Consensus Guidelines on FMT

Recent links from AGA for FMT (fecal microbiota transplantation) for Clostridium difficile –excellent resource:

Also, summary of recent abstracts from ACG regarding FMT for C difficile, IBS, and IBD: http://t.co/7LFnDYq5V5

Some previous blog posts on this topic:

Newest FODMAPs Study for IBS

From AGA twitter feed: http://t.co/vFwhS5YEF4 -Full text article.

From Abstract:

Methods

In a study of 30 patients with IBS and 8 healthy individuals (controls, matched for demographics and diet), we collected dietary data from subjects for 1 habitual week. Participants then randomly were assigned to groups that received 21 days of either a diet low in FODMAPs or a typical Australian diet, followed by a washout period of at least 21 days, before crossing over to the alternate diet. Daily symptoms were rated using a 0- to 100-mm visual analogue scale. Almost all food was provided during the interventional diet periods, with a goal of less than 0.5 g intake of FODMAPs per meal for the low-FODMAP diet. All stools were collected from days 17–21 and assessed for frequency, weight, water content, and King’s Stool Chart rating.

Results

Subjects with IBS had lower overall gastrointestinal symptom scores (22.8; 95% confidence interval, 16.7–28.8 mm) while on a diet low in FODMAPs, compared with the Australian diet (44.9; 95% confidence interval, 36.6–53.1 mm; P < .001) and the subjects’ habitual diet. Bloating, pain, and passage of wind also were reduced while IBS patients were on the low-FODMAP diet. Symptoms were minimal and unaltered by either diet among controls. Patients of all IBS subtypes had greater satisfaction with stool consistency while on the low-FODMAP diet, but diarrhea-predominant IBS was the only subtype with altered fecal frequency and King’s Stool Chart scores.

Conclusions

In a controlled, cross-over study of patients with IBS, a diet low in FODMAPs effectively reduced functional gastrointestinal symptoms. This high-quality evidence supports its use as a first-line therapy.

Related Blog Posts:

Microscopic, Lymphocytic and Collagenous Colitis

Microscopic Colitis (MC) is a rare pediatric problems and occurs when chronic diarrhea occurs in the presence of a normal-appearing endoscopic exam but with abnormal histology.  In adult populations, microscopic colitis is seen more frequently and can be confused with irritable bowel syndrome.  The two subtypes:

  • Lymphocytic Colitis (LC):  >20 intraepithelial lymphocytes/100 colonocytes
  • Collagenous Colitis (CC): thickened subeptihelial collagen band in addition to changes seen with LC

In a recent study (JPGN 2013; 57: 557-61), 27 MC cases were identified from a pathology database between 1995-2011.  5 were excluded due to an enteric infection.  Among the 22 other cases, 19 had LC and 3 had CC.  Association with celiac disease was evident in 4 patients and many had preceding drug exposures.

Treatment included steroids, melamine, an bismuth.

Additional references:

  • -JPGN 2011; 53: 579. lymphocytic colitis case report
  • -Clincal Gastro & Hep 2011; 9: 13.  Celaic with persistent symptoms: consider poor adherence**, SBBO*, pancreatic insufficiency*, refractory celiac (rare), PLE, giardia, malignancy, lactose intolerance, functional d/o*, microscopic colitis, Crohn’s*, NSAIDs
  • -Gut 2009; 58: 68-72. Collagenous colitis: Budesonide at 6mg/day maintained remission in ~25%.
  • Gastro 2008; 135: 1510.  Budesonide effective for collagenous colitis; n=48, 9mg/day.
  • -Gastro 2011; 140: 1155. Review of microscopic colitis/collagenous colitis.
  • -Am J Gastroenterol 2010; 105: 859-865.  n=466 & 451 controls.  Microscopic colitis present in 1.5% of IBS patients.  IBS pts with lower incidence of adenomas (7.7.% vs 26%).  9% had diverticulosis (lower).
  • -Clin Gastro & hep 2009; 7: 1210. 4.3% of pts w microscopic colitis had celiac. 44/1009.

