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14Cellular Therapy and Transplantation (CTT). Vol. 12, No. 2, 2023 doi: 10.18620/ctt-1866-8836-2023-12-2-4-14 Submitted: 10 May 2023, accepted: 26 May 2023
Origin and consequences of intestinal dysfunction following cytostatic chemotherapy and hematopoietic stem cell transplantation
Oleg V. Goloshchapov ', Maxim A. Kucher ', Yury A. Eismont 2, Alexei B. Chukhovin 1
1 RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantology, Pavlov University, St. Petersburg, Russia
2 Pediatric Research Clinical Center of Infectious Diseases, St. Petersburg, Russia
Dr. Oleg V. Goloshchapov, RM Gorbacheva Research Insti- Phone: +7 (921) 979-29-13
tute of Pediatric Oncology, Hematology and Transplantology, E-mail: golocht@yandex.ru
Pavlov University, 6-8 L. Tolstoy St, 197022, St. Petersburg, Russia
Citation: Goloshchapov OV, Kucher MA, Eismont YA, Chukhovin AB. Origin and consequences of intestinal dysfunction following cytostatic chemotherapy and hematopoietic stem cell transplantation. Cell Ther Transplant 2023; 12(2): 4-14.
Summary
The review article deals with pathogenesis and diagnostics of common gastrointestinal (GI) complications in patients with oncohematological diseases subjected to intensive chemotherapy and allogeneic hematopoietic stem cell transplantation (allo-HSCT). The associated GI disorders may present with hyporexia, nausea, vomiting, diarrhea, dehydration and intoxication thus causing protein-energy malnutrition and reducing efficiency of cancer therapeutics. The symptoms of intestinal dysfunction may develop early before HSCT due to cytostatic and antibacterial therapy. As a rule, it manifests with diarrhea caused by different reasons, e.g., antibiotic-associated bacterial dysbiosis, or enteropathogenic infections, impaired intestinal motility, or due to immune-mediated graft-versus-host disease (GvHD).
The initial dose-dependent mucosal damage following cytostatic therapy may impair intestinal and endothelial interfaces, then being complicated by severe superposing infections with intestinal bacteria, especially, antibiotic-resistant strains. Sufficient changes in gut microbiota are revealed early upon chemotherapy of leukemia patients. Typical pathological findings in cytopenic period and subsequent aGvHD after allo-HSCT, include: (1) cytotoxic damage to intestinal mucosal cells, (2) additional immune-mediated enterocyte lesions induced by donor T cells. The intestinal bacterial dysbiosis caused by anti-
microbial therapy leads to suppression of metabolically active microbiota, thus causing the exhaustion of essential nutrients. Therefore, intestinal colonization with antibiotic-resistant bacterial strains may be observed. In particular, a complex interplay between bacterial and viral microbiota seem to be important for the outcomes of HSCT. A number of endogenous viruses (adeno- and herpes viruses) are commonly activated post-transplant, thus potentially modifying the disease pattern.
To manage the GI complications after HSCT, some clinical measures should be taken to alleviate these conditions, e.g., (1) Reduced-intensity conditioning regimens; (2) Rational preventive antibacterial therapy in order to spare normal intestinal microbiota; (3) Timely detection of antibiotic-resistant bacterial strains; (4) Immu-nosuppressive therapy optimization to prevent severe intestinal GvHD; (5) Correction of impaired intestinal microbiota using conventional and autologous probio-tic bacterial strains, fecal microbiota transplantation; (6) Rational approach to dietary restrictions, timely nutritional support and the use of prebiotics to increase the functional microbiota activity.
Keywords
Hematopoietic stem cell transplantation, gastrointestinal toxicity, mucositis, intestinal dysfunction, graft-versus-host disease, intestinal microbiota.
Introduction
Gastrointestinal (GI) complications are common in the patients undergoing anticancer treatment and, especially, upon allogeneic hematopoietic cell transplantation (allo-HSCT). They are associated with the development of acute protein-energy malnutrition, deficiency and imbalance of macro- and micronutrients, vitamins, thus affecting basic energy supply, as well as cellular regenerative processes, recovery of donor hematopoiesis and immune functions [1]. The malnutrition is known to make a great impact on overall survival, frequency of infectious and immune complications, delayed graft engraftment post-transplant [2]. Severe intestinal dysfunction is among the most dramatic complications in the HSCT setting. Its severity is scored by the degree of diarrhea, dehydration, systemic intoxication due to bacterial toxins, biomarkers of cytokine storm, imbalance of both innate and adaptive immunity, being, generally, associated with altered integrity of gut/blood barrier, thus causing septicemia and bloodstream infections. According to the generally accepted WHO determination, 'Diarrhoea is the passage of 3 or more loose or liquid stools per day, or more frequently than is normal for the individual' (https://www.who.int/ru/news-room/ fact-sheets/detail/diarrhoeal-disease).
