Intestinal microecological transplantation for a patient with chronic radiation enteritis: A case report

Abstract

BACKGROUND

The gut microbiota is strongly associated with radiation-induced gut damage. This study aimed to assess the effectiveness and safety of intestinal microecological transplantation for treating patients with chronic radiation enteritis.

CASE SUMMARY

A 64-year-old female with cervical cancer developed abdominal pain, diarrhea, and blood in the stool 1 year after radiotherapy. An electronic colonoscopy was performed to diagnose chronic radiation enteritis. Two courses of intestinal microecological transplantation and full-length 16S rRNA microbiological analysis were performed. The patient experienced short- and long-term relief from symptoms without adverse effects. Whole 16S rRNA sequencing revealed significant differences in the intestinal flora’s composition between patient and healthy donors. Pathogenic bacteria, such as Escherichia fergusonii and Romboutsia timonensis, were more in the patient. Beneficial bacteria such as Faecalibacterium prausnitzii, Fusicatenibacter saccharivorans, Ruminococcus bromii, and Bifidobacterium longum were more in the healthy donors. Intestinal microbiota transplantation resulted in a significant change in the patient's intestinal flora composition. The composition converged with the donor's flora, with an increase in core beneficial intestinal bacteria, such as Eubacterium rectale, and a decrease in pathogenic bacteria. Changes in the intestinal flora corresponded with the patients' alleviating clinical symptoms.

CONCLUSION

Intestinal microecological transplantation is an effective treatment for relieving the clinical symptoms of chronic radiation enteritis by altering the composition of the intestinal flora. This study provides a new approach for treating patients with chronic radiation enteritis.

Key Words: Chronic radiation enteritis; Gut microbial transplantation; Intestinal microecology; Cancer; Quality of life; Case report

Core Tip: This study explores the efficacy of fecal microbiota transplantation (FMT) in a patient with chronic radiation enteritis. A 64-year-old patient experienced significant symptom relief and long-term remission after FMT. Microbial analysis revealed beneficial shifts in gut flora composition. This highlights FMT as a promising intervention for managing radiation-induced gastrointestinal complications, offering short-term relief and sustained benefits. Targeting intestinal microbiota presents a novel approach to improving patient outcomes and quality of life in chronic radiation enteritis, showing a potential paradigm shift in treatment strategies.

INTRODUCTION

Radiation enteritis is an intestinal complication caused by radiotherapy for pelvic, abdominal, and retroperitoneal malignancies affecting the small intestine, colon, and rectum. Radiation enteritis is divided into acute and chronic according to onset: acute enteritis may occur immediately or within 3 months after radiotherapy, and chronic enteritis may occur after 9–14 months, approximately 30 years, affecting the quality of life of patients[1]. The American Society of Colorectal Surgeons suggests treatments for chronic radiation enteritis, which mainly include formalin, aluminum thioglycollate, argon beam plasma coagulation, hyperbaric oxygen therapy, surgery, and other symptomatic treatments with limited efficacy[2]. Clinical studies have shown significant changes in the gut flora of patients after irradiation, such as an increase in Clostridium and other unclassified bacteria; a significant decrease in Firmicutes and Bacteroidetes; a significant increase in Phascolarctobacterium, Lachnospiraceae, Veillonella, Erysipelotrichaceae, Roseburia, Clostridium, Ruminococcus, Cmethylpentosum, and Leptom; and a significant decrease in the relative abundance of other enteric genera such as Clostridiales, Faecalibacterium, Peptococcus, Peptostreptococcus, Lactobacilli, Roseburia, and other anaerobes[3]. Recently, intestinal microecology has been used to prevent and treat patients with radiation enteritis. For instance, administering a dual-strain dual-conjugate probiotic (Lactobacillus acidophilus LAC-361 and Bifidobacterium longum BB536) reduces grade 2, 3, and 4 diarrhea induced by radiation enteritis in patients undergoing radiotherapy after pelvic surgery[4]. In a randomized, double-blind, placebo-controlled trial involving 38 patients undergoing postoperative radiotherapy for gynecological cancer, the probiotic group experienced fewer days of watery stools than the placebo group[5]. Simultaneously administering synbiotics containing Lactobacillus royale and soluble fiber during radiation therapy for patients with prostate cancer can reduce the diarrheal symptoms of proctitis and improve the quality of life of patients with radiation-induced acute proctitis[6]. Currently, clinical studies are being conducted on fecal microbiota transplantation (FMT) for treating patients with radiation enteritis. This study aimed to assess the effectiveness and safety of intestinal microecological transplantation for treating patients with chronic radiation enteritis.

