Gastric Microbiome Alterations in Sepsis‐Related Gastrointestinal Bleeding: Two Case Reports and Literature Review

ABSTRACT

Sepsis, characterized by life‐threatening organ dysfunction resulting from an uncontrolled response to infection, can impact various systems of the body, including the digestive system. Prior research has identified sepsis as a significant risk factor for gastrointestinal bleeding. However, there is limited reporting on the gastric microecology of individuals with sepsis complicated by gastrointestinal bleeding. This paper presents the cases of two patients, shedding light on this issue. The first case was a 29‐year‐old female who developed sepsis during perioperative liver transplantation, while the second case features a 34‐year‐old female with acute pancreatitis complicated by septic shock. Both patients underwent gastroscopy following gastrointestinal bleeding, revealing evident gastric mucosal injuries. Notably, the second patient exhibited suppurative gastritis. Metagenomic Next‐Generation Sequencing (NGS) of gastric juice from these two patients unveiled microecological alterations in the stomach. The sequencing results indicated a substantial presence of pathogenic sequences, underscoring the role of direct gastric mucosal injury due to infection as a significant contributor to gastrointestinal bleeding. This study not only introduces a novel approach to pinpointing the causes of gastrointestinal bleeding in sepsis but also provides valuable insights for clinical diagnosis and treatment.

1. Background

Sepsis is a critical medical condition characterized by life‐threatening organ dysfunction resulting from the uncontrolled immune response to infection. It can lead to multiple organ dysfunction syndrome, posing a substantial risk to the lives of critically ill patients [1, 2]. The gastrointestinal tract, encompassing the esophagus, stomach, duodenum, small intestine, and colon, plays a crucial role in maintaining a dynamic balance between epithelial tissue, the microbiota, and the immune system. This balance contributes to various essential functions, including nutrient absorption, immune regulation, and defense against pathogen invasion [3].

In individuals with sepsis, the combination of inflammatory reactions and oxidative stress often leads to gastrointestinal mucosal ischemia, thereby impacting the functionality of the digestive system. Extensive research has established sepsis as a significant risk factor for gastrointestinal bleeding. Nevertheless, there is a notable scarcity of reports focusing on the alterations in gastric microecology among septic patients who develop gastrointestinal bleeding.

This paper presents detailed insights into the gastric microecology and the diagnostic and treatment procedures applied to two patients afflicted by sepsis complicated by gastrointestinal bleeding. We explored the gastric microecology of these patients by NGS examination. NGS uses high‐throughput sequencing technology to extract and sequence nucleic acids in samples, compare them with the nucleic acid sequences of existing microorganisms in the database, and generate test reports after automatic analysis by gene data analysis software.

This contribution aims to enhance our understanding of the underlying causes of gastrointestinal bleeding in such cases and offers valuable guidance for the adjustment of treatment strategies.

2. Clinical Presentation

2.1. Case 1

A 34‐year‐old female was admitted to the hospital due to a history of “abnormal liver function for over nine years.” Upon admission, the patient was conscious, exhibiting moderate jaundice in the skin and sclera, along with slight abdominal distension. No other significant abnormalities were noted during the physical examination. Abdominal contrast‐enhanced CT scans revealed liver cirrhosis, ascites, and signs of portal hypertension with collateral circulation. Furthermore, a liver biopsy confirmed the diagnosis of nodular cirrhosis with intrahepatic cholestasis. Gastroscopy upon admission revealed mild esophageal varices, along with gastric mucosal congestion and edema (Figure 1A).

FIGURE 1.

Gastroscopic results of the first case. (A) Gastroscopy showed gastric mucosal congestion and edema. (B) Gastroscopy showed multiple huge ulcers in the gastric body, extensive exfoliation‐like changes in the gastric mucosa.

The patient underwent an allogeneic liver transplantation on September 4, 2022, following which she was transferred to the ICU. After surgery, the patient received mycophenolate mofetil and tacrolimus to modulate immune function. Despite these interventions, the bilirubin levels remained elevated after the procedure. Subsequently, percutaneous transhepatic biliary drainage was performed.

