Patrizia Kump

Alteration of intestinal dysbiosis by fecal microbiota transplantation does not induce remission in patients with chronic active ulcerative colitis.

Background: In patients with ulcerative colitis (UC), alterations of the intestinal microbiota, termed dysbiosis, have been postulated to contribute to intestinal inflammation. Fecal microbiota transplantation (FMT) has been used as effective therapy for recurrent Clostridium difficile colitis also caused by dysbiosis. The aims of the present study were to investigate if patients with UC benefit from FMT and if dysbiosis can be reversed. Methods: Six patients with chronic active UC nonresponsive to standard medical therapy were treated with FMT by colonoscopic administration. Changes in the colonic microbiota were assessed by 16S rDNA–based microbial community profiling using high-throughput pyrosequencing from mucosal and stool samples. Results: All patients experienced short-term clinical improvement within the first 2 weeks after FMT. However, none of the patients achieved clinical remission. Microbiota profiling showed differences in the modification of the intestinal microbiota between individual patients after FMT. In 3 patients, the colonic microbiota changed toward the donor microbiota; however, this did not correlate with clinical response. On phylum level, there was a significant reduction of Proteobacteria and an increase in Bacteroidetes after FMT. Conclusions: FMT by a single colonoscopic donor stool application is not effective in inducing remission in chronic active therapy–refractory UC. Changes in the composition of the intestinal microbiota were significant and resulted in a partial improvement of UC-associated dysbiosis. The results suggest that dysbiosis in UC is at least in part a secondary phenomenon induced by inflammation and diarrhea rather than being causative for inflammation in this disease.

European consensus conference on faecal microbiota transplantation in clinical practice.

Faecal microbiota transplantation (FMT) is an important therapeutic option for Clostridium difficile infection. Promising findings suggest that FMT may play a role also in the management of other disorders associated with the alteration of gut microbiota. Although the health community is assessing FMT with renewed interest and patients are becoming more aware, there are technical and logistical issues in establishing such a non-standardised treatment into the clinical practice with safety and proper governance. In view of this, an evidence-based recommendation is needed to drive the practical implementation of FMT. In this European Consensus Conference, 28 experts from 10 countries collaborated, in separate working groups and through an evidence-based process, to provide statements on the following key issues: FMT indications; donor selection; preparation of faecal material; clinical management and faecal delivery and basic requirements for implementing an FMT centre. Statements developed by each working group were evaluated and voted by all members, first through an electronic Delphi process, and then in a plenary consensus conference. The recommendations were released according to best available evidence, in order to act as guidance for physicians who plan to implement FMT, aiming at supporting the broad availability of the procedure, discussing other issues relevant to FMT and promoting future clinical research in the area of gut microbiota manipulation. This consensus report strongly recommends the implementation of FMT centres for the treatment of C. difficile infection as well as traces the guidelines of technicality, regulatory, administrative and laboratory requirements.

Repeated fecal microbiota transplantations attenuate diarrhea and lead to sustained changes in the fecal microbiota in acute, refractory gastrointestinal graft-versus-host-disease

Acute graft- versus -host disease (aGvHD) is a serious complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT).[1][1] Although aGvHD of any target organ represents morbidity, lower gastrointestinal (GI) tract involvement is complicated by high mortality.[2][2] Here,

