Evaluation of The Role of Fecal Microbiota Transplantation in The Management of Ulcerative Colitis in Egyptian Patients

DISCUSSION

Fecal microbiota transplantation seems beneficial and safe for treatment of active UC based on the results of this study. As regard patients preparation we use bowel lavage with poly ethylene glycol and we did not use antibiotics before FMT as done by the four Randomized Clinical Trials (RCT)  Paramsothy⁹ et al, Rossen¹⁰ et al , Moayyedi¹¹ et al and Costello⁷ et al  and other studies used antibiotics before FMT include Wei et al 12 who used Vancomycin 500 mg bd 3 days before FMT ,Ishikawa¹³ et al who used Amoxicillin (1500mg/d),and metronidazole (750 mg/d) and Angelberger¹⁴ et al who used Metronidazole 5-10 days before FMT.

Although the concept of adjuvant interventions, such as bowel lavage or pretreatment antibiotics, to decrease the bacterial burden and enable healthy microbial engraftment in the host has been speculated, it may also interfere with the function of the new microbiota.¹⁵

In our study we use of multiple donors (8-10) who un related to patients as done by Paramsothy et al 9 who used (3-7) donors and Costello et al who used (3-4)

donors un related to patients on both studies.Un like  Moayyedi¹¹ et al and Rossen¹⁰ et al who used single donor for fecal microbiota transplantation infusion. It was initially considered that related donors. might lead to a better tolerance of FMT. However, the relatives of IBD patients have been recently demonstrated to possibly have themselves gut dysbiosis.¹⁶ Multi donor fecal microbiota transplantation infusions were utilized in our study, both to ensure an adequate supply of infusions for fecal microbiota transplantation and to minimize the possibility of patients receiving only therapeutically ineffective donor stool.

In our study the amount of stool was (50 -100) gm. For each fecal microbiota transplantation with total amount reaching (200-400) gm at the end of study. This amount of stool was similar to Rossen¹⁰ et al who used 120 gm of stool per week and Costello⁷ et al who used 100gm of stool, per week, and disagree with paramsothy⁹ et al who used the most intensive amount of stool who used (187.5) gm of stool per week for 8 weeks and moayyedi¹¹ et al who used amount of (8.3) gm of stool along the study.

In  our  study  we  use  frozen  donor  stool  from  de- identified,   unrelated   healthy  donors   as   done   by Paramsothy9  et al and Costello7  et al  who used the same method of processing. Other studies including Rossen10  et al and moayeddi11  et al who used fresh stool from single donor, Stool processed aerobically in   our   study   as   done   by   Moayyedi11     et   al, Paramsothy9    et   al   and   Rossen10    et   al   un   like Costello7  et al the only study in which donors stool processed      anaerobically      without      significant differences between studies, so it seems that neither anaerobic vs aerobic stool preparation, nor fresh or frozen stool, significantly influences the efficacy of FMT.17

In  our  study  we  used  colonoscopy  as  a  route  for delivery of fecal microbiota as done by Paramsothy9 et al  and  Costello7  et al  who  used  colonoscopy for microbiota    transplantation,    other    studies    using different routes were done by Moayyedi¹¹  et al who used retention enema and Rossen10  et al who used naso  duodenal  tube  as  a  route  of  delivery  of  fecal microbioa.

In  our  study  we  use  of  colonoscopy to  ensure  that large quantity of stool delivered and  to  ensure that microbiota reaching the ileum and right colon, other studies used retention enemas explained that enemas are less expensive and safer to administer and more practical than colonoscopy.¹¹

As  to  the  administration  route,  in  agreement  with studies who  used  colonoscopy   reported  a possible increased   benefit   by   using   the   lower   route   of administration  in  subgroup  analyses,  it  has  been speculated   that   the   upper   gastrointestinal   route could   interfere   with   the   activity  of   some   FMT components   before   they   reach   the   colon   (since gastric  acid  can  damage  Bacteroidetes),  However, many  bacteria  belonging  to  the  Firmicutes  phylum require  an  upper  GI  tract  transit  in  order  to  be activated,  supporting  a  possible  advantage  of  the upper route.18