In neutropenic patients, e.g., following HSCT, the situation is complicated by restrictions of low-microbial diet primarily based on infectious safety of the nutrition with minimal contents of microorganisms (<500 CFU per 1 gram of meal) as proposed by several study groups [3, 4]. However, there are no convincing data on proven efficiency of a low-micro-bial diet for prevention of infectious complications in the neutropenic patients [5, 6]. Moreover, an increasing body of evidence shows a negative impact of a restrictive diet on the risk of infectious episodes and graft-versus-host disease (GvHD) [7]. These trends are based on decreased ability of such balanced diet to protect and maintain the vital activity of intestinal microbiota, like as anatomical and functional integrity of the GI tract [8].
GI complications may occur at different terms after HSCT, from the beginning of cytostatic (conditioning) therapy to
the late posttransplant period. Upon the stem cell engraftment (1st month post-HSCT), the diarrhea may be also ascribed to acute GvHD (aGvHD), causing immune damage to the skin and GI mucosal epithelium [9]. However, if diarrhea in GvHD occurs as an isolated intestinal dysfunction, the other possible causes must be excluded before initiating the GvHD treatment, especially, infectious factors [10].
Any type of early or late GI complications, especially, GvHD, is always associated with overgrowth or suppression of viral, bacterial, and fungal pathogens inhabiting GI system. Toxic effects of antitumor, anti-infectious and immunosuppressive drugs may also predispose for intestinal dysfunction post-HSCT, thus determining its proper diagnostics and management.
Hence, the distinct time periods should be considered for intestinal dysfunction, in order to specify their possible causes. Four post-transplant periods may be discerned, with respect to prevailing pathogenic factors:
• Pre-transplant period of conditioning therapy (Day -7 to D0): acute toxic effects of cytostatic therapy causing loss of appetite, nausea and vomiting, severe oral mucositis and initial damage of intestinal crypt associated with dysbiosis of microbiota;
• Posttransplant period: cytopenia and engraftment (D0 to D+15): profound cytopenia, massive anti-infectious treatment and start of immunosuppressive therapy; prolonged intestinal crypt damage, profound dysbiosis (exhaustion) of intestinal microbiota; enhanced risk of bloodstream infections;
• Post-engraftment period (D+16 to D+100): immune/toxic damage of intestinal epithelium (GvHD), established im-munosuppressive therapy; continuing bacterial dysbiosis; endogenous viruses activated; mixed microbial and viral infections;
• Late posttransplant period (D+100>): autoimmune tissue disorders; failure of gut/blood barrier; high risk of viral and fungal invasions (Fig. 1).
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Previous Conditioning >>HSCT>Engraftment>Acute GvHD>Overlap>Chronic GvHD therapy treatment >>Cytopenia>> Death of enterocytes > Septicemia
Figure 1. Time course of gross microbiota changes (top line) after chemotherapy and following hematopoietic stem cell transplantation. Pre- and posttransplant terms (days) are shown at the straight arrow. Bottom lines show the sequence of common posttransplant complications.
1. Conditioning regimen and early posttransplant period
Acute mucosal damage
Early GI toxicity (a week before and after HSCT) is a common complication of conditioning regimen prior to bone marrow transplantation [11]. Intensive chemotherapy causes severe tissue damage, like as high-dose total body irradiation (TBI). Biological effects include oral mucositis, necrosis of intestinal cells, degeneration of epithelial mucosal crypts and flattening of rectal epithelium. Therefore, diarrhea often quite often during the conditioning treatment and over the posttransplant cytopenic phase. The early diarrhea is caused by the cytotoxic chemotherapy or TBI which inflict deadly insult to hematopoietic, intestinal and other dividing cell populations. Moreover, the evolving immune suppression allows activation of opportunistic and enteropathogenic mi-crobiota. Hence, initial affection of intestinal cells may be readily exacerbated by superposing infection, mainly, by the microorganisms of oral and gut origin.
HSCT procedure was first tested in classical experimental studies [12]. E.g., the dogs given cyclophosphamide at my-eloablative doses followed by autologous HSCT developed pronounced leukopenia and severe GI toxicity. Early clinical studies with busulphan and melphalan as a preparative regimen for autologous HSCT have also shown pronounced GI toxicity with nausea, vomiting and diarrhea, in most cases combined with severe oral mucositis [13]. Early GI complications were observed with other chemotherapeutic regimens in autologous HSCT settings [14, 15]. Rapoport et al. [16] registered clinical signs of posttransplant myelosuppression, oral mucositis as well as profuse diarrhea after completion of high-dose conditioning therapy in a large mixed group of patients (n=202) subjected to auto- or allogeneic HSCT. The authors found significant associations between oral mucositis, blood cytopenia and bacterial complications over early posttransplant period, but no correlations between the cyto-toxicity of conditioning therapy and diarrhea, probably, due to overall high-dose treatment.