Opposing Roles of Prostaglandin D2 Receptors in Ulcerative Colitis

Proresolution functions were reported for PGD2 in colitis, but the role of its two receptors, D-type prostanoid (DP) and, in particular, chemoattractant receptor homologous molecule expressed on Th2 cells (CRTH2), is less well defined. We investigated DP and CRTH2 expression and function during human and murine ulcerative colitis (UC). Expression of receptors was measured by flow cytometry on peripheral blood leukocytes and by immunohistochemistry and immunoblotting in colon biopsies of patients with active UC and healthy individuals. Receptor involvement in UC was evaluated in a mouse model of dextran sulfate sodium colitis. DP and CRTH2 expression changed in leukocytes of patients with active UC in a differential manner. In UC patients, DP showed higher expression in neutrophils but lower in monocytes as compared with control subjects. In contrast, CRTH2 was decreased in eosinophils, NK, and CD3+ T cells but not in monocytes and CD3+/CD4+ T cells. The decrease of CRTH2 on blood eosinophils clearly correlated with disease activity. DP correlated positively with disease activity in eosinophils but inversely in neutrophils. CRTH2 internalized upon treatment with PGD2 and 11-dehydro TXB2 in eosinophils of controls. Biopsies of UC patients revealed an increase of CRTH2-positive cells in the colonic mucosa and high CRTH2 protein content. The CRTH2 antagonist CAY10595 improved, whereas the DP antagonist MK0524 worsened inflammation in murine colitis. DP and CRTH2 play differential roles in UC. Although expression of CRTH2 on blood leukocytes is downregulated in UC, CRTH2 is present in colon tissue, where it may contribute to inflammation, whereas DP most likely promotes anti-inflammatory actions.

Diarrhea Caused By Circulating Agents

Circulating agents cause intestinal secretion or changes in motility with decreased intestinal transit time, resulting in secretory-type diarrhea. Secretory diarrhea as opposed to osmotic diarrhea is characterized by large-volume, watery stools, often more than 1 L per day; by persistence of diarrhea when patients fast; and by the fact that on analysis of stool-water, measured osmolarity is identical to that calculated from the electrolytes present. Although sodium plays the main role in water and electrolyte absorption, chloride is the major ion involved in secretion.

A case of opportunistic skin infection with Mycobacterium marinum during adalimumab treatment in a patient with Crohn's disease

Opportunistic infections, especially reactivation with M. tuberculosis, are major complications during treatment with anti-TNF agents. Infections with atypical mycobacteria like Mycobacterium marinum are rare and tend to turn into a difficult and prolonged course due to delayed diagnosis. This is the first case of M. marinum infection during adalimumab therapy in a patient with Crohns disease. The most important diagnostic step was a detailed medical history as PCR tested for M. tuberculosis and for atypical subspecies was false negative. Up to now a discontinuation of anti-TNF therapy has been recommended, however, there is no consensus about the reintroduction of biologicals after sufficient anti-infective therapy. In this patient anti-TNF therapy had to be reintroduced because of increasing activity with no relapse of M. marinum after a follow-up of 12 months.

Distribution of CD4pos -, CD8pos – and Regulatory T Cells in the Upper and Lower Gastrointestinal Tract in Healthy Young Subjects

The gastrointestinal immune system is involved in the development of several autoimmune-mediated diseases, including inflammatory bowel disease, multiple sclerosis, and type 1 diabetes mellitus. Alterations in T-cell populations, especially regulatory T cells (Tregs), are often evident in patients suffering from these diseases. To be able to detect changes in T-cell populations in diseased tissue, it is crucial to investigate T-cell populations in healthy individuals, and to characterize their variation among different regions of the gastrointestinal (GI) tract. While limited data exist, quantitative data on biopsies systematically drawn from various regions of the GI tract are lacking, particularly in healthy young humans. In this report, we present the first systematic assessment of how T cells—including Tregs—are distributed in the gastrointestinal mucosa throughout the GI tract of healthy young humans by means of multi-parameter FACS analysis. Gastroduodenoscopy and colonoscopy were performed on 16 healthy volunteers aged between 18 and 32. Biopsies were drawn from seven GI regions, and were used to determine the frequencies of CD8+-, CD4+- and Tregs in the gastrointestinal mucosa by means of multi-parameter FACS analysis. Our data show that there is significant variation in the baseline T-cell landscape along the healthy human gastrointestinal tract, and that mucosal T-cell analyses from a single region should not be taken as representative of the entire gastrointestinal tract. We show that certain T-cell subsets in the gastrointestinal mucosa vary significantly among regions; most notably, that Tregs are enriched in the appendiceal orifice region and the ascending colon, and that CD8pos T cells are enriched in the gastric mucosa.