Eleven days post‐operation, the patient had a high fever (39°C) with abdominal distension. Blood cultures identified the presence of Enterococcus faecium and Candida albicans , leading to a diagnosis of sepsis. Fifteen days following the transplantation, the patient experienced acute gastrointestinal bleeding, characterized by a profusion of dark stools and decreased blood pressure. Immediate interventions included fluid resuscitation, blood transfusion, and intravenous use of proton pump inhibitors. A subsequent gastroscopy revealed multiple extensive ulcers in the gastric body and pronounced exfoliation‐like alterations in the gastric mucosa (Figure 1B).

Unfortunately, the patient's gastroscopy showed that the lesions of the stomach body were significantly worse than those on admission. Gastric fluid analysis reported a pH level of 6.0. We retained gastric juice samples by gastroscopy and sent blood culture again at the same time. We collected gastric juice samples for next‐generation sequencing (NGS) detection (visionseq 1000) by targeted and selectively amplifying specific regions of the 16S rRNA gene. Both NGS and culture analysis of the gastric fluid disclosed the presence of Klebsiella aerogenes and Pseudomonas aeruginosa , which correlated with the findings from simultaneous blood cultures (Table 1). In response to these results, the anti‐infection regimen was further adjusted to colistin sulfate, cefoperazone sodium sulbactam sodium, caspofungin, and hemostatic therapy involving the administration of human fibrinogen, human prothrombin complex, fresh frozen plasma, and transfusion of red blood cell suspension. Tragically, 2 days later, the patient's condition deteriorated drastically, resulting in severe gastrointestinal hemorrhage, hypovolemic shock, disseminated intravascular coagulation (DIC), and ultimately, respiratory and cardiac arrest. Despite extensive rescue efforts, the patient succumbed to her condition.

TABLE 1.

Pathogen and clinical manifestation of two cases.

	Case 1	Case 2
Gastric pH	6.0	6.5
Gastric mucosal manifestations	Multiple extensive ulcers; pronounced exfoliation‐like alterations in gastric mucosa	Ulcers and numerous dark‐brown protuberances
Gastric fluid NGS	Klebsiella aerogenes , Pseudomonas aeruginosa	Pseudomonas aeruginosa , Stenotrophomonas maltophilia , Acinetobacter baumannii , Saccharomyces cerevisiae , Aspergillus fumigatus , Candida albicans .
Blood culture	Klebsiella aerogenes , Pseudomonas aeruginosa	Pseudomonas aeruginosa .
Antibiotic treatment	Colistin sulfate, cefoperazone sodium sulbactam sodium, caspofungin	Tigecycline, colistin sulfate, voriconazole
Outcome	Clinical death	Clinical death

2.2. Case 2

A 29‐year‐old female patient was admitted to the hospital with a complaint of “abdominal pain persisting for 20 days, dyspnea for one day.” The patient had experienced sustained epigastric colic for the preceding 20 days, starting at the 39 + 1 week of her gestation period, which was accompanied by bouts of vomiting. She was diagnosed with acute severe pancreatitis, leading to the performance of an emergency cesarean section. Postoperative blood culture and abdominal drainage identified the presence of carbapenem‐resistant Acinetobacter baumannii . The patient's dyspnea was further aggravated. Subsequently, she was transferred to our hospital following endotracheal intubation. Importantly, the patient had no history of digestive tract disorders.

Upon admission, tigecycline and colistin sulfate were given due to pathogenic results. The patient was in a state of analgesia and sedation. Wet rales could be heard in both lungs. The whole abdomen is distended and tender, and 6 drainage tubes can be seen in the abdomen. Abdominal enhanced CT: Pancreatic swelling, extensive peripancreatic exudation, gastrointestinal wall swelling, stratified enhancement (Figure 2A).

FIGURE 2.

Results of CT and gastroscopy in the second patient. (A) CT showed gastrointestinal wall swelling, with stratified enhancement. (B) Gastroscopy showed ulcers and a large number of dark‐brown protuberances in the middle curvature of the gastric body.