In  our  study  the  duration  of  FMT  was  9  weeks  of transplantation(colonoscopy   was   done   and   FMT was done at 0,3,6,9 weeks of study ) and follow up was  done  up  to  the  24th  week  of  study,  Similar duration was used by paramsothy9  et al who had the duration    of    8    week    of    transplantation    and Moayyedi11   et  al  demonstrated  efficacy  of  FMT over placebo for  7 weeks, other studies  used short duration    include    Rossen10     et    al    demonstrated efficacy  of  FMT  over  placebo  for    6  weeks  and Costello7  et al who used the shortest duration of 3- dose,   1-week   of   transfusion.   The   duration   and intensity    of    faecal    microbiota    transplantation therapy might need to be individualized    treatment once  a  week  could  be  effective  in  some  patients whereas more intensive therapy might be needed in others.

Both groups start  with anemia HB (9.6) in group I and  (9.4)  in  group  II  then  improvement  start  to develop by the third week HB (9.8) on both groups and continue along the 6th week, the 9th week and the18th week, By the week 24 improvement in HB is more significant in group II HB (12.4) compared to  (11.9)  in  group  I  with  statistically  significant difference between both groups P value (0.027).

Both  groups  start  with  leucocytic  count  (8.4)  in group  I  and  (8.3)  in  group  II  with  no  statistically significant  difference  between  both  groups  II  then improvement start to develop by the third week on both  groups  and  continue  along  the  6th  week,  the 9th   week   and   the18th   week,   By   the   week   24 reduction in leucocytic count is more significant in group II HB (5.8) compared to (6.2) in group I with statistically   significant   difference   between   both groups P value (0.008).

Patients  of  both  groups  start  with  high  ESR  level (35.3)   in   group   I   and   (33.8)   in   group   II   then reduction in ESR achieved on both groups along the study,  By  the  24th  week  ESR  become  normal  on both groups (8.2) in group I and (7.5) in group II.

Patients  of  both  groups  start  with  high  CRP  level (29.8)   in   group   I   and   (30.3)   in   group   II   then reduction in ESR achieved on both groups along the study,  By  the  24th  week  CRP  become  normal  on both groups (3) in group I and (2,7) in group II. The clinical  response  is  defined  as  reduction  in  mayo score equal or less than three points from base line score.  The  remission  is  defined  as  a  resolution  of clinical   symptoms,   including   cessation   of   rectal bleeding  and  improvement  in  bowel  habits  (total mayo score equal or less than 2).

At   the   start   of   study   both   groups   were   in exacerbation (mayo score was 12).  At  the  third week  both  groups  start  to  improve  with  where  4% (1/25)   of   patients   of   group   I   achieved   clinical response  and  20%  (5/25)  of  patients  of  group  II achieved    clinical    response    and    no    remission achieved   on   both   groups   with   no   statistically significant  difference  between  both  groups.  By  the 6th  week  of  study  more  patients  of  both  groups achieved  clinical  response  where  72%(18/25)  of patients of group II become responsive to treatment and 48%(12/25) of patients of group I responsive to treatment as regard reduction in mayo score to (9.4) in  group  I  compared  to  (8.4)  reduction  in  mayo score  in  group  II  with  no  statistically  significant difference  between  both  groups.  By  the  9th  week 92% (23/25) of patients of group II achieved clinical response  compared  to  64%(16/25)  and  one  patient of   group   II   (4%)   achieved   clinical   remission (reduction  mayo  score  to  equal  or  less  than  two) with no remission achieved in group I. By the 18th week  of study 40%  (10/25) of patients  of group  II achieved clinical remission and only one patient of group  I  achieved  clinical  remission.  At  the  end  of the study by the 24th week 72% (18/25) of patients of  group  II  achieved  clinical  remission  and  only 20%(5/25)  of  patients  of  group  I  achieved clinical remission.

The end result of this study agree with paramsothy9

et al   in   which   remission   induction   achieved   in 44%(18/41)   and   Costello7    et   al   where   is   50% (19/38)  achieved  clinical  remission,  And  disagree with   moayddei11    et   al,   Angelberger14  

et   al   and nishida19    et   al   in   which   no   clinical   remission achieved in all patients and Rossen10  et al in which 30% only of patients achieved clinical remission.

CONCLUSION

FMT provides a promising new therapy for UC with Successful FMT associated with decreased activity of the disease and more well designed studies on large scale   of   patients   and   long-term   follow-up   are necessary to confirm the effects of FMT.