The taxonomic composition of the donor intestinal microbiota is a major factor influencing the efficacy of faecal microbiota transplantation in therapy refractory ulcerative colitis

Faecal microbiota transplantation is an experimental approach for the treatment of patients with ulcerative colitis. Although there is growing evidence that faecal microbiota transplantation is effective in this disease, factors affecting its response are unknown.

Any Future for Fecal Microbiota Transplantation as Treatment Strategy for Inflammatory Bowel Diseases

Fecal microbiota transplantation (FMT) is a novel therapeutic procedure aiming at restoring a normal intestinal microbiota by application of fecal microorganisms from a healthy subject into the gastrointestinal tract of a patient. FMT is the most effective treatment for recurrent Clostridium difficile infections (CDI). These infections also occur in patients with inflammatory bowel diseases (IBDs), where case series demonstrated a successful treatment of CDI by FMT in 83-92% of patients. The effect of FMT on the activity of IBD has mainly been investigated in ulcerative colitis (UC) patients, including 3 randomized controlled trials. So far, 2 randomized controlled trials showed a superiority of FMT compared to placebo in inducing remission in UC, while 1 study found no significant difference to placebo. The variation in response to FMT between these studies as well as in the uncontrolled trials might be explained by many differences in the way of FMT application, patient pretreatment and patient and donor selection. The data for the use of FMT in Crohns disease and pouchitis are sparse; currently, no conclusion can be drawn regarding the effectiveness of FMT in these indications. It needs to be noted that cases of IBD activation after FMT have been reported. So far, FMT can only be recommended to be used for the treatment of concomitant CDI in IBD in clinical practice. For treating IBD irrespective of CDI, FMT should be only used in clinical trials. Current forms of FMT, especially protocols using repeated application, are very time and personnel consuming. Future trends are the use of defined stable microbiota preparations, in particular oral preparations, which will enable better and larger controlled trails for investigating FMT in IBD.

Tempered Enthusiasm for Fecal Transplantation

TO THE EDITOR—We read the case report by Solari et al [1] with great interest because the authors presented a fatal case of relapsing Clostridium difficile infection treated with fecal microbiota transplantation (FMT) using a gastrojejunostomy tube. This tube was placed through an already existing gastric feeding tube, and the patient died 4 days later due to septic shock; Pseudomonas aeruginosa, Escherichia coli, and Lactobacillus casei grew in blood culture. Although this deadly progression tempered the authors’ enthusiasm regarding FMT, 2 considerations should be taken into account before drawing such a conclusion. First, although the position of the tip of the gastrojejunostomy tube near the ligament of Treitz was confirmed by contrast injection under fluoroscopy and routine abdominal radiography just prior to the fecal instillation, during the emergent surgical procedure 3 days later, the gastrostomy tube was found to be dislodged, causing pneumoperitoneum. It is therefore unclear whether donor feces reached the targeted stomach/duodenum, or the peritoneal cavity, leading to septic shock. The latter may also explain the missing effect of FMT and suspected deterioration of C. difficile infection with megacolon after stopping fidaxomicin and metronidazole. Therefore, we believe it is very likely that septic shock was caused by the dislodged gastrojejunostomy tube and challenge the hypothesis of the authors that stopping antimicrobials for treatment of C. difficile was responsible. Second, we wonder that the authors applied FMT using a gastrojejunostomy tube, as this route has been considered to have lower success rates compared with application into the colon [2]. Although infusion of donor feces through a nasoduodenal tube has been successfully used previously [3, 4], fatal outcome due to pneumonia and peritonitis after application of donor feces in the upper gastrointestinal (GI) tract has already been reported [5]. We conclude that the presented case adds to the knowledge that FMT administered through the upper GI tract is potentially life threatening. Because colonoscopic application of FMT offers assessment of colonic mucosa and control of correct donor feces placement [6], we suggest this to be the preferred route of application. Furthermore, C. difficile infection is a disease affecting the colon and therefore the rationale of administration of donor feces to the upper GI tract has been questioned [6]. We are not enthusiastic about the procedure, but are grateful to have FMT available for certain therapy-resistant cases of C. difficile infection.