Gut dysbiosis and its treatment in patients with critical illness

Abstract

The gut is a target organ that functions as the “motor” of critical illness. In patients with critical illness, the disrupted gut microbiota following infection and injury could cause diarrhea, pneumonia, and systemic inflammation. For maintaining the gut microbiota, therapeutic approaches are required to modulate host responses and prevent systemic inflammation. Probiotics and synbiotics could maintain the gut microbiota and decrease not only the incidence of diarrhea but also that of ventilator‐associated pneumonia. The effects of probiotics/synbiotics differ with the type of bacteria and disease severity. Adverse effects of probiotics have been reported; therefore, the selection of safe and effective probiotics/synbiotics is warranted. Refractory diarrhea with prolonged dysbiosis may require a novel intestinal therapy, such as fecal microbiota transplantation, to alleviate gut dysbiosis.

After severe injury, such as trauma, operation, burn, infection, shock, and bleeding, systemic inflammation progresses in various organs simultaneously. The gut is considered to have an important role in promoting systemic inflammation through bacterial translocation, intestinal lymphatic mediators, gut immunity, etc.

ROLE OF THE GUT IN CRITICAL ILLNESS

Severe trauma, burns, infections, and other major injuries to the body can induce Systemic Inflammatory Response Syndrome (SIRS), which can progress to multiple organ failure. ¹ The gut is an important target organ following infection and injury. In particular, infection and injury could alter the gut microbiota, reduce gut immunity represented by IgA and other factors, cause bacterial translocation by disrupting the intestinal barrier, and induce the influx of inflammatory cytokines into the systemic circulation via the intestinal lymph. ² In a mouse burn model, Escherichia coli was detected in the spleen and liver merely 5 min after injury. ³ Altered levels of intestinal tight junction proteins, such as decreased claudin‐5 and occludin levels and increased claudin‐2 levels, were found to change gut permeability in a cecal ligation puncture model. ⁴ In clinical research, bacterial translocation was noted in the mesenteric lymph nodes of 35% of patients who underwent hepatectomy for biliary cancer. ⁵ Disrupted tight junctions may facilitate the translocation of pathogenic bacteria from the intestines to other tissues and organs. Such intestinal dysfunction is thought to play a crucial role in the progression of systemic inflammatory response and subsequent systemic multiple organ failure. The gut thus serves as the “motor” of critical illness.

The systemic inflammatory response is common in the acute phase, in which the immune system is triggered by foreign substances, such as bacteria, or by self‐tissue damage from trauma, resulting in the activation of both inflammatory Th1‐type immune responses and anti‐inflammatory Th2‐type immune responses (Figure 1). ⁶ Prolonged systemic inflammation could also cause immunosuppression and increase the susceptibility to infection. Persistent Inflammation, Immunosuppression, and Catabolism Syndrome (PIICS) is a condition characterized by pro‐inflammatory and anti‐inflammatory responses. ⁷ On the pro‐inflammatory side, macrophages are mainly activated. On the anti‐inflammatory side, regulatory T cells or myeloid‐derived suppressor cells serve as compensatory mediators following infection and injury. ⁸ In this review, we focus on the gut microbiota of patients with critical illness.

FIGURE 1.

The concept of injury‐induced imbalances in the immune system. The host immune response induces inflammation following injury; this is known as Systemic Inflammatory Response Syndrome (SIRS). The immunosuppression coincidentally begins at the onset of inflammation; this is known as compensatory anti‐inflammatory response (CARS). If the SIRS and CARS state is prolonged, it progresses to a state known as multiple organ dysfunction syndrome (MODS). Progressive immunosuppression is known as Persistent Inflammation, Immunosuppression, and Catabolism Syndrome (PIICS). This pro‐inflammatory state is mainly driven by macrophages, neutrophils, and regulatory T cells (cited and edited from reference [1]).