DISCUSSION

Fecal microbiota transplantation seems beneficial and safe for treatment of active UC based on the results of this study. As regard patients preparation we use bowel lavage with poly ethylene glycol and we did not use antibiotics before FMT as done by the four Randomized Clinical Trials (RCT)  Paramsothy⁹ et al, Rossen¹⁰ et al , Moayyedi¹¹ et al and Costello⁷ et al  and other studies used antibiotics before FMT include Wei et al 12 who used Vancomycin 500 mg bd 3 days before FMT ,Ishikawa¹³ et al who used Amoxicillin (1500mg/d),and metronidazole (750 mg/d) and Angelberger¹⁴ et al who used Metronidazole 5-10 days before FMT.

Although the concept of adjuvant interventions, such as bowel lavage or pretreatment antibiotics, to decrease the bacterial burden and enable healthy microbial engraftment in the host has been speculated, it may also interfere with the function of the new microbiota.¹⁵

In our study we use of multiple donors (8-10) who un related to patients as done by Paramsothy et al 9 who used (3-7) donors and Costello et al who used (3-4)

donors un related to patients on both studies.Un like  Moayyedi¹¹ et al and Rossen¹⁰ et al who used single donor for fecal microbiota transplantation infusion. It was initially considered that related donors. might lead to a better tolerance of FMT. However, the relatives of IBD patients have been recently demonstrated to possibly have themselves gut dysbiosis.¹⁶ Multi donor fecal microbiota transplantation infusions were utilized in our study, both to ensure an adequate supply of infusions for fecal microbiota transplantation and to minimize the possibility of patients receiving only therapeutically ineffective donor stool.

In our study the amount of stool was (50 -100) gm. For each fecal microbiota transplantation with total amount reaching (200-400) gm at the end of study. This amount of stool was similar to Rossen¹⁰ et al who used 120 gm of stool per week and Costello⁷ et al who used 100gm of stool, per week, and disagree with paramsothy⁹ et al who used the most intensive amount of stool who used (187.5) gm of stool per week for 8 weeks and moayyedi¹¹ et al who used amount of (8.3) gm of stool along the study.

In  our  study  we  use  frozen  donor  stool  from  de- identified,   unrelated   healthy  donors   as   done   by Paramsothy9  et al and Costello7  et al  who used the same method of processing. Other studies including Rossen10  et al and moayeddi11  et al who used fresh stool from single donor, Stool processed aerobically in   our   study   as   done   by   Moayyedi11     et   al, Paramsothy9    et   al   and   Rossen10    et   al   un   like Costello7  et al the only study in which donors stool processed      anaerobically      without      significant differences between studies, so it seems that neither anaerobic vs aerobic stool preparation, nor fresh or frozen stool, significantly influences the efficacy of FMT.17

In  our  study  we  used  colonoscopy  as  a  route  for delivery of fecal microbiota as done by Paramsothy9 et al  and  Costello7  et al  who  used  colonoscopy for microbiota    transplantation,    other    studies    using different routes were done by Moayyedi¹¹  et al who used retention enema and Rossen10  et al who used naso  duodenal  tube  as  a  route  of  delivery  of  fecal microbioa.

In  our  study  we  use  of  colonoscopy to  ensure  that large quantity of stool delivered and  to  ensure that microbiota reaching the ileum and right colon, other studies used retention enemas explained that enemas are less expensive and safer to administer and more practical than colonoscopy.¹¹

As  to  the  administration  route,  in  agreement  with studies who  used  colonoscopy   reported  a possible increased   benefit   by   using   the   lower   route   of administration  in  subgroup  analyses,  it  has  been speculated   that   the   upper   gastrointestinal   route could   interfere   with   the   activity  of   some   FMT components   before   they   reach   the   colon   (since gastric  acid  can  damage  Bacteroidetes),  However, many  bacteria  belonging  to  the  Firmicutes  phylum require  an  upper  GI  tract  transit  in  order  to  be activated,  supporting  a  possible  advantage  of  the upper route.18

In  our  study  the  duration  of  FMT  was  9  weeks  of transplantation(colonoscopy   was   done   and   FMT was done at 0,3,6,9 weeks of study ) and follow up was  done  up  to  the  24th  week  of  study,  Similar duration was used by paramsothy9  et al who had the duration    of    8    week    of    transplantation    and Moayyedi11   et  al  demonstrated  efficacy  of  FMT over placebo for  7 weeks, other studies  used short duration    include    Rossen10     et    al    demonstrated efficacy  of  FMT  over  placebo  for    6  weeks  and Costello7  et al who used the shortest duration of 3- dose,   1-week   of   transfusion.   The   duration   and intensity    of    faecal    microbiota    transplantation therapy might need to be individualized    treatment once  a  week  could  be  effective  in  some  patients whereas more intensive therapy might be needed in others.