Intestinal mucositis and pre-transplant microbiota
Immunocompromised state develops in all patients prior to HSCT as a part of previous cytostatic treatment. Early programmed death of enterocytes and resulting denudation of intestinal mucosa were documented in heterogenous group of cancer patients subjected to different cytostatic therapies [17]. Intestinal mucositis is a common side effect of chemotherapy also leading to diarrhea, abdominal pain and increased risk of infections. The general epitheliala damage leads to impairment of the intestine/blood barrier, thus potentially causing higher risk of microbial migration into the bloodstream, bacterial endotoxemia and systemic inflammatory responses which are potentially life-threatening conditions [18].
Impaired intestinal barrier integrity may be confirmed by neutrophil detection in gut lumen, as shown in murine models with different conditioning treatment schedules [19].
Influx of neutrophil granulocytes to the intestinal lamina propria (LP), reflecting an innate immune response to translocation of microbes and their products, showed distinct correlation with severe intestinal damage caused by TBI or chemotherapy.
Decreased levels of plasma citrulline may be another marker of intestinal damage resulting from toxic death and loss of enterocytes, with nadir values of ca. D+7 after conditioning therapy and HSCT [20]. The authors have tested five myelo-ablative conditioning regimens (MAC) which caused severe inflammatory response associated with dose-dependent loss of intestinal epithelium.
Meanwhile, the frequency and incidence of distinct pathogens are only poorly studied in these groups. E.g., a prospective cohort study of 112 allogeneic and autologous HCT recipients was conducted by Kubiak et al. [21]. Fecal samples were collected within a week before HSCT, and tested for 22 diarrheal pathogens using the BioFire FilmArray PCR diagnostic panel. Different GI pathogens were detected in 37% of cases. In particular, pretransplant detection of C. difficile and diarrhea-provoking E. coli was frequently associated with post-transplant diarrhea.
General biodiversity of gut microbiota before HSCT seem not to influence clinical outcomes in HSC recipients, as suggested by Doki et al. [22]. The authors analyzed fecal samples before conditioning in 107 allo-HSCT recipients. Composition of intestinal microbiota was evaluated by next-generation sequencing (NGS) of bacterial 16S rRNA gene. The patients were classified into three groups based on the low, intermediate, or high biodiversity indexes. No significant differences were revealed in the 20-month overall survival, cumulative incidence of relapse, and non-relapse mortality among three groups as well as grade II-IV GvHD. The only finding was higher abundance of phylum Firmicutes in the patients who later developed aGvHD (p<0.01).
The novel approaches to assessment of bacterial diversity using the 16S rRNA gene variability allowed to follow the time-dependent changes of gut microbiota after anticancer therapy [23]. The authors showed an association of intestinal microbiota with enterocyte loss and systemic inflammation when treating pediatric patients with lymphoblastic leukemia (ALL) by means of high-dose induction chemotherapy. Several plasma inflammation markers (CRP), citrulline levels (marker of functional enterocytes mass) were tested on days 1, 8, 15, 22 and 29 of therapy. Bacterial DNA in fecal samples of patients and their healthy siblings was subject to 16S rRNA gene sequencing (V3-V4 region). The study has shown a substantial decrease in bacterial alpha diversity in the treated patients within first 20 days. The abundance of unclassified Lachnospiraceae spp. was correlated with citrul-line on days 8-15 thus suggesting an association between en-terocyte damage and microbiota exhaustion.
The issues of chemotherapy and intestinal microbiota were considered in details by the Chinese group [24]. Analysis of literature data concerned changes in composition and biodiversity of gut microbiota in acute myeloid leukemia and ALL during chemotherapy. They have summarized a number of heterogeneous studies on impaired microbiota,
with changingratios of Bacteroides, Akkermansia as well as biodiversity indexes prior to treatment and in the course of cytostatic chemotherapy. These data are not equivocal, showing quite different shifts in gut bacterial microbiota at distinct steps of therapy. Moreover, the authors discuss possible correlation between post-treatment restoration of intestinal microbiota and development of late complications, thus affecting clinical outcomes.
2. Cytopenic period and posttransplant engraftment
The early engraftment period (7-15 days post HSCT) is accompanied by exhaustion of all leukocyte and platelet populations, thus being a reason for massive preventive anti-infectious therapy. Along with prevention of early infectious complications, this treatment causes a pronounced suppression of multiple bacterial species at different sites (including oral cavity and intestines), as revealed by classic bacteriology and modern high-throughput NGS techniques [25]. Therefore, normal intestinal microbiota is exhausted within first month after HSCT, with partial reconstitution of dominant bacteria at later terms. However, selection and colonization with antibiotic-resistant bacterial strains, e.g., Klebsiella spp., Pseudomonas spp., Acinetobacter spp., pathogenic E.coli, etc., may occur within this time period [26]. Nevertheless, local bacterial dysbiosis may persist for long terms, thus promoting the intestinal dysfunction post-transplant.