CASE PRESENTATION

Chief complaints

A 64-year-old female presented with intermittent abdominal pain, diarrhea, and blood in the stool that had been occurring for 1 year.

History of present illness

On April 9, 2020, the patient was diagnosed with cervical squamous cell carcinoma. Radiation therapy was commenced on April 27 with a 5000 cGy dose for external radiation therapy and four intermittent sessions of three-dimensional intracavitary radiotherapy between June 15 and June 29 with a 700 cGy dose. The patient experienced no discomfort during radiotherapy. In May 2021, the patient developed abdominal and colic pains. The patient had diluted watery bowel movements 7–8 times a day. The patient self-administered antidiarrheal drugs but did not experience significant relief. In June, the patient reported intermittent blood in her stool with a volume of 100 mL per occurrence. She visited a local hospital, where an electronic colonoscopy revealed rectal and sigmoid colonies. The medical history suggested chronic radiation enteritis, and mesalazine-soluble tablets and compound glutamine-soluble capsules were prescribed for symptomatic treatment. After receiving mesalazine enteric-coated tablets and compound glutamine enteric-coated capsules for symptomatic treatment, abdominal pain, diarrhea, and blood in the stool persisted, significantly affecting the patient's quality of life. The patient was admitted to our hospital for further treatment.

History of past illness

The patient has no previous medical history.

Personal and family history

The patient and family histories were negative.

Physical examination

The abdomen exhibited tenderness in the mid and lower regions, with no other positive signs.

Laboratory examinations

The patient's laboratory tests were within the normal range, including tests for blood routine, liver and kidney function, electrolytes, and tumor markers.

Imaging examinations

An electronic colonoscopy revealed diffuse congestion and edema of the mucosa 20 cm below the anus, multiple congestive spots, disappearance of the mucosal vascular texture, and multiple capillary dilatations. The patient was diagnosed with chronic radial enterocolitis (Figure 1).

Figure 1 Patient's electron colonoscopy.

FINAL DIAGNOSIS

The patient's medical history, clinical manifestations, and colonoscopy results were collectively utilized to facilitate the diagnosis of chronic radiation enteritis.

TREATMENT

As the patient had received conventional symptomatic treatment with little success, she was informed about the indications and potential adverse effects of FMT in treating chronic radiation enteritis. Relevant studies and applications were also discussed. The patient agreed to undergo FMT and provided informed consent. The Ethics Committee of the First Medical Center of the General Hospital of the People's Liberation Army approved the use of FMT for the treatment of radiation enteritis (Ethics Approval Number: S2022-300-01).

Therapy for intestinal microecological transplantation

Donor selection method: The research team conducted research, and a 27-year-old woman with no gastrointestinal symptoms, no history of infectious diseases, or family history was recruited[7,8]. The sample taken from the patient did not contain any of the following: Human immunodeficiency virus; Hepatitis A, B, C, and E; Pathogenic Escherichia coli; Shigella; Salmonella; Clostridium difficile toxin; Epstein-Barr virus; fungi; eggs; or encapsulation. The patient did not use antibiotics, probiotics, or other medications that affected the intestinal flora 4 wk before fecal donation.

The patient received FMT from a healthy participant with mesalazine enteric-coated tablets. The patient underwent two courses of FMT. The first course included a colonoscopic microbial product transplantation of 300 mL on August 16, 2022, an enema microbial product of 200 mL on August 18, and another enema microbial product of 200 mL on August 22. The second course included colonoscopic microbial product transplantation of 300 mL on October 24, 2022, and enema microbial product transplantation of 200 mL on October 26, 2022. A total of 200 mL of the microbiological enema product was administered.

Collection of stool samples and analysis of the full-length 16S rRNA flora

Before and after each treatment and before and during the gut microbial transplantation, stool samples were collected from the patients for full-length 16S rRNA sequencing to examine the microbiota's diversity and composition at each time point. Donor stool samples were obtained.

