microbial communities and key metabolites in sepsis immunomodulation is necessary to optimize the design of microbial therapies. Modern technologies like metabolomics, spatiotemporal omics, and single-cell RNA sequencing are providing previously unheard-of precision in exposing the intricate web of interactions between host immune cells and gut microbiota.^21,203–205 The immune regulatory mechanisms of important microbial metabolites can be targeted with single-cell RNA sequencing, which can also shed light on the diversity of immune cells during sepsis and the regulation of T-cell, macrophage, and dendritic cell subpopulation differentiation and function by intestinal signals. With the help of systems biology and metagenomics and metabolomics technologies, personalized medicine can be established by precisely identifying the key bacterial strains and their metabolites that impact the sepsis process, investigating possible biomarkers, and building prognostic models.

Even with the remarkable outcomes, there are still issues. The effectiveness and safety of human microbiome therapies must be thoroughly confirmed in extensive randomized clinical trials. The long-term consequences on sepsis survivors are also unknown, as are the best ways to administer probiotics, prebiotics, and fecal microbiota transplants, as well as their dosage and duration. To avoid jeopardizing the effectiveness of microbiome therapy, it is also important to carefully think about how other treatments, such as antibiotics and immunomodulatory medications, may alter the gut microbiota. To sum up, while microbiome therapy is at the vanguard of treating sepsis, more research and clinical validation are required before it can be developed into a sophisticated and successful individualized medicine.

Abbreviations

FMT, fecal microbiota transplantation; SDD, selective digestive decontamination; ICU, intensive care unit; SCFAs, short-chain fatty acids; MODS, multiple organ dysfunction syndrome; AKK, Akkermansia muciniphila; SAE, sepsis-associated encephalopathy; ARDS, acute respiratory distress syndrome; AKI, kidney injury; PAMPs, pathogen-associated molecular patterns; DAMPs, damage-associated molecular patterns; TLRs, Toll-like receptors; LPS, lipopolysaccharides; NF-κB, nuclear factor-κB; TNF-α, tumor necrosis factor-α; IL-6, interleukin-6; FXR, farnesoid X receptor; PXR, pregnane X receptor; HDCA, hyodeoxycholic acid; TDCA, Taurodeoxycholate; IND, Indole; IAA, 3-Indoleacetic acid; IPA, Indole-propionic acid; PPA, Phenylpyruvate; PSA, Polysaccharide A; AhR, aryl hydrocarbon receptor; RKH, Arg-Lys-His; NLRs, Nod-like receptors; IL-1β, interleukin-1β; LBP, lipopolysaccharide-binding protein; BPI, bactericidal permeability increasing protein.

Funding

There is no funding to report.

Disclosure

The author declares that they have no competing interests in this work.

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