Malnutrition factors associated with diarrhea
Along with abovementioned microbiota changes, the reasons for posttransplant diarrhea include toxic effects of conditioning regimen on the endocrine organs, oral mucositis caused by GI mucosal damage, intoxication and inflammatory effect due to local overgrowth of resistant bacteria. There are no detailed data about pathophysiology of posttrans-plant diarrhea. However, if comparing the known stages of the diarrhea pathogenesis and the mechanisms of action for different cytostatic agents, antibiotics and other toxic drugs, pathogenic microorganisms, the secretory-osmotic form of diarrhea seems to be the most likely in HSCT, at least until additional provoking factors are added [27]. In this case, a disturbed breakdown, digestion and assimilation of nutrients are observed in these patients, thus promoting the malnutrition states [28]. For example, with the development of neutropenic colitis characterized by swelling of the intestinal mucosa and increased intra-abdominal pressure, the risk of septicemia significantly increases due to the translocation of pathogenic microorganisms into the systemic circulation [29]. The development of infectious complications, in particular, those associated with toxigenic C.difficile infection, activation of cytomegalovirus, Epstein-Barr virus, Candida spp., Aspergillus species also leads to the diarrhea manifestation [30]. Hence, toxic chemotherapy and immune damage to the pancreas, liver, along with the generally accepted use of anti-ulcer therapy (usually with proton pump inhibitors), along with higer infectious risk leads to a decrease in the functional activity of digestive system, i.e., its inability to adequately absorb nutrients from the intestinal lumen. The above conditions contribute negatively to the rapid
depletion of the body's nutrient depot, the development of malnutrition and require timely correction with the by means of pathogenetic anti-infective treatment, nutritional support, liver protection and pancreatic enzyme replacement therapy.
A positive effect in the context of damaged intestinal mi-crobiota restoration can be provided by prebiotics therapy, mainly consisting of oligo- and polysaccharides, peptides, fatty acids and a number of other substances, the main function of which is to stimulate common to the certain organism microorganisms strains growth by participating in their physiological metabolic processes. At the same time, there is evidence of the prebiotics therapy efficacy not only directly on the state of the intestinal microbiota, but also on reducing the risk of aGvHD [31].
Probiotic microbial strains, i.e., different preparations of Lactobacilli and Bifidobacteria are widely used in order to prevent and treat a number of intestinal disorders [32]. Given the uncertain therapeutic effect and safety profile of classical commercially provided probiotics in the period of cytopenia and immunodeficiency after HSCT, until sufficient immune reconstruction, the routine probiotics therapy is not currently applied in immunocompromised patients, and further studies are required [33]. Promising results are obtained with clinical isolates of autologous probiotic microorganisms, e.g., non-toxigenic enterococci from the patients' microbiota, aiming for treatment of intestinal bowel syndromes, both in experiment and in clinical settings. These data are also reviewed elsewhere in literature [34].
3. Post-engraftment period (D+16 -D+21 to D+100)
Acute intestinal GvHD
Following engraftment and proliferation of donor stem cells, the intestinal mucosa, alike skin epithelium, may be affected by aggressive donor T-cells, as well as targeted by commensal microbes that reside within the intestinal lumen leukocytes [35]. Over this time period, the clinical pattern of GI aGvHD is determined by several pathogenic factors: (1) residual cytotoxic damage to intestinal cells, (2) additional enterocyte lesions induced by donor T cells; (3) intestinal dysbiosis with exhaustion of microbial species promoting host survival; (4) proliferation of pathogenic antibiotic-resistant microbi-al strains. Therefore, severe intestinal aGvHD (grade 3-4) is considered a life-threatening condition with high mortality rates.
Some data on bacterial diversity with NGS of 16S rRNA gene were performed after chemotherapy of acute leukemia in children [23]. E.g., bacterial alpha diversity was lower in patients compared to healthy siblings, being increased on Day 29. Shannon alpha diversity index was correlated with CRP levels on Days 15-29 (r=-0.33 to -0.49; p < 0.05) and with citrulline on Days 15 and 29 (although at p<0.06, r=0.32-0.34). The abundance of unclassified Enterococcus species (spp.) was correlated with CRP on Days 22-29 (r=0.42-0.49; p < 0.009). In conclusion, restoration of intestinal microbio-ta seems to be associated with changed markers of systemic inflammation after the therapy.
The NGS studies of bacterial microbiota yielded new vision of intestinal microbiota composition and its changes after chemotherapy and HSCT, showing exhaustion of un-culturable anaerobic bacteria thus being associated with severe immune disorders posttransplant [36] However, the disadvantage of 16S rRNA gene sequencing is the lack of taxonomic resolution at species and strain-specific levels. Whole-genome metagenomic sequencing of bacterial and viral sequences may be more effective in detailed evaluation of the whole microbiome. These studies revealed a sufficiently decreased biodiversity of bacterial microbiota post-HSCT correlating with increased aGvHD mortality. Among exhausting "favorable" bacteria are the SCFA-producing members of the families Lachnospiraceae and Ruminococ-caceae, which may have a protective effect protection against aGvHD. Hence, correction of the gut microbiota posttrans-plant is a perspective direction in transplantology.
