Modulation of gut microbiome of ulcerative colitis patients: a ramdomized, double blind, controled study

Abstract

Ulcerative colitis (UC) is an intestinal disease manifesting in the colon mucosa as ulcerations, of varying intensity and extension which are detected in colonoscopy examinations. It is incurable, of unknown cause and associated with several factors, including disequilibrium in species composition of the microbiome (dysbiosis). Gut dysbiosis in UC implies not only in the reduction of microbial diversity, but also in the elevation of a number of potentially pathogenic species, such as Escherichia coli, and reduction in the abundance of bacteria which play significant roles in maintenance of intestinal homeostasis, as Faecalibacterium prausnitzii. Despite a link between UC and a given infectious agent has not yet been established, dysbiosis per se must at least aggravate the disease's symptoms. Thus, management of UC based on restoration of gut bacteria (bacteriotherapy) has been viewed as a promising therapeutic strategy which, taken to an extreme, considers the transfer of stools from health donors (fecal transplantation - FT) to patients' gut. Studies carried out thus far indicate that the efficacy of FT for UC therapy varies between patients and that in some cases remission can be achieved only after a massive regime, lasting up to over four weeks of uninterrupted daily applications. In addition, fecal material to be transferred should present with a high microbial diversity, which can be achieved by mixing stools from distinct donors to form a pool to be used in the FT procedure. The classical FT procedure consisting in the use of retention enemas is a limitation to the adoption of a massive regime, given patient's discomfort and uncertainty as to his or her observance to full regime schedule. To circumvent these limitations posed by multiple FT applications, the protocol proposed in the present study consists in the transfer of stools inside capsules of delayed disintegration, through oral route. These capsules, which will contain processed stools from multiple donors, will be prepared and cryopreserved at -80ºC before initiation of the FT regime. Fecal donors will be selected among individuals indicated by the UC patients enrolled in the study (at least one individual per patient). Criteria for donor eligibility will be health status, based on clinical and laboratory examinations and fecal microbial diversity. A total of 32 UC patients, presenting with mild to moderate clinical activity will be enrolled in this study. These patients will be randomly included in two cohorts of 16 subjects, the FT therapy group (FTTG), including individuals who will ingest feces filled capsules and the Placebo group (PG), comprising patients who will take capsules with saline. FTTG will be subjected to a regime of 20 capsules/day filled with feces from four distinct donors, 5 days per week during 8 continuous weeks. PG will subjected to a regime of capsules administration identical to that of FTTG. Capsules administration protocol will be double blind. Before, during and after the regime, all the patients in both cohorts will be evaluated by means of clinical and laboratory examinations, aiming at determining their health condition and gut microbiome diversity. In addition, they will periodically inform the medical staff of possible adverse events, by filling a form. Clinical remission will be evaluated by Mayo score. This work is expected to contribute not only with relevant information for the management of UC but also must generate data which could be used in formulating FT protocols for the control of other diseases wherein dysbiosis is an underlying component. (AU)