Extensive Workup Not Needed for IBS

Another study has shown that an extensive workup is not needed for IBS (Clin Gastro Hepatol 2013; 11 956-62).

In this study from Denmark, the authors enrolled 302 patients aged 18-50 from a primary care setting with suspected IBS.  250 patients completed the entire study including a 1-year followup.  These patients fulfilled Rome III criteria and had no alarm signals which were the following:

  • Unexplained weight loss >3 kg
  • Rectal bleeding
  • Unexplained fever or anemia
  • Family history of inflammatory bowel disease (IBD) or colorectal cancer (CRC)
  • Abnormal physical exam

Patients were randomly assigned to either an extensive diagnostic group which included blood tests (including celiac screen & lactase gene test), stool exams, and sigmoidoscopy or to a “positive strategy” which involved testing only with a blood count (CBC/diff) and C-reactive protein.

The group which underwent a more extensive workup had no cases of serious disease, like IBD or CRC identified.  11 patients were identified with lactose intolerance, 1 patient had a rectal adenoma, 1 patient had a benign polyp, and 1 patient had giardiasis.

Overall, the authors and the accompanying editorial (pgs 963-964) conclude that the positive strategy was noninferior to the more extensive evaluation.  One limitation of this study was that patients had carried symptoms compatible with IBS for an average of 7 years before enrollment.

Take-home message: this study “adds to the growing body of evidence in favor of a relatively minimal symptom-based approach to diagnosing IBS.”

Related blog posts:

IBS Symptoms in Patients with Celiac Disease

While a gluten-free diet (GFD) is the optimal treatment, adult patients with celiac disease still have a high prevalence of irritable bowel symptoms (IBS) (Clin Gastroenterol Hepatol 2013; 11: 359-65).

The authors examined the prevalence of IBS symptoms by reviewing cross-sectional and case-control studies in adults with celiac disease (≥16 years old).  Initially, the literature search identified 624 studies; the vast majority did not fit the study requirements.  Seven studies (n=3383 participants) reported the prevalence of IBS symptoms in celiac disease.  These studies took place between 2002 to 2011 in five different countries.  IBS was defined using either Rome I, II, or III criteria.  Only one of these studies assessed adherence to a GFD by using negative tissue transglutaminase antibodies on the 2 most recent outpatient visits.

Results: IBS symptoms were present in 38% of all patients with celiac disease.  The pooled odds ratio was higher for celiac disease than controls (OR 5.6, with 95% CI 3.23-9.7).  Nonadherence to a GFD increased the likelihood over those who were adherent by an odds ratio of 2.69

Take-home message: IBS symptoms are present in a high proportion of patients with celiac disease.  While a GFD may improve these symptoms, some individuals will have persistent symptoms.

Related blog entry:

Is functional pain more common in children with … – gutsandgrowth  Previous blog entry examines functional abdominal pain in children and celiac disease.

Additional references:

  • -JPGN 2011; 53: 216. Case report of refractory celiac treated with 6-MP.
  • -Clincal Gastroenterol & Hep 2011; 9: 13. Celaic with persistent symptoms: consider poor adherence**, SBBO*, pancreatic insufficiency*/subclinical pancreatitis, refractory celiac (rare), PLE, giardia, malignancy, lactose intolerance, functional d/o*, microscopic colitis, Crohn’s*, NSAIDs
  • -Gastroenterol 2009; 136: 81, 91, 99, 32. Refractory celiac can be divided into 2 types; 2nd type assoc c abnormal IEL and has poor prognosis. Risk of non-hodgkins lymphoma 3.8-5 .3 fold over gen population in larg Sweish study. n=37869 c NHL, 236,408 controls, 613,961 1st degree relatives. Relatives c 2 fold risk. Absolute NHL risk ~1 in 1421 person-yrs for celiac pt.
  • -Clin Gastroenterol & Hep 2007; 5: 445-450. Causes of nonresponsive celiac.
  • -NEJM 2007; 356: 2548. Nonresponsive due to inhaled gluten in farm setting.
  • -Clin Gastro & Hep 2007; 5: 445. Gluten exposure in 36%, IBS n 22%, lactose intol 8%, refractory CD 10%
  • -Gastroenterol 2011; 141: 1187.  Prevalence of celiac similar in IBS as general population though higher number (7%) with celiac antibodies (esp gliadin).