DYSBIOSIS OF GUT MICROBIOTA AND ENVIRONMENT FOLLOWING INFECTION AND INJURY

Assessment of the gut microbiota by the culture method

The human gut microbiota is thought to contain more than 1000 microbial species and 100 trillion microbes. The predominant bacteria in the intestinal tract are Bacteroides and Bifidobacterium species, which are obligate anaerobes that can only grow in an anaerobic environment. The intestinal microbiota is associated with various diseases and conditions, such as obesity, gastrointestinal disease, allergy, liver cirrhosis, rheumatoid arthritis, cancer, heart failure, and autism. It also regulates the efficacy of anticancer drugs, such as immune checkpoint inhibitors. ⁹ In critically ill conditions, gut microbiota could be altered because of the present disease and the various kinds of treatments, such as antacids for bleeding prevention, catecholamines for blood pressure control, and oxygen via mechanical ventilation for respiratory failure. Especially, antibiotics for infection control could be one of the main factors to change gut microbiota ¹⁰ and lead to antibiotic‐associated diarrhea. ¹¹

To quantitatively assess the gut microbiota, stool samples were collected from 25 critically ill patients in a previous study. The total number of commensal obligate anaerobes was significantly lower in the stool samples of critically ill patients than in those of healthy individuals (8.3 ± 2.3 vs. 10.5 ± 0.5 log₁₀ colony‐forming units/g, p < 0.05). In particular, Bifidobacterium and Lactobacillus counts were reduced to 1/100–1000 of those in healthy individuals (Table 1). ¹² Assessment of the organic acid contents in the stool samples revealed a significant decrease in short‐chain fatty acid (SCFA) levels (acetic acid, propionic acid, and butyric acid levels). However, the pH of the stool samples of critically ill patients was significantly higher than that of healthy individuals (7.4 ± 0.6 vs. 6.6 ± 0.3; Table 2). The total number of obligate anaerobes already decreased within 6 h of admission ¹³ and continued to be low over the following weeks. ¹⁴ The increased number of pathogenic bacteria and decreased number of obligate anaerobes were associated with bacteremia and mortality in critically ill patients. ¹⁵ These results reveal the deterioration of the gut microbiota with the progression of systemic inflammation.

TABLE 1.

Fecal flora in patients with severe SIRS.

	SIRS patients	Normal
Total obligate anaerobes	8.3 ± 2.3*	10.5 ± 0.5
Bacteroidaceae	7.3 ± 3.0*	10.1 ± 0.4
Bifidobacterium	4.8 ± 3.3*	9.6 ± 0.7
Clostridium	2.1 ± 1.0	2.1 ± 0.7
Veillonella	3.1 ± 1.8*	7.0 ± 1.2
Total facultative anaerobes	7.8 ± 1.4	7.5 ± 0.4
Lactobacillus	2.7 ± 1.5*	5.0 ± 1.0
Enterobacteriaceae	4.1 ± 2.7*	7.4 ± 0.8
Enterococcus	6.4 ± 2.5	7.0 ± 0.9
Staphylococcus	5.3 ± 1.7*	2.7 ± 0.8
Pseudomonas	2.8 ± 1.4*	ND
Candida	2.5 ± 1.0	2.0 ± 0.5

Note: Data are mean ± SD (Log₁₀ counts/g feces).

Abbreviations: ND, not detected; SIRS, Systemic Inflammatory Response Syndrome.

^* p < 0.05 versus Normal.

TABLE 2.

Fecal organic acid concentrations and pH in patients with severe SIRS.

	SIRS patients	Normal
Total organic acid	30.3 ± 20.3*	88.4 ± 21.2
Succinic acid	2.0 ± 2.5	0.9 ± 1.2
Lactic acid	3.8 ± 5.5	0.5 ± 0.3
Formic acid	1.7 ± 2.9	0.4 ± 0.3
Acetic acid	18.7 ± 15.9*	50.8 ± 13.1
Propionic acid	2.5 ± 4.6*	18.7 ± 6.8
Isobutyric acid	0.1 ± 0.5	1.1 ± 0.3
Butyric acid	0.9 ± 2.3*	16.6 ± 6.7
Isovaleric acid	0.5 ± 1.9	1.4 ± 0.7
Valeric acid	0.1 ± 0.7	0.6 ± 0.4
pH	7.4 ± 0.6*	6.6 ± 0.3

Note: Data are mean ± SD (μmol/g feces).