OUTCOME AND FOLLOW-UP

Efficacy and safety of intestinal microecology after transplantation

Following the initial FMT, the patient experienced a significant improvement in diarrhea symptoms. The frequency of bowel movements decreased from 7–8 times per day to 2–3 times per day, blood in the stool was significantly reduced, and abdominal pain was significantly relieved. The patient’s diarrhea and abdominal pain were gradually alleviated after the first FMT course. However, 1 month later, blood in the stool reappeared, and a second course of transplantation was performed. At the end of the second course, the volume and frequency of blood in the stool decreased again, and remission was prolonged. The patient reported no diarrhea or abdominal pain one year after the second course of treatment. She occasionally noticed small amounts of blood in her stool; however, this did not significantly affect her daily life. The patient did not experience adverse reactions related to the FMT during the process.

Analysis of full-length 16S rRNA flora in fecal specimens before and after gut microbial transplantation

α-diversity and β-diversity of the bacterial flora: The Chao index was used to measure the alpha diversity of the bacterial community in the patients’ fecal specimens at the Amplicon Sequence Variant level (Figure 2). The alpha diversity was lowest before transplantation and increased significantly with the number of intestinal microecological transplants, similar to that of the donor.

Figure 2 α-diversity Chao index. Fecal microbiota transplantation (FMT)_0: Before gut microbiota transplantation; FMT_1: During course 1 of gut microbiota transplantation; FMT_2: During course 2 of gut microbiota transplantation. ASV: Amplicon sequence variant; FMT: Fecal microbiota transplantation.

A study based on the Bray-Curtis principal coordinates analysis revealed that the donor, gut microbiota transplantation during the first course, and gut microbiota transplantation during the second course were relatively separated, and the groups clustered together (r = 0.248, P = 0.042). Moreover, the composition of the patient's intestinal flora gradually shifted closer to that of the donor as the number of transplanted gut microbiota increased (Figure 3).

Figure 3 β-diversity principal coordinate analysis analysis. Fecal microbiota transplantation (FMT)_0: Before gut microbiota transplantation; FMT_1: During course 1 of gut microbiota transplantation; FMT_2: During course 2 of gut microbiota transplantation. PCoA: Principal coordinate analysis; ASV: Amplicon sequence variant; FMT: Fecal microbiota transplantation.

Comparison of dominant flora composition: Phylum levels: At the phylum level, the patient's gut microbiota contained fewer thick-walled phyla and more metaplastic phyla than the donor’s fecal composition before transplantation. However, after transplantation, the abundance of thick-walled bacterial phyla in the patient's gut gradually increased, whereas the abundance of metaplastic bacterial flora decreased (Figure 4).

Figure 4 Sequences were classified at the phylum level. Fecal microbiota transplantation (FMT)_0: Before gut microbiota transplantation; FMT_1: During course 1 of gut microbiota transplantation; FMT_2: During course 2 of gut microbiota transplantation. FMT: Fecal microbiota transplantation.

Species levels: Fisher’s exact test was used to assess the variability in the dominant flora. Some bacteria had a significantly higher pre-transplant abundance in the patient than in healthy individuals. These bacteria included Escherichia fergusonii, Romboutsia timonensis, Anaerobutyricum halleii, and Faecalimonas umbilicata. Unclassified Blautia, Mediterraneibacter faecis, Blautia wexlerae, unclassified Bifidobacterium, Faecalibacterium prausnitzii, Eubacterium coprostanoligenes, Fusicatenibacter saccharivorans, unclassified Eubacteriales, Ruminococcus bromii, and Bifidobacterium longum were decreased (P < 0.05; Figure 5A). The following bacteria were more common on day 1 after the first course of gut microbial transplantation than before the transplantation: Blautia obeum, Streptococcus thermophilus, Streptococcus parasanguinis, unclassified g Streptococcus, Streptococcus anginosus, and Streptococcus oralis. Weissella confusa, Haemophilus parainfluenzae, Escherichia fergusonii, Romboutsia timonensis, Anaerobutyricum hallii, unclassified g Blautia, Mediterraneibacter faecis, unclassified g Bifidobacterium, and Faecalimonas umbilicata were decreased (P < 0.05; Figure 5B).