Differential diagnostics of intestinal aGvHD
Intestinal crypt loss and enterocyte apoptosis are key signs of acute intestinal damage [37]. Melson et al. [38] have also performed basic studies in aGvHD pathology. The authors have taken colonic biopsies in 23 patients with aGvHD after HSCT. The crypt loss was present in most cases, and in 11 cases, contiguous areas of crypt loss were observed which associated with severe diarrhea. The patients with severe crypt loss had a pathologic appearance at endoscopy, steroid-refractory disease and worse prognosis for survival. Hence, aberrant mucosal architecture and apoptotic colonic crypt cells seem to be typical to GvHD [39].
The three adopted histopathological scales of gut aGvHD assessment were compared by Kreft et al. [40]. A group of 157 patients with sufficient intestinal samples (>3 biopsies) was studied within 20-200 days after allo-HSCT. The grade of aGvHD was evaluated in serial H&E stained preparations using Lerner, Sale, or and Melson grades of morphological changes, then correlating with clinically approved Glucksberg GvHD grading. A significant association was found between non-relapse mortality, mean Lerner grade, minimum Melson grade, Glucksberg organ staging. In brief, the best correlation with clinical GvHD was obtained with Lerner grading system. It includes: Normal mucosa (Grade 0); Crypt cell apoptosis (Grade 1); Crypt destruction (Grade 2); Focal mucosa denudation (Grade 3); Diffuse mucosa denudation (Grade 4). Therefore, exact diagnosis of acute intestinal GvHD is largely based on histopathological studies of intestinal biopsies while detecting specific signs typical to autoaggressive inflammatory lesions. Once the diagnosis of aGvHD is established, systemic therapy with corticosteroids is administered, and non-responders can be treated with a wide range of second-line therapies (ruxolitinib etc.). In view of gastroenterologists, one should perform extensive management of its complications, especially, profuse diarrhea, malnutrition, and intestinal bleedings [41].
4. Late posttransplant period (D+100>)
By the existing NIH criteria for chronic GvHD, the respective incidence rates of esophageal, upper GI, and lower
GI involvement are 16%, 20%, and 13%, according to a cross-sectional analysis from the Chronic GvHD (cGvHD) Consortium [42]. In general, intestinal syndrome at later terms (>100 days) after HSCT is relatively uncommon and may be ascribed to cGvHD. However, histopathological results are difficult to interpret in these cases. The main his-tological features of late or cGvHD of intestinal mucosa are summarized in a review by Mourad et al. [43], as follows: apoptotic bodies, glandular destruction, ulceration, and features of chronic course such as architectural, distortion, Paneth cell metaplasia, lymphoplasmacytic inflammation, and lamina propria fibrosis, being, however, unspecific for cGvHD. Submucosal and subserosal fibrosis of the intestines are rare in cGvHD, with intact muscularis propria. Hence, making a proper histopathological conclusion needs integration of clinical and histological findings with exclusion of other potential causes of the disorder.
Differentiation between morphological features of acute and chronic gut GvHD was attempted in an early study by Akpek et al. [44]. A cohort of 40 patients with clinically suspected cGvHD (diarrhea, abdominal pains, dysphagia, weight loss) underwent endoscopic examination. Four groups were defined based on the following histological criteria: (1) consistent with GI aGvHD (marked apoptosis with or without cryp-titis); (2) suggestive of acute GI GvHD (scattered apoptosis with or without cryptitis; (3) suspected cGvHD (fibrosis and significant crypt distortion). Acute GvHD or overlap syndrome were diagnosed in vast majority of this group (86%), whereas a suspected cGvHD was revealed in only 14% of the patients.
A special large study concerned late GI complications (100 days post-HSCT) in allo-HSCT adult recipients at Duke University observed over a 6-year period [45]. The study included 392 patients who survived for at least 100 days post-transplant. The late GI symptoms required endoscop-ic evaluation in 71 cases. The endoscopy revealed GI GvHD in 45 cases (63%), i.e., late aGvHD in 39 cases (87%), and 5 patients (11%) had the overlap disease (a combination of acute and chronic GvHD). Of the patients free of GvHD, the symptoms were mostly related to infectious and inflammatory causes. In a multivariate analysis the factors most indicative of GI GvHD were histological findings of apoptosis on the tissue specimen (odds ratio, 2.35; 95% confidence interval, 1.18 to 4.70; P=.015) and clinical findings of diarrhea (odds ratio, 5.43; 95% confidence interval, 1.25 to 23.54; P=.024). In general, up to 20% of allogeneic transplant recipients experienced late GI complications.