Abbreviation: SIRS, Systemic Inflammatory Response Syndrome.

^* p < 0.05 versus Normal.

Assessment of the gut microbiota by metagenomic analysis

While culture is the main method to determine the number of bacteria quantitatively, comprehensive metagenomic analysis using the 16S ribosomal RNA (16S rRNA) genes enables the analysis of hundreds of microbial taxa at the phylum, order, family, genus, and species levels. It can also be used to analyze unknown causative organisms. At the phylum level, Bacteroidetes (including the genus Bacteroides) and Firmicutes (including the genus Clostridium) were found to be predominant in the gut microbiota, followed by Proteobacteria (including Escherichia coli), Actinobacteria (including Bifidobacterium), and Fusobacteria. In the acute phase of the disease, the balance of the gut microbiota changed from that at the time of admission. On ICU admission, the gut microbiota differed significantly from that of healthy individuals (Figure 2A). At the genus level, the prevalence of Blautia, Clostridium, Faecalibacterium, and other genera decreased more significantly a week after admission. ¹⁶ On the other hand, the prevalence of the genus Enterococcus significantly increased in a week (Figure 2B). These losses of commensal microbiota, expansion of pathobionts, and loss of diversity are defined as gut dysbiosis. Dysbiosis is characterized by (i) loss of beneficial microbial organisms, (ii) expansion of pathobionts or potentially harmful microorganisms, and (iii) loss of overall microbial diversity. ¹⁷ The Bacteroidetes/Firmicutes ratio (B/F ratio) has been reported to be associated with mortality. ¹⁸ Obligate anaerobic bacteria, a major component of the gut microbiota, are the principal inhibitors of bacterial overgrowth and the translocation of E. coli and other potentially pathogenic bacteria. This phenomenon is known as colonization resistance. ¹⁹ Moreover, the gut microbiota plays a role in producing immune signals that affect host metabolism, immunity, and immune response to infection. ²⁰ In one study, germ‐free mice exhibited a smaller mucus barrier, Peyer's patches, and lamina propria, lower IgA concentrations, and lower T‐cell and B‐cell counts than normal mice. ²¹ Regarding adaptive immunity, Th17 cells were induced by segmented filamentous bacteria. ²² Regulatory T cells were induced by 17 bacterial species, including those belonging to Clostridiales. ²³ IFN‐γ‐producing CD8+ cells were induced by 11 bacterial species belonging to the phyla Bacteroidetes, Firmicutes, and Fusobacteria. ²⁴ Thus, gut dysbiosis may lead to a loss of immune cells and immunity following infection and injury. ²⁵

FIGURE 2.

(A) Altered gut microbiota in ICU patients. Serial changes in the average proportions of genera in patients' fecal microbiota. Commensal bacteria (e.g., Bacteroidetes, Prevotella) decreased, whereas opportunistic bacteria (e.g., Enterococcus, Corynebacterium) increased (edited from reference [16]). (B) Serial changes in the fecal microbiota of ICU patients. The genera Blautia, Faecalibacterium, and Clostridium serially decreased in the fecal microbiota. On the other hand, the genus Enterococcus increased. An asterisk (*) indicates significant differences between the groups (cited and edited from reference [16]).