Figure 5 Differential bacteria at the species level. A: Fecal microbiota transplantation (FMT)_0 vs donor variability analysis of bacterial flora - species level. FMT_0: Before gut microbiota transplantation; B: FMT_0 vs FMT_1_1 colony variability analysis at the species level. FMT_1_1: On day 1, after the first course of gut microbial transplantation; C: FMT_0 vs fecal microbiota transplantation 1 60 colony variability analysis at the species level. FMT_1_60: Following the transplantation, was conducted on day 60.

Bacteria that increased 2 months after the first course of transplantation of the patient's gut microorganisms compared with the gut microorganisms before transplantation included Enterococcus faecium, Eubacterium rectale, Blautia luti, Faecalibacillus intestinalis, Dorea formicigenerans, Anaerostipes hadrus, Dorea longicatena, Blautia wexlerae, unclassified g Blautia, unclassified g Bifidobacterium, unclassified g Blautia, unclassified g Bifidobacterium. The bacteria with reduced abundance were Escherichia fergusonii, Romboutsia timonensis, Anaerobutyricum hallii, Faecalimonas umbilicata, and Mediterraneibacter faecis (P < 0.05; Figure 5C).

DISCUSSION

This case demonstrates that intestinal microbial transplantation provides significant relief in the short- and long-term remission of chronic radiculitis enterica. The patient experienced significant improvement in symptoms such as abdominal pain, diarrhea, and blood in the stool after the first course of intestinal microbial transplantation. Two months after the initial intestinal microbial transplantation, the patient's abdominal pain and diarrhea were alleviated. However, the patient had a small amount of blood in the stool, which disappeared shortly after the second course of intestinal microbial transplantation. One year after the second course, the patient's abdominal pain and diarrhea remained in remission, with occasional small amounts of blood in the stool. However, this did not affect the patient's quality of life.

Radiation enteritis development is linked to alterations in the composition of intestinal flora. A study of patients who underwent pelvic radiotherapy found that the number of Clostridium difficile and other unclassified bacteria increased, while the numbers of Firmicutes and Bacteroides bacteria significantly decreased[3]. Analysis of the fecal flora in this study showed similar results: before intestinal microbial transplantation, the diversity of the fecal flora was significantly lower than that of the healthy individual, with decreased Phylum Firmicutes and increased Proteobacteria. After intestinal microbial transplantation, the patient's intestinal flora showed significantly higher diversity, a gradual increase in Phylum Firmicutes, and a decrease in Proteobacteria, similar to that of the donor. Escherichia fergusonii, a gram-negative bacterium belonging to the genus Escherichia of the family Enterobacteriaceae, is an emerging pathogen with zoonotic potential. Escherichia fergusonii has been isolated from patients with wound infections, urinary tract infections, inflammatory bowel disease, ischemic bowel disease, pancreatic cancer, and Alzheimer's disease; however, its virulence determinants are not well understood[9-12]. Romboutsia timonensis is a pathogenic bacterium first reported in 2016. Romboutsia timonensis was isolated from a French man with anemia and black stools[13]. Faecalibacterium prausnitzii produces butyric acid. Faecalibacterium prausnitzii has anti-inflammatory properties and promotes intestinal barrier integrity by increasing the tight junction proteins[14]. Fusicatenibacter saccharivorans is a member of Clostridium subcluster XIVa. Fusicatenibacter saccharivorans helps maintain immune system homeostasis by supporting regulatory T cells. In addition, Fusicatenibacter saccharivorans produces short-chain fatty acids, including lactic and acetic acids, via glucose fermentation. This is crucial for improving the intestinal barrier function and host immune system[15]. Ruminococcus bromii is considered crucial for breaking down resistant starch. The resulting product serves as a substrate for the mutualistic growth of other beneficial microorganisms in the gut, and its abundance determines fecal butyrate levels[16,17]. Bifidobacterium longum is a prevalent member of the intestinal tract that protects the intestinal epithelial barrier and tissue structure, balances intestinal microbiota, and relieves colitis symptoms. In addition, bifidobacteria secrete several active metabolites that influence interactions between the digestive, endocrine, cardiovascular, immune, and nervous systems to maintain the host’s health[18]. Fecal flora composition underwent significant changes after gut microbiota transplantation. The abundance of pathogenic bacteria decreased, whereas that of probiotics increased, alleviating the patient's clinical symptoms.