Over the course of her hospitalization, the patient underwent blood culture and abdominal drainage culture assessments. It was also observed that a small amount of brown drainage fluid could be seen in the gastrointestinal decompression device. On the third day following her admission, gastroscopy revealed ulcers and numerous dark‐brown protuberances in the middle curvature of the gastric body and across the mucosa from the anterior wall to the antrum, indicative of ulcerated gastric mucosa and purulent secretions. This presentation was consistent with suppurative gastritis (Figure 2B).

Gastric fluid analysis reported a pH level of 6.5. Gastric fluid samples were sent to NGS and culture testing. Subsequent findings indicated the presence of Pseudomonas aeruginosa , Stenotrophomonas maltophilia , Acinetobacter baumannii , Saccharomyces cerevisiae , Aspergillus fumigatus , and Candida albicans . On the sixth day, culture results from the abdominal drainage fluid indicated Candida albicans , while blood cultures identified Pseudomonas aeruginosa . Simultaneously, gastric juice cultures revealed the presence of Stenotrophomonas maltophilia and Candida albicans (Table 1). In response to these findings, voriconazole antifungal therapy was initiated, accompanied by component blood transfusions. Unfortunately, despite these efforts, there was no significant improvement in the patient's hemodynamic status. Her condition continued to deteriorate, characterized by progressive gastrointestinal bleeding and multiorgan dysfunction. Tragically, the patient's clinical state failed to respond to rescue efforts and was ultimately declared deceased.

3. Main Finding

Main findings are given in Table 1.

4. Discussion

In a healthy physiological state, the stomach undertakes the initial steps of food digestion, creating a unique internal environment and microecology. Conventionally, the acidic nature of gastric juice and the presence of digestive enzymes were thought to be inhospitable to most microorganisms entering the digestive system, with only specific microorganisms able to survive [4]. Studies have identified common gastric bacteria, including Bacteroides, Proteus, Lactobacillus, and Streptococcus, which show significant correlation with gastric acid secretion [5]. Dietary and environmental factors further influence the composition of gastric microorganisms [6].

4.1. Sepsis and PPI Administration

Patients with sepsis frequently experience excessive systemic inflammatory responses and oxidative stress, leading to gastrointestinal mucosal ischemia, which in turn impairs secretory and immune barrier functions. Notably, the prophylactic use of proton pump inhibitors (PPIs) in the intensive care unit (ICU) has gained prominence in recent years. However, recent research has shown no significant clinical differences in gastrointestinal bleeding incidence between sepsis patients who received prophylactic PPIs and those who did not [7]. Furthermore, the significance of gastric acid in immune responses and nutrient absorption has become more apparent, underlining the need for a judicious evaluation of PPI use, considering both indications and treatment duration for patients [8].

Both patients in this case report were administered proton pump inhibitors, which may further disrupt the acidic gastric environment and lead to alterations in the gastric microecology. Animal studies have indicated that in a mouse model with impaired gastric acid secretion and increased gastric juice pH, the colonization and copy number of pathogens like Yersinia and Salmonella significantly increased in the stomach [9]. In vitro experiments have demonstrated that low pH could effectively inhibit the accumulation and invasion of Klebsiella pneumoniae in intestinal mucosal epithelial cells [10]. Furthermore, Aneta Kiecka and Marian Szczepanik have found that PPI can also act on neutrophils, natural killer cells and cytokines, affecting gastrointestinal immune regulation [11]. In both cases, the patient's gastric fluid culture and NGS results were not normal gastric flora. This may be related to the increased gastric juice pH caused by the use of PPI, which makes the gastric mucosa lose the protective barrier and become susceptible. However, methods for assessing gastric microecological composition remain limited, and traditional gastric juice cultures have constraints in terms of sensitivity, specificity, timeliness, and depth of information. In addition, both patients were immunosuppressed and complicated with sepsis. This may lead to their gastrointestinal mucosal immune dysfunction, which is a susceptible factor for infection.