Commensal bacteria could therefore be essential to maintain homeostasis in the human body. The gut–lung axis perspective is important because intestinal dysbiosis is associated with increased pneumonia due to exacerbated inflammation. ²⁶ Severe COVID‐19 patients also have gastrointestinal complications with decreased commensal gut microbiota and increased opportunistic bacteria. ²⁷ , ²⁸

Fecal gram staining as a bedside marker

Gram staining of endotracheal sputum targeting phagocytosed bacteria for antibacterial therapy has been reported to reduce the incidence of ventilator‐associated pneumonia and acute respiratory distress syndrome. ²⁹ Fecal phagocytosed bacteria could also be a target for intestinal infection. ³⁰

For gut dysbiosis, gram staining of fecal bacteria is also a quick bedside diagnostic marker (Figure 3). ³¹ If there are no phagocytosed bacteria, the Gram staining patterns can be classified into three types. In the diverse pattern, large numbers of multiple types of bacteria completely cover the field. In the single pattern, a specific type of bacterium or fungus predominantly covers the field. In the depleted pattern, most bacteria are diminished in the field. Alterations in the gut microbiota usually progress from a diverse pattern to a single pattern and then to a depleted pattern. In the case of a single or a depleted pattern, a therapeutic approach for microbiota reconstruction may be required using probiotics and synbiotics. Alternatively, fecal microbiota transplantation (FMT) may be required.

FIGURE 3.

Pattern classification by fecal gram staining. If phagocytosed bacteria are detected, antibiotics can be administered in accordance with phagocytosed bacteria. If there are no phagocytosed bacteria, the Gram staining patterns are classified into three types with bacteria. In the diverse pattern, many types of bacteria cover the field. In the single pattern, a few types of bacteria predominantly cover the field. In the depleted pattern, most bacteria are depleted in the field. The dysbiosis progresses from a diverse pattern to a single pattern and from a single pattern to a depleted pattern.

Assessment of the gut environment by SCFAs and pH

Gut microbiota‐derived metabolites, especially SCFAs, could influence systemic inflammation. Acetate could improve intestinal defense and protect the host against lethal O157 infection. ³² Butyrate could induce the differentiation of colonic regulatory T cells. ³³ In a fecal metabolomic analysis based on the cecal ligation puncture model, the levels of SCFAs, such as butyric acid, were found to decrease. ³⁴ In clinical research, assessment of the organic acid contents in the stool samples revealed a significant decrease in SCFA levels (acetic acid, propionic acid, and butyric acid; Table 2). In addition, the pH of the stool samples of critically ill patients was significantly higher than that of healthy individuals (7.4 ± 0.6 vs. 6.6 ± 0.3).

Gastrointestinal pH also has a significant impact on bacterial flora, the absorption of vitamins and electrolytes, and the activity of digestive enzymes. ³⁵ Nakahori et al. found that an increase in lactate levels and a decrease in propionate and acetate levels were significantly associated with mortality ³⁶ An increase in fecal pH (>6.6) is significantly associated with increased mortality (odds ratio [OR], 2.46; 95% confidence interval [CI], 1.25–4.82) or the incidence of bacteremia (OR, 3.25; 95% CI, 1.67–6.30). ³⁷ Fecal pH could be an important indicator of the gut environment. These results indicate that the deterioration of the gut microbiota and gut environment is associated with the prognosis of patients with critical illness.

