Alteration of the Intestinal Microbiome
Alteration of the Intestinal Microbiome
Although the most common application for FMT has been in the setting of recurrent CDI, there is ongoing research to assess benefit in other gastrointestinal diseases. These include inflammatory bowel disease (IBD), irritable bowel syndrome (IBS) and chronic constipation. There are also isolated reports of FMT effects in nongastrointestinal disease, including multiple sclerosis and Parkinson's disease. The current areas of intestinal microbiome research are presented in Box 1.
IBD is a chronic inflammatory disease commonly composed of Crohn's disease (CD) and ulcerative colitis (UC). Although a clear etiology for IBD remains unknown, hypotheses include exposure to an unidentified infectious agent, genetic predisposition and/or an excessive mucosal immune response contributing to chronic inflammation and inevitable disruption of normal enteric microbiota.
FMT via retention enema was initially performed as a self-experiment by Bennet, who was afflicted with UC. He had successful alleviation of symptoms (bloody diarrhea, cramping, tenesmus, skin lesions and arthritis) that persisted for at least 6 months. Also in 1989, Borody documented two patients, one with CD and the other with UC, who were treated with FMT via enemas. Both patients remained symptom free for at least 3 months following donor stool transplant. More recently, Borody retrospectively reviewed the outcomes of FMT for six UC patients with severe disease for >5 years. These patients had previously been treated with steroids and anti-inflammatory agents, and then with donor stool retention enemas for 5 days followed by tapering off of all UC medications. All six patients experienced disease remission ranging from 1 to 13 years post-FMT.
With the ongoing work of the Human Microbiome Project, additional characterization of the intestinal microbiota in IBD patients is underway. A 2012 systematic review of existing research acknowledges a limited and weak evidence base, but highlights the potential for FMT to be a safe and effective IBD treatment. Building on these initial studies by Bennet and Borody in UC patients, there are ongoing studies investigating FMT as treatment for this population on a larger scale.
Few studies have evaluated the benefit of FMT on IBS and/or chronic constipation. One of the earliest reported case series included 55 patients with IBD and/or IBS treated with fecal retention enemas. In this report, Borody describes 20 patients with 'cure' (as defined by improvement in bowel frequency, less need for laxatives, becoming pain free and resolution of diarrhea), 9 patients with improvement in symptoms (bowel habits and abdominal pain) and 26 patients with no response. In a subsequent study, Andrews and Borody created a mixture of 18 different bacteria paralleling the normal colonic microbiota and infused this 'starter culture' into the cecum of IBS patients. They report that 76% of patients with severe chronic constipation benefitted without any further need for laxatives, with a 4–52 week follow-up period (mean of 21 weeks). Andrews presents a case report of a woman with chronic idiopathic constipation who had long-term resolution (at least 18 months) following retention enema with her husband's stool suggesting that there may be a role for FMT in constipation-predominant IBS. Despite these positive findings, additional studies are required to further evaluate the benefit of FMT in this population, particularly in the setting of a benign disease, whereby patients would be exposed to an invasive therapy with low, but nontrivial risk of complications.
There is limited information on the relationship between the gut microbiota and neurologic disease. Collins comments on the ability of the gut to influence the brain and behavior. There are weak associations between depression and carbohydrate malabsorption, varying levels of Clostridia in autistic patients and alterations in feeding in patients with chronic Helicobacter pylori infection.
There is one case series of FMT performed in three patients with 'atypical' multiple sclerosis. One patient underwent five FMT infusions with resolution of constipation and remission of multiple sclerosis symptoms, regaining the ability to walk again after being wheelchair-bound. A second patient underwent 10 FMT infusions and also regained the ability to walk and experienced overall resolution of neurologic symptoms. The third patient was 80-years old and had resolution of both neurologic symptoms and constipation following five FMT infusions. Borody hypothesized that a gastrointestinal infection may be responsible for symptoms of multiple sclerosis in these patients and FMT resulted in restoration and/or alteration of microbiota contributing to resolution of clinical symptoms. Similarly, it has been suggested that Parkinson's disease may be related to an intestinal pathogen that crosses the mucosal barrier of the gastrointestinal system via enteric neurons, thereby entering the central nervous system. Borody has performed similar FMT infusions on patients with Parkinson's disease, also with positive results, although the details have not been published.