4.2. Possible Reasons for Gastrointestinal Bleeding

In the case of our first patient, who developed sepsis complicated by gastrointestinal bleeding, gastroscopy revealed multiple large ulcers and extensive mucosal exfoliation, markedly different from the typical erosion seen in stress ulcers. Moreover, gastric juice pH was elevated beyond normal levels. As a response, we conducted a gastric juice NGS test to explore infection‐related factors, which yielded a substantial quantity of pathogen sequences. Some of these pathogens corresponded with the findings of blood culture, suggesting the possibility of blood‐borne transmission leading to gastric mucosal infection.

The second patient, suffering from acute pancreatitis and septic shock, had no prior history of digestive tract disease. Abdominal CT scans revealed pronounced swelling and stratified enhancement of the gastrointestinal wall, while gastroscopy revealed ulcers of varying sizes and numerous dark‐brown protuberances, indicative of suppurative gastritis. Suppurative gastritis is a rare occurrence in patients with septic gastrointestinal bleeding, with the capacity to infiltrate the gastric mucosa, submucosal structures, and even the lamina propria, carrying a mortality rate as high as 27% [12]. The treatment of suppurative gastritis hinges on prompt diagnosis and the administration of broad‐spectrum antibiotics [13]. In this case, the pronounced gastric mucosal injury resulted from infection. The pathological changes associated with gastric mucosal infection in this patient might stem from blood‐borne transmission or direct invasion related to abdominal infection.

Gastrointestinal bleeding in sepsis patients can arise from various sources. One source could be blood‐borne transmission, as evidenced by the NGS results aligning with blood culture outcomes. Another potential origin may be gastrointestinal colonization or translocation of intestinal flora. Moreover, invasive procedures, such as the indwelling of gastric tubes during hospitalization, could serve as vectors for pathogen transmission. It is worth noting that the gastrointestinal mucosal function of patients with sepsis is often destroyed, and the pathogen may also invade into the blood through a fragile mucosal barrier. Mucosal biopsy may help to identify the path of pathogen invasion. Although this study did not engage in a comparative analysis of pathogenic microorganisms in different regions, the findings from blood culture and gastric juice NGS in the two patients indicate that blood infection might contribute to gastric mucosal lesions in these cases.

In the study of gastrointestinal dysfunction caused by sepsis, most investigations center on intestinal mucosal dysfunction. The mechanisms underlying intestinal dysfunction entail intestinal cell apoptosis, an exaggerated inflammatory response, oxidative stress, and mitochondrial dysfunction [14, 15]. This interplay leads to the rupture of the intestinal epithelial cell membrane, intercellular junction damage, and compromised mucosal barrier function [16]. Whether these mechanisms similarly apply to gastric mucosal injury in sepsis needs further examination.

In this study, we have innovatively employed gastric juice NGS to comprehensively elucidate the stomach's microecology, confirming that infection‐induced gastric mucosal injury plays a significant role in gastrointestinal bleeding. The limitation of this study is that although NGS can comprehensively reflect the microecology of the stomach, it is difficult to identify whether these microorganisms are the source of infection or only colonized bacteria. Further research and examination are needed. Another limitation is that due to the presence of gastrointestinal bleeding in patients, gastric juice samples may be contaminated by blood, resulting in the test results not accurately reflecting the gastric microecology. Although both gastric juice and blood samples were sent for examination at the same time, it is still difficult to identify, and larger sample data studies may be needed in the future.

This approach provides a novel methodology for determining the causes of septic gastrointestinal bleeding. In clinical practice, patients presenting with septic gastrointestinal bleeding can benefit from gastric juice pH monitoring, gastric juice culture, and gastric juice NGS examination. These tools can be instrumental in characterizing alterations in gastric microecology, helping to find the causes of bleeding and enabling timely treatment adjustments. As a result, this study offers a vital reference for comprehending the origins of gastrointestinal bleeding in these patients.

Funding

The authors have nothing to report.

Ethics Statement

The authors have nothing to report.

Consent

Written informed consent to publish the report was obtained from the patient's legal guardians.

Conflicts of Interest

The authors declare no conflicts of interest.

Data Availability Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.