Following intestinal microcosm transplantation, the pathogenic bacteria Escherichia fergusonii and Romboutsia timonensis exhibited a significant decrease, which persisted at low levels even after 2 months. Conversely, the probiotic abundance significantly increased, with Streptococcus thermophilus and parasanguinis showing significant increases shortly after transplantation. Streptococcus thermophilus is a probiotic bacterium recognized for its antioxidant properties, which reduce the risk of some cancers and its anti-inflammatory, anti-mutagenic, and stimulatory effects on the intestinal immune system[19]. Streptococcus parasanguinis is a major colonizer of the intestinal tract of newborn infants and bacterial species in the adult small intestine. Streptococcus parasanguinis can moderately activate NFκB through TLR2/6 signaling, inducing the maturation, activation, and secretion of the cytokine IL-12 from human monocyte-derived dendritic cells[20]. This patient experienced significant symptoms shortly after gut flora transplantation, directly related to a decline in pathogenic bacteria and an increase in probiotics. Moreover, the number of some probiotics, such as Blautia wexlerae, Blautia luti, Eubacterium rectale, and Dorea formicigenerans, did not significantly increase at the start of intestinal flora transplantation. However, they demonstrated an increase two months after transplantation. Blautia wexlerae and luti are linked not only to obesity and insulin resistance but also to preserving intestinal immune homeostasis in healthy individuals[21]. Eubacterium rectale constitutes 13% of all microorganisms in human feces. Eubacterium rectale is a significant producer of butyric acid, which may alleviate leukodystrophy symptoms via the dendritic cell pathway[22]. However, this bacterium also plays a crucial role in tumor development, and its abundance is significantly reduced in patients with pancreatic ductal adenocarcinoma and lymphoma[23,24]. Dorea formicigenerans is positively correlated with response to immune checkpoint inhibitors in patients with tumors[25]. These probiotics undergo gut microbial transplantation and colonize over time. This may be the key reason for long-term relief from abdominal pain and diarrhea in these patients. The patient had fewer good bacteria, Faecalibacterium prausnitzii, Fusicatenibacter saccharivorans, Ruminococcus bromii, and Bifidobacterium longum. This was not due to changes in the number of gut microorganisms caused by radiation damage after transplantation. The low abundance of these probiotics may be associated with occasional stool hematochezia. Further investigations are required to determine this specific situation. The colonization of this part of the probiotic may depend on the interactions between the flora or metabolites of the flora. Additionally, late clinical regression should be considered.

FMT can effectively treat patients with chronic radiation enteritis by providing short-term relief and long-term symptom remission. Furthermore, this case study elucidated the higher prevalence of pathogenic bacteria and lower prevalence of certain essential intestinal bacteria in patients with chronic radiation enteritis than in healthy individuals, as determined via sequencing three-generation full-length amplicons at the bacterial species level. The intestinal flora’s composition in patients changed significantly after FMT, corresponding to the alleviation of clinical symptoms. This provides further evidence for the effectiveness of FMT in treating patients with chronic radiation enteritis and improving quality of life. One limitation of this study was that the patient did not undergo further transplantation at a later stage for personal reasons. The patient was followed up via telephone for information on clinical symptoms. Based on the results of bacterial flora analysis, additional courses of intestinal microcosm transplantation could provide additional benefits.

In this study, transplanting intestinal microorganisms resulted in relief in the short- and long-term. Sequencing the entire amplicon at the strain level revealed an altered intestinal flora composition in patients with chronic radiation enteritis. Additionally, the benefits of FMT at the floral level were demonstrated. These results indicated that radiotherapy affects intestinal microorganisms. They also showed that intestinal microecology could be used as a target to prevent and treat radiation enteritis. Radiotherapy affects microorganisms in the gut, supporting the idea of targeting intestinal microecology in preventing and treating radiation enteritis.

CONCLUSION

FMT is a valuable therapeutic option for chronic radiation enteritis. The significant symptom relief and long-term remission observed post-FMT underscore its efficacy in managing radiation-induced gastrointestinal complications. Microbial analysis further supports FMT's role in restoring a healthier gut flora composition. Based on these findings, we recommend considering FMT as part of the treatment algorithm for chronic radiation enteritis, particularly in cases refractory to conventional therapies. Because people with chronic radiation enteritis have very different symptoms, more research needs to be conducted to find the best way to treat them and how to perform intestinal microcosm transplantation.