Both groups start  with anemia HB (9.6) in group I and  (9.4)  in  group  II  then  improvement  start  to develop by the third week HB (9.8) on both groups and continue along the 6th week, the 9th week and the18th week, By the week 24 improvement in HB is more significant in group II HB (12.4) compared to  (11.9)  in  group  I  with  statistically  significant difference between both groups P value (0.027).

Both  groups  start  with  leucocytic  count  (8.4)  in group  I  and  (8.3)  in  group  II  with  no  statistically significant  difference  between  both  groups  II  then improvement start to develop by the third week on both  groups  and  continue  along  the  6th  week,  the 9th   week   and   the18th   week,   By   the   week   24 reduction in leucocytic count is more significant in group II HB (5.8) compared to (6.2) in group I with statistically   significant   difference   between   both groups P value (0.008).

Patients  of  both  groups  start  with  high  ESR  level (35.3)   in   group   I   and   (33.8)   in   group   II   then reduction in ESR achieved on both groups along the study,  By  the  24th  week  ESR  become  normal  on both groups (8.2) in group I and (7.5) in group II.

Patients  of  both  groups  start  with  high  CRP  level (29.8)   in   group   I   and   (30.3)   in   group   II   then reduction in ESR achieved on both groups along the study,  By  the  24th  week  CRP  become  normal  on both groups (3) in group I and (2,7) in group II. The clinical  response  is  defined  as  reduction  in  mayo score equal or less than three points from base line score.  The  remission  is  defined  as  a  resolution  of clinical   symptoms,   including   cessation   of   rectal bleeding  and  improvement  in  bowel  habits  (total mayo score equal or less than 2).

At   the   start   of   study   both   groups   were   in exacerbation (mayo score was 12).  At  the  third week  both  groups  start  to  improve  with  where  4% (1/25)   of   patients   of   group   I   achieved   clinical response  and  20%  (5/25)  of  patients  of  group  II achieved    clinical    response    and    no    remission achieved   on   both   groups   with   no   statistically significant  difference  between  both  groups.  By  the 6th  week  of  study  more  patients  of  both  groups achieved  clinical  response  where  72%(18/25)  of patients of group II become responsive to treatment and 48%(12/25) of patients of group I responsive to treatment as regard reduction in mayo score to (9.4) in  group  I  compared  to  (8.4)  reduction  in  mayo score  in  group  II  with  no  statistically  significant difference  between  both  groups.  By  the  9th  week 92% (23/25) of patients of group II achieved clinical response  compared  to  64%(16/25)  and  one  patient of   group   II   (4%)   achieved   clinical   remission (reduction  mayo  score  to  equal  or  less  than  two) with no remission achieved in group I. By the 18th week  of study 40%  (10/25) of patients  of group  II achieved clinical remission and only one patient of group  I  achieved  clinical  remission.  At  the  end  of the study by the 24th week 72% (18/25) of patients of  group  II  achieved  clinical  remission  and  only 20%(5/25)  of  patients  of  group  I  achieved clinical remission.

The end result of this study agree with paramsothy9

et al   in   which   remission   induction   achieved   in 44%(18/41)   and   Costello7    et   al   where   is   50% (19/38)  achieved  clinical  remission,  And  disagree with   moayddei11    et   al,   Angelberger14  

et   al   and nishida19    et   al   in   which   no   clinical   remission achieved in all patients and Rossen10  et al in which 30% only of patients achieved clinical remission.

CONCLUSION

FMT provides a promising new therapy for UC with Successful FMT associated with decreased activity of the disease and more well designed studies on large scale   of   patients   and   long-term   follow-up   are necessary to confirm the effects of FMT.