TREATMENTS FOR GUT DYSBIOSIS IN CRITICALLY ILL PATIENTS

Probiotics and synbiotics

Probiotics are defined by the International Scientific Association for Probiotics and Prebiotics (ISAPP) as live microorganisms that, when administered in adequate amounts, confer a health benefit on the host. ³⁸ Probiotics, most commonly Lactobacillus and Bifidobacterium, ³⁹ have been found to exert preventive effects in various diseases and conditions, such as acute diarrhea, antibiotic‐induced diarrhea, inflammatory bowel disease, and allergy. ⁴⁰ Prebiotics are currently defined as nondigestible food ingredients that beneficially affect the host by selectively stimulating the growth and/or activity of one or a limited number of bacteria in the colon. ⁴¹ Synbiotics is a combination of probiotics and prebiotics. In the abdominal surgery setting, the perioperative administration of either probiotics or synbiotics was found to significantly reduce the risk of infectious complications following abdominal surgery. In a meta‐analysis involving 2723 patients, synbiotics exhibited a greater effect on postoperative infections than probiotics alone. ⁴² In the ICU setting, synbiotics increased the levels of both obligate and facultative anaerobes, such as Bifidobacterium and Lactobacillus, which could increase the SCFA levels and decrease the pH. ⁴³ This virtuous circle could prevent infectious complications. In a meta‐analysis of ventilated patients in the ICU, the administration of probiotics reduced the incidence of diarrhea and ventilator‐associated pneumonia (VAP), duration of mechanical ventilation, length of ICU stay, and in‐hospital mortality. ⁴⁴ , ⁴⁵ Moreover, in patients with sepsis, the synbiotic group exhibited significantly greater levels of beneficial bacteria (Bifidobacterium and Lactobacillus) and acetate than the nonsynbiotic group. Synbiotics also lowered the incidence of diarrhea and VAP in ventilated patients with sepsis. ⁴⁶ In a meta‐analysis of 281 patients in the trauma setting, the use of probiotics was associated with a decrease in the incidence of nosocomial infections. ⁴⁷ These reports indicate that the administration of probiotics and synbiotics could maintain the gut microbiota balance and have preventive effects against infectious complications in critically ill patients.

The mechanisms of action of probiotics and synbiotics involve several factors, including gut microbiome modulation and barrier function: (a) Inhibition of Proteobacteria expansion: The aerobic condition consistently causes a shift of bacterial communities from obligate anaerobes to facultative anaerobes. ³⁴ A dysbiotic expansion of facultative anaerobic bacteria, including Proteobacteria, could reduce the levels of SCFAs and form a dysfunctional colonic surface. ⁴⁸ Probiotics/synbiotics could prevent the expansion of Proteobacteria and maintain gut homeostasis. (b) Bacterial inhibition by SCFAs: Acetate generated by the gut microbiota could inhibit pathogenic bacteria. A decrease in pH caused by probiotics/synbiotics could increase undissected acetate, resulting in further inhibition. (c) Tight junction strengthening: In an intestinal multidrug‐resistant Acinetobacter baumannii infection model, probiotics/synbiotics could maintain the levels of the tight‐junction‐related proteins claudin‐1, occludin, and ZO‐1 and serum diamine oxidase activity, a marker of intestinal integrity. ⁴⁹ In biliary cancer patients, synbiotics could reduce the incidence of bacterial translocation in the mesenteric lymph nodes. ⁵⁰ These factors could prevent bacterial translocation and infectious complications (Figure 4).

FIGURE 4.

Potential infection prevention mechanism of probiotics/synbiotics. (Left) Severe injury deteriorates the gut microbiota and results in the progression of dysbiosis, thereby causing systemic inflammation, pneumonia, and multiple organ dysfunction syndrome. (Right) Probiotics/synbiotics could improve the gut microbiota and prevent infectious complications. SCFA, short‐chain fatty acids.

Not all types of probiotics are effective in critically ill patients. In vitro, even the same Lactobacillus strains exhibited different effects on endocarditis models. ⁵¹ In one randomized controlled trial, Lactobacillus had no significant effect on diarrhea and VAP. ⁵² Some probiotics could cause bacteremia and necrotizing enterocolitis. ⁵³ , ⁵⁴ These results indicate that not all probiotics are beneficial to the host. The effect and safety of probiotics differ with the type of gut microbiota, type of disease, and severity of disease. The type and number of bacteria should be elucidated to determine the appropriate effects of probiotics in critically ill patients.