What is the risk with Rifaximin?

While no one knows how quickly resistance of gut microbes will develop in response to rifaximin, the likelihood of resistance is high and this should temper its usage (J Clin Gastroenterol 2013; 47: 205-11).

Rifaximin, along with other antibiotics, has been shown to relieve symptoms in certain cohorts of irritable bowel syndrome (IBS) patients.  Generally, the results of these studies have been modest (see below); however, because it is a “gut specific” antibiotic with minimal systemic absorption (<1%) and therefore minimal adverse effects, it has been considered a reasonable and safe treatment by many.  It has been useful as well for traveler’s diarrhea, hepatic encephalopathy, and colonic diverticular disease.  With regard to IBS, the major concern is that this is a chronic disorder and repeated usage will result in antimicrobial resistance.

Resistance to rifaximin could result in serious consequences if it provoked a class effect resistance.  Rifaximin belongs to the rifamycin class of antibiotics which treat numerous diseases including tuberculoses, meningococcal disease, Clostridium difficile, and methicillin-resistance Staphylococcus aureus.

Given the limited number of suitable alternatives and emerging resistance patterns, wise stewardship of our current antibiotics is essential, though unlikely.  It is not difficult to foresee a rise in mortality from some infectious problems that are easily treated currently.

Related references:

  • -JPGN 2011; 52: 382.  Double-blind, placebo-controlled study of rifaximin in children with RAP.  n=75.  Not effective in this study.
  • -NEJM 2011; 364: 22 (pg 81-editorial). About 10% improvement over placebo in pts with IBS-D. Effects lasted up to 3 months.
  • -DDW 2010, 475 abstract. Target 1 & Target 2. n=623, n=637. Relief of IBS in ~41% vs ~32% placebo. 550mg TID x 14days.

Related blog posts:

FMT -fecal microbiota transplant

An excellent review of FMT, especially in regard to C difficile infection, has been published (Am J Gastroenterol 2013; 108: 177-85)  Thanks to Ben Gold for sharing this reference.

FMT has been around for a long time.  It is first documented in the 4th century as a treatment for food poisoning or severe diarrhea.  Its current application has focused on C difficile infection (CDI), though its use in a number of other settings is being explored.  This includes irritable bowel syndrome and inflammatory bowel disease.

This articles makes several useful points.  In the ‘how to do it’ section, the author notes that at the NIH, donor screening includes screening for pathogens in the stool:

  • Bacteria: C difficile, Listeria monocytogenes, Vibrio cholera, Vibrio parahemoltyicus, H pylori
  • Parasites: Giardia, Cryptosporidium, Isospora (acid fast stain)
  • Viruses: Rotavirus
  • Blood: for Hepatitis A IgM, Hep B (HBsAg, anti-HBc ([gG & IgM]), HIV, Syphilis, HCV

However, the author notes that testing in the community tends to rely on screening only for enteric pathogens (stool tests only).  Donors should be excluded if they have received antibiotics in the preceding 3 months, if they participate in high-risk sexual behaviors, recent tattoo piercing, or recent incarceration.  Additional exclusions: history of IBD, IBS, immunocompromise, morbid obesity, metabolic syndrome, atopy, and chronic fatigue.

Related donors may provide a better long-term outcome.  In a recent review, FMT using a related donor yielded a 93% CDI resolution compared with 84% for unrelated donors.