Alteration of the Microbiome Through FMT in Other Diseases
Although the most common application for FMT has been in the setting of recurrent CDI, there is ongoing research to assess benefit in other gastrointestinal diseases. These include inflammatory bowel disease (IBD), irritable bowel syndrome (IBS) and chronic constipation. There are also isolated reports of FMT effects in nongastrointestinal disease, including multiple sclerosis and Parkinson's disease. The current areas of intestinal microbiome research are presented in Box 1.
Inflammatory Bowel Disease
IBD is a chronic inflammatory disease commonly composed of Crohn's disease (CD) and ulcerative colitis (UC). Although a clear etiology for IBD remains unknown, hypotheses include exposure to an unidentified infectious agent, genetic predisposition and/or an excessive mucosal immune response contributing to chronic inflammation and inevitable disruption of normal enteric microbiota.
FMT via retention enema was initially performed as a self-experiment by Bennet, who was afflicted with UC. He had successful alleviation of symptoms (bloody diarrhea, cramping, tenesmus, skin lesions and arthritis) that persisted for at least 6 months. Also in 1989, Borody documented two patients, one with CD and the other with UC, who were treated with FMT via enemas. Both patients remained symptom free for at least 3 months following donor stool transplant. More recently, Borody retrospectively reviewed the outcomes of FMT for six UC patients with severe disease for >5 years. These patients had previously been treated with steroids and anti-inflammatory agents, and then with donor stool retention enemas for 5 days followed by tapering off of all UC medications. All six patients experienced disease remission ranging from 1 to 13 years post-FMT.
With the ongoing work of the Human Microbiome Project, additional characterization of the intestinal microbiota in IBD patients is underway. A 2012 systematic review of existing research acknowledges a limited and weak evidence base, but highlights the potential for FMT to be a safe and effective IBD treatment. Building on these initial studies by Bennet and Borody in UC patients, there are ongoing studies investigating FMT as treatment for this population on a larger scale.
IBS & Chronic Constipation
Few studies have evaluated the benefit of FMT on IBS and/or chronic constipation. One of the earliest reported case series included 55 patients with IBD and/or IBS treated with fecal retention enemas. In this report, Borody describes 20 patients with 'cure' (as defined by improvement in bowel frequency, less need for laxatives, becoming pain free and resolution of diarrhea), 9 patients with improvement in symptoms (bowel habits and abdominal pain) and 26 patients with no response. In a subsequent study, Andrews and Borody created a mixture of 18 different bacteria paralleling the normal colonic microbiota and infused this 'starter culture' into the cecum of IBS patients. They report that 76% of patients with severe chronic constipation benefitted without any further need for laxatives, with a 4–52 week follow-up period (mean of 21 weeks). Andrews presents a case report of a woman with chronic idiopathic constipation who had long-term resolution (at least 18 months) following retention enema with her husband's stool suggesting that there may be a role for FMT in constipation-predominant IBS. Despite these positive findings, additional studies are required to further evaluate the benefit of FMT in this population, particularly in the setting of a benign disease, whereby patients would be exposed to an invasive therapy with low, but nontrivial risk of complications.
Neurological Disease
There is limited information on the relationship between the gut microbiota and neurologic disease. Collins comments on the ability of the gut to influence the brain and behavior. There are weak associations between depression and carbohydrate malabsorption, varying levels of Clostridia in autistic patients and alterations in feeding in patients with chronic Helicobacter pylori infection.
There is one case series of FMT performed in three patients with 'atypical' multiple sclerosis. One patient underwent five FMT infusions with resolution of constipation and remission of multiple sclerosis symptoms, regaining the ability to walk again after being wheelchair-bound. A second patient underwent 10 FMT infusions and also regained the ability to walk and experienced overall resolution of neurologic symptoms. The third patient was 80-years old and had resolution of both neurologic symptoms and constipation following five FMT infusions. Borody hypothesized that a gastrointestinal infection may be responsible for symptoms of multiple sclerosis in these patients and FMT resulted in restoration and/or alteration of microbiota contributing to resolution of clinical symptoms. Similarly, it has been suggested that Parkinson's disease may be related to an intestinal pathogen that crosses the mucosal barrier of the gastrointestinal system via enteric neurons, thereby entering the central nervous system. Borody has performed similar FMT infusions on patients with Parkinson's disease, also with positive results, although the details have not been published.