Moreover, during last decades, the so-called cord colitis syndrome was described after umbilical cord blood transplantation (UCBT) manifesting with late-onset diarrhea, absence of infection or GvHD, chronic active colitis and granulomatous inflammation [39]. The authors made a blinded histological review of 153 colon biopsies taken in UCBT recipients and 45 matched allografted controls (D+70 to day +365 post-transplant). Diarrhea was the primary indication for biopsy in 10 UCBT recipients and 11 controls. The comparative study did not show any histological differences between UCBT and control HSCT with diarrhea. Hence, this type of colitis proved to be histological similar to aGvHD and colitis in other allograft recipients.
5. Bacterial microbiota following cytostatic therapy and HSCT
Possible clinical role of early intestinal dysbiosis
Routine bacteriological techniques used in the hospital clinical laboratories (microscopy and cultural methods) reveal a number of pathogenic microorganisms. However, recent studies show that, e.g., 90% of intestinal bacteria are strict anaerobes which require very special cultural conditions. They are detectable mostly by DNA diagnostics, i.e. PCR or, more recently, with next-generation sequencing. Moreover, one should take a plethora of eukaryotic cell viruses and bacteriophages shaping the intestinal microbiota (Fig. 2).
Anaerobic non-cultivable bacteria - PCR and NGS detection
Viruses of eukaryotic cells, bacteriophages
Figure 2. Classic aerobic cultures in clinical bacteriological laboratories detect <10% of intestinal human microbiota. Most fecal bacteria, being strict anaerobes, are detectable by means of nucleic acid-based diagnostics (multiple PCR, or next-generation DNA sequencing).
In general, the intestinal viral microbiome (virome) is much less studied than bacterial microbiota (bacteriome). Meanwhile, the infectious pathogenic viruses, as well as latent endogenous viruses (e.g., herpesviruses) and bacterial viruses (bacteriophages) still dominate in the microbiome. Today, a lot of viral infections seem to affect bacterial gut microbio-ta. So far, however, the gut virome is insufficiently studied, especially, its interactions with intestinal bacteriome [46]. Interactions between the intestinal mucosa and local micro-biota are yet poorly understood. However, the interactions between host epithelium and gut microbiota may be of importance for searching novel tools of prevention and treatment of aGvHD [35, 47].
Early intestinal syndrome due to conditioning therapy may be somewhat connected with subsequent aGvHD, as shown by Goldberg et al. [48]. The authors used diarrhea as a marker of early gut damage in HSCT in CML patients in order to assess relation of conditioning therapy to aGvHD risk grade.
The study showed a significant correlation between the sum of diarrhea on days 4 to 7 after SCT and acute GvHD. Such correlation between early diarrhea and risk of aGvHD was later confirmed by Liu et al. [49]. Duration of diarrhea (>5.5 days), and its high volume over days -3 to 0 proved to be risk factors of grade II to IV aGvHD. Thus, early diarrhea, increased TNF-a and IL-6 during the conditioning regimen could be potentially effective predictors for aGvHD, allowing preventive therapy, e.g., with low-dose glucocorticoids.
A recent study by van Praet et al. [50] was based on multiple PCR assessment by Taqman Array Card technology detecting 9 bacterial pathogens, 8 protozoan pathogens, and 8 viral pathogens in diarrheal syndromes in 140 patients post-transplant. The authors searched for intestinal pathogens in diar-rheal episodes post-HSCT. Most affected patients (82%) had only one episode of infectious diarrhea within 1 year after HSCT with a cumulative incidence of 32%, mostly as bacterial infections in the pre-engraftment phase. C.difficile, adenovirus, enteropathogenic E.coli, and C. jejuni proved to be most common pathogens.
6. Potential interactions between viral and bacterial microbiota in severely Immunocompromised patients
Viral microbiota is an important component of intestinal mucosal cells and surface. The viruses affecting eukaryotic cells may persist in enterocytes lifelong (e.g., adenoviruses, or Epstein-Barr herpes virus), or may be transported from other organs and tissues (e.g., with migrating blood cells), or behave as a foodborne infection (rota-, noro-, astrovirus-es etc). Meanwhile, practical and ethical constraints limit functional studies of the virome in humans with enteric and bowel disorders. Therefore, a large body of information on intestinal virome is obtained in animal models [51]. This approach allows tracing the interplay between viruses, bacteria, and the animal host in health and disease.
There are several recent reviews concerning relative roles of eukaryotic cell viruses and bacteriophages in different disorders affecting gastrointestinal system [52, 53]. E.g., sufficient attention is drawn to the inflammatory bowel disorders [54] which may be promoted by common viral infections, e.g., by noro- and rotavirus. Their pathogenetic role may also depend on genetic variants of specific intestinal receptors. Therefore, future studies using new techniques such as metagenomic analysis of intestinal microbiome could further specify the exact relations between bacteriome and virome in health and disease.