Fecal microbiota transplantation

Antibiotic‐associated diarrhea (AAD) could cause dysbiosis following antibiotic administration. Antibiotics are mandatory drugs; therefore, the prevention of gut microbiota effects is an important topic. Clostridioides difficile infection (CDI) is a severe healthcare‐related infection characterized by AAD in the US. In refractory cases, FMT is recommended to reconstruct a normal gut microbiota. ⁵⁵ FMT has been reported to be effective in not only CDI cases but also non‐CDI cases, such as inflammatory bowel disease, ⁵⁶ graft versus host disease, ⁵⁷ and refractory diarrhea. ⁵⁸ In one study, AAD in the ICU was improved in 86.7% (13/15) after FMT. ⁵⁹ Prolonged diarrhea with gut dysbiosis might be a good indication to restore gut microbiota and alleviate gastrointestinal symptoms in critically ill patients (jRCTs051220110). PIICS occurred in patients with prolonged stays in the ICU. Actually, 40% of patients following burn died after 30 days due to sepsis and pneumonia. ⁶⁰ Gut dysbiosis prolonged 6 weeks after injury in the ICU. ¹⁴ As gut dysbiosis could associate with immunity, FMT might be a new solution to restore gut microbiota and prevent infection.

However, the screening of donors is crucial ⁶¹ and warranted because of ESBL infections for immunocompromised patients. ⁶² Safer screening and purification are required to manufacture fecal microbiota products.

Future intestinal therapy

Preventive effects of live biotherapeutic products on the gut microbiome or intestinal epithelium have been reported. In particular, oral microbiome therapy with live purified Firmicutes bacterial spores could reduce the risk of CDI recurrence with no adverse events. ⁶³ The pharmacological efficacy of the oral microbiome and associated metabolites may restore the gut microbiota and reduce CD growth. Regarding other treatments, hydrogen exhibits antioxidant, anti‐inflammatory, and antiapoptotic effects. ⁶⁴ Ikeda et al. found that the gastric administration of hydrogen water to a mouse peritonitis model significantly suppressed intestinal Enterobacteriaceae burst and improved survival. ⁶⁵ High‐molecular‐weight polyethylene glycol, functioning as surrogate mucin, improved the survival rate in an intestinal Pseudomonas aeruginosa infection model. ⁶⁶ Moreover, epidermal growth factor improved gut apoptosis and proliferation in a P. aeruginosa pneumonia mouse model. ⁶⁷ With regard to tight junction proteins, claudin‐2 knockout mice upregulated intestinal permeability in a cecal ligation sepsis model. ⁶⁸ Molecular targeted therapy with tight junction proteins may be considered for gut dysbiosis in the future.

In conclusion, the gut microbiota deteriorates in critical illnesses, such as trauma, burns, and sepsis. Gut dysbiosis reduces gut immunity and bacterial translocation, which could induce a systemic inflammatory response and cause multiple organ dysfunction. To prevent gut dysbiosis, intestinal treatments, such as the administration of probiotics/synbiotics, could maintain the gut microbiota and prevent infectious complications. A novel therapeutic approach involving the use of live biotherapeutic products and microbiological products may modulate the gut microbiota and environment.

CONFLICT OF INTEREST STATEMENT

Dr. Hiroshi Ogura is an Editorial Board member of AMS Journal and a co‐author of this article. Also, Dr. Jun Oda is the Editor‐in‐Chief of the journal and the co‐author of this article. To minimize bias, they were excluded from the peer‐review process and all editorial decisions related to the acceptance and publication of this article. Peer‐review was handled independently by AMS Journal editorial office and Dr. Yasuyuki Kuwagata as the Editor to minimize bias.

ETHICS STATEMENT

Approval of the research protocol: N/A.

Informed consent: N/A.

Registry and the registration no. of the study/trial: N/A.

Animal studies: N/A.

Shimizu K, Ogura H, Oda J. Gut dysbiosis and its treatment in patients with critical illness. Acute Med Surg. 2025;12:e70068. 10.1002/ams2.70068

DATA AVAILABILITY STATEMENT

Data sharing not applicable to this article as no datasets were generated or analysed during the current study.