Efficacy of fecal microbiota transplantation in a patient with chronic intractable constipation

Key Clinical Message We have presented the first case report of FMT therapy for a patient with chronic intractable constipation. This therapy resulted in good, medium‐term outcomes. Follow‐up analysis of the intestinal flora suggested that transplanted microbes from the donor, particularly Bifidobacterium and Clostridium cluster IX, may have been incorporated into the recipient.


| INTRODUCTION
Fecal microbiota transplantation (FMT) therapy for patients with Clostridium difficile infection colitis has been found to have surprising efficacy. 1 Dysbiosis of the intestinal flora is a problem and possible cause in diseases such as colorectal carcinoma, hepatocellular carcinoma, diabetes mellitus, obesity, and NASH. [2][3][4][5] In addition, dietary habits strongly affect the intestinal flora. Many patients have chronic constipation, and although these patients take laxatives and pre-and probiotics to improve their intestinal flora, the success of these approaches is limited. We used FMT therapy for a patient with chronic intractable constipation and achieved significant short-and medium-term efficacy. This is the first case report of FMT therapy for such a patient.

| CASE HISTORY/EXAMINATION
The patient was an 83-year-old male who had suffered with chronic intractable constipation for over fifty years. He had been treated with many anti-constipation agents and probiotics, including magnesium oxide, carmellose sodium, D-sorbitol, sodium picosulfate hydrate, and yogurt containing Lactobacillus gasseri 21, but the frequency of defecation remained at 7-10 days and the stool volume was small, with a Bristle Stool Score (BSS) of 1 for classification of fecal properties. Based on an abdominal X-ray, feces accumulated in the intestines, resulting in a very firm abdomen and anorexia. A general examination indicated that the patient had a mild Alzheimer's type of dementia that caused forgetfulness in daily life.

INVESTIGATION OF THERAPY
Colonoscopy findings did not show any diseases that could contribute to constipation, such as a tumor, polyp, or bowel stenosis. Mucosal melanosis was present, and was probably due to use of laxatives. We consulted with the patient and his family about treatment and reached a decision of FMT therapy. The intestinal flora of the patient and a 19-year-old healthy donor, who was the patient's nephew, were first examined ( Figure 1 and Table 1). We confirmed the validity of the donor based on several infectious disease tests and the results of intestinal flora analysis. Also, the donor gave a guarantee to provide feces for transplant. The analysis of the patient's intestinal flora showed a depletion of both Bifidobacterium and some short chain fatty acids (SCFAs), especially acetic acid, propionic acid, and butyric acid ( Table 2). The intestinal flora was analyzed by a terminal fragment length polymorphism (T-RFLP) method after DNA extraction from feces. 6,7 The concentrations of seven SCFAs in the fecal samples were measured by gas chromatography-mass spectrometry. 8 The transplant-microbial solution was prepared from the donor's feces, 1 and then about 400 mL was infused into the recipient by colonoscopy. The solution was infused into the cecum to the ascending colon only once. FMT therapy was performed at Fukushima Daiichi Hospital.

| OUTCOME AND FOLLOW-UP
Immediately after FMT therapy, the recipient defecated every day and developed abdominal distensions without the need for drug therapy. The fecal properties and bowel movements are summarized in Table 3. The efficacy of the FMT therapy was remarkable and continued for 1 month. An examination of the patient's intestinal flora at 1 month after FMT therapy showed that the composition resembled that of the donor, with a notable increase in the populations of Bifidobacterium and Clostridium cluster IX in the recipient ( Figure 1 and Table 1). The patient's dementia symptoms of forgetfulness also showed a minor improvement after FMT therapy. The positive effects of FMT therapy on normal bowel movements, frequent passage, and normal fecal properties were still present after more than 11 months.

| DISCUSSION
Bowel movements are accelerated by SCFAs such as butyric acid and propionic acid, 8 and SCFAs 9 are generated by Bifidobacterium, Lactobacillus, various types of clostridium clusters, and intestinal flora in general. Incorporation of transplanted microbes after FMT therapy has not been reported, but the results from our follow-up examination suggested that Bifidobacterium and Clostridium cluster IX were incorporated into the recipient's intestinal flora. This beneficial effect of FMT therapy may be applicable for other diseases, such as diabetes mellitus, inflammatory bowel disease, and dementia. We plan to perform a full analysis of the incorporated microbes in a further study.

| CONCLUSIONS
We have presented the first case report of FMT therapy for a patient with chronic intractable constipation. This therapy resulted in good short-and medium-term outcomes. Follow-up analysis of the intestinal flora suggested that transplanted microbes from the donor, particularly Bifidobacterium and Clostridium cluster IX, may have been incorporated into the recipient's intestinal flora analyzed by T-RFLP method. It may be a possibility that the further follow-up observation and the detailed full analysis of microbes in this case lead to the new developments of FMT treatment.  Data are shown as concentrations (μmol/g). A blank indicates a value lower than the limit of detection (LOD). The LODs for acetic acid, propionic acid and butyric acid were 2.0, 0.7 and 0.7 μmol/g, respectively. The LODs for isobutyric acid, valeric acid, isovaleric acid and caproic acid were all 0.3 μmol/g.

T A B L E 3 Changes of fecal properties and bowel movements in
the recipient before and after FMT therapy