Possible interplay between bacterial and viral microbiota seem to be important for the outcomes of HSCT. E.g. a special study was performed to search for potential association between detection of enteropathogenic viruses or bacteria in stools and subsequent occurrence of GI aGvHD [55]. Among 121 allo-HSCT patients, acute diarrhea has been registered in 71% of cases thus requiring PCR testing for the primary GI pathogens. One or more GI pathogens were
detected in 31% of diarrhea cases, especially, enteropatho-genic viruses (12.7%) including Astrovirus, Norovirus, Sapo-virus, Adenovirus, and Rotavirus. Thirty patients were diagnosed with all grade GI aGvHD by histopathology. Enteric viruses were found in 8 out of 30 patients with GvHD. In sum, the detection of enteric viruses was not significantly associated with subsequent GI aGvHD development in this unselected cohort.
Moreover, some endogenous herpes viruses may be also activated in the intestinal wall (CMV, EBV, HSV, etc.) at various time periods after HSCT and show a definite time dynamics in the patients with posttransplant intestinal syndromes [56].
Potential interactions of bacteria and viruses in the infectious conditions
Most viruses first encounter host cells at mucosal surfaces, which are typically colonized by a complex ecosystem of microbes collectively referred to as the microbiota. Recent studies show that microbiota actively participates in host-viral interactions and determining the final outcomes of various disorders [57]. The authors illustrate these relations by mutual impact of bacteria and viruses (rotavirus, reovirus) during infectious processes. These effects may occur as direct bacterial-viral interactions or mediated through the innate and/or adaptive host immunity.
In the course of infectious diseases, the viruses may have substantial and intimate interactions with the commensal microbiota [58]. Ample evidence indicates that commensal microbiota regulates the invading viruses through diverse mechanisms, thereby having stimulatory or suppressive roles in viral infections. Vice versa, the integrity of the commensal microbiota can be altered by invading viruses, causing bacterial dysbiosis in the host.
The interplay between commensal and pathogenic bacteria is now better elucidated, with studying the effects of intestinal microbiota on viral pathogenesis [59]. It has reported that commensal bacteria within the mammalian intestinal tract enhance enteric virus infections through a variety of mechanisms. Commensal bacteria or bacterial glycans can increase the stability of enteric viruses, enhance virus binding to host receptors, modulate host immune responses in a proviral manner, expand the numbers of host cell targets, and facilitate viral recombination.
Competitive or symbiotic relations of intestinal bacteria and viruses and studies on their pathogenic mechanisms tend to focus on one pathogen alone. Bacterial and viral co-infections occur frequently in clinical settings, and infection by one pathogen can affect the severity of infection by another pathogen, either directly or indirectly [60]. The bacterial-viral-gut interactions involve multiple aspects of inflammatory and immune signaling, nutritional immunity, and shaping the gut microbiome. Possible regulatory mechanisms of bacterial/viral co-infections at the host intestinal mucosal surfaces may create a specialized immune interface.
Conclusion
Current advances in microbiology, especially, DNA sequencing of multiple bacterial species have revealed hundreds of
microbial species living in human intestines. Normal gut microbiome is mostly presented by anaerobic bacteria which provide stable metabolism of nutrients in symbiosis with the host organism. They exist in a well-coordinated network which largely depends on the type of diet consumed.
The normal balance of gut microbiota may be, however, disturbed by several factors, e.g., changes in diet, microbial or viral infections, immune-related damage to intestinal mucosa, or effects of medicinal drugs. All these pathogenic factors are acrtual in blood cancer patients subjected to cytostatic therapy and, finally, to bone marrow transplantation which provide a chance for radical cure of the disease.
Intestinal microbiota at different terms of HSCT is modified by several disease- and therapy-related factors: 1) acute toxicity to enterocytes and suppression of gut microbiota by preventive antibacterial treatment; 2) pronounced lym-pho- and neutropenia caused by conditioning treatment and immunosuppressive drugs; 3) immune damage to intestinal epithelium during early engraftment of donor cells; 4) significant depletion changes and restriction in the diet, according to requirements of a low-microbial nutritional regimen; 5) Deficiency of macro- and micronutrients essential for enterocyte metabolism and cellular regeneration. All these pathogenic factors cause imbalance of intestinal microbi-ota and promote selection of antibiotic-resistant bacterial strains. Due to damage of intestinal crypts and suppressed local immunity, the intestinal pathogens migrate to blood, lymph nodes causing septicemia and infection in secondary sites. Hence, the management of the post-transplant patients with intestinal complications requires distinct approaches to repair of intestinal epithelium and microbiota, dependent on the stage of underlying pathogenetic events at early and *late phases of posttransplant period.
In order to increase protective potential of intestinal micro-biota, the attempts were made to systematize the nutritional support therapy in HSCT patients. In particular, the EBMT working group proposed updated nutrition principles, in which a greater emphasis is placed on compliance with the rules of personal hygiene, rules for food storage and cooking, the so-called food safety-based diet, rather than on rigid dietary restrictions [61].
As seen from the data discussed, different pathogenic factors prevail at distinct periods of host and microbiota impairment after HSCT. In clinical terms, however, it manifests as an intestinal dysfunction proceeding with diarrhea, dehydration, intoxication and high risk of septicemia.
To manage these intestinal complications, one should try some clinical measures aimed for prevention and reduction of these conditions, as follows:
1. Less intensive conditioning regimens associated with reduced epithelial damage.
2. Rational preventive antibiotic therapy with broad-spectrum antibacterial drugs in order to spare normal intestinal microbiota.
3. Effective prevention and treatment of aGvHD, and optimization of immunosuppressive therapy, aiming for alleviation of immune-mediated enterocyte damage.
4. Correction of impaired intestinal microbiota by means of common and novel probiotics, autologous probiotics, or fecal microbiota transplantation.
5. Timely detection of the evolving bacterial strains resistant to antibiotics using bacteriological and DNA-based diagnostics.
6. Rational approach to dietary restrictions, timely nutritional support and usage of prebiotics to increase the functional microbiota activity.
Acknowledgement
This study was supported by a research grant from Russian Science Foundation No. №22-15-00149 of 18.05.2022.
Conflict of interest
None reported.
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Природа и последствия кишечной дисфункции после цитостатической химиотерапии и трансплантации гемопоэтических стволовых клеток
Олег В. Голощапов Максим А. Кучер Юрий А. Эйсмонт 2, Алексей Б. Чухловин 1
1 НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой, Первый Санкт-Петербургский государственный медицинский университет им. акад. И. П. Павлова, Санкт-Петербург, Россия
2 Детский научно-клинический центр инфекционных болезней ФМБА РФ, Санкт-Петербург, Россия
Резюме
Данный обзор касается вопросов патогенеза и диагностики желудочно-кишечных осложнений у больных онкогематологического профиля после аллоген-ной трансплантации гемопоэтических стволовых клеток (алло-ТГСК). Эти состояния, отягощающие течение посттрансплантационного периода, обычно протекают в форме гипорексии, тошноты, рвоты, диареи, дегидратации и интоксикации, провоцируя белково-энергетической недостаточности - фактора, снижающего эффективность ТГСК. Симптомы кишечной дисфункции может развиваться еще до ТГСК, в связи с цитостатической и антибактериальной терапией, и после нее, как правило - в виде диареи различной этиологии, в т.ч. в форме антибио-тик-ассоциированного бактериального дисбиоза, энтеропатогенных инфекций, нарушенной моторики кишечника и иммуно-опосредованной реакции «трансплантат против хозяина» (РТПХ). Таким образом, синдром желудочно-кишечной токсичности связан как с гибелью клеток кишечного эпителия, так и с нарушением нормального баланса кишечной бактериальной микробиоты. Инициальные дозо-за-висимые повреждения клеток слизистой желудочно-кишечного тракта (ЖКТ) при цитостатической терапии могут привести к нарушениям кишечно-эн-дотелиального барьера и тяжелым инфекционным осложнениям, в частности - септицемии, вызванной бактериями кишечного происхождения, особенно - антибиотикорезистентными бактериями. Существенные изменения кишечной микробиоты выявляются еще на этапе химиотерапии пациентов с лейкозами. После выполнения ТГСК, в период ци-топении и при последующей РТПХ, выявляется ряд типичных патологических изменений: (1) токсические повреждения кишечного слизистого эпителия; (2) дополнительные иммуно-опосредованные повреждения энтероцитов, вызванные донорскими Т-лимфоцитами. Наряду с этим дисбиоз кишечной микробиоты, вызванный антибактериальной терапией, ведет к подавлению метаболически активных микробных видов, что приводит к истощению питательных ресурсов. На этом фоне отмечается колонизация патогенными антибиотикорезистентными линиями бактерий. В частности, могут быть важными
сложные взаимодействия между бактериальной и вирусной микробиотой в прогнозе исходов ТГСК. Многие эндогенные вирусы (в т.ч. адено- и герпесви-русы) часто активируются после ТГСК, что может модифицировать картину заболевания. В процессе ведения больных с кишечными осложнениями после ТГСК, следует разработать клинические мероприятия для облегчения этих состояний, в частности: (1) Снижение интенсивности кондиционирующей терапии; (2) Рациональную превентивную антибактериальную терапию с целью сохранения нормальной кишечной микробиоты; (3) Своевременное выявление антибиотикорезистентных штаммов бактерий;
(4) Оптимизацию иммуносупрессивной терапии для предотвращения тяжелых форм кишечной РТПХ;
(5) Коррекцию нарушенной кишечной микробиоты с применением традиционных и аутологичных про-биотических штаммов, трансплантации фекальной микробиоты; (6) Повышение функциональной активности микробиоты за счет рационального подхода к ограничениям в диете при ТГСК, своевременной нутриционной терапии и применения пребиотиков.
Ключевые слова
Трансплантация гемопоэтических стволовых клеток, синдром желудочно-кишечной токсичности, мукозит, дисфункция кишечника, реакция «трансплантат против хозяина», кишечная микробиота.