Nuts and bolts:

  1. Donor is instructed to take a double dose of milk of magnesia at bedtime the night before procedure.
  2. Soft stool is passed into a clean plastic container; preference is for stool to be produced within 8 hour of FMT.  Stool does not need to be frozen or refrigerated (though can be refrigerated).
  3. Saline is added to the stool which is stirred and shaken (some use blenders, some use milk or water as suspending solutions).
  4. Typical amount of stool would be 50 g in 250 cc diluent.  For colonic administration, about 300 cc are administered in cecal region.  For duodenal administration, about 60 cc are administered.
  5. Prior to administration, it is best to filter the mixture through gauze pads to remove particulate matter that would interfere with administration.
  6. Though the author notes that there have been recommendations to prepare stool under a hood as stool is considered a level 2 biohazard, he states that this is not practical and in fact, the stool in this situation is the safest stool that gastroenterologists encounter.
  7. Recipients receive a colon lavage before the procedure regardless of route of FMT administration. If possible, all antibiotics are withheld 3 days prior.
  8. On the morning of administration, the author instructs recipient to take two lopermide tablets.

As positive experience gains in CDI, further efforts in a number of other diseases (>30 listed in Table 1 of article) with altered microbiome will be explored.  Thus far, FMT has been used in autism, fibromyalgia, metabolic syndrome, multiple sclerosis, obesity, and even parkinson’s disease.

Hippocrates stated “All disease begins in the gut.”  Given the diversity of diseases in which FMT is being examined, this sentiment may be close to the truth.

Related blog entries:

UVA Links

My alma mater, the University of Virginia, has a fair amount of useful GI educational material on their website.

Here are a few links:

Low FODMAP Diet

Irritable Bowel Syndrome (IBS) diet

Short Bowel Syndrome Diet (Long Version)

Nutritional Considerations for Patients with Inflammatory Bowel Disease

Fiber (dietary recommendations handout)

Gluten-free Diet

Linaclotide –not for kids

Linaclotide has been approved for adults (≥18 years) with chronic constipation and constipation-predominat irritable bowel syndrome (IBS-C) (Gastroenterol & Hepatol 2012; 8: 653-60).

Linaclotide is a 14-amino acid peptide that stimulates guanylyl cyclase C (GCC) receptors.  It mimics the endogenous peptides guanylin (15 amino acids) and uroguanylin (16 amino acids) which activate GCC through a cascade which activates CFTR to increase luminal levels of bicarbonate, chloride and water.  This in turn improves gastrointestinal transit.

There were several trials undertaken to assess the efficacy of linaclotide in IBS-C:

  • 47 patients (36 women) with IBS-C were treated with linaclotide (100 μg or 1000 μg) or placebo –5 day study. The 1000 μg dose significantly decreased colonic transit time compared with placebo.  No serious adverse events were reported.
  • 420 patients were enrolled in a 12-week, randomized, double-blind, placebo-controlled, dose-ranging study.  The population was 92% female, 80% caucasian with a mean age of 44 years.  337 patients completed the study.  There were improvements in the number of complete spontaneous bowel movements (CSBMs) per week and in abdominal pain.  Additional results:
  1. With 300 μg dose, there were 3.93 CSBMs/week, with150 μg dose 2.79 CSBMs/week compared with 1.47 for placebo.
  2. With 300 μg dose, there was -0.90 in pain score, with 150 μg dose -0.71 compared with -0.49 for placebo.  Overall, abdominal pain improved in 31.1-38.7% of linaclotide-treated patients compared with 22.7% of placebo-treated patients.

For chronic constipation, four trials (n=42, n=310, n=630, and n=642) have shown increased CSBMs/week.  On average, a dose of 290-300 μg dose resulted in 1.8-2.7 CSBMs/week, a dose of 145-150 μg dose resulted in 1.6-2.0 CSBMs/week compared with 0.5-0.6 CSBMs/week for placebo.  Changes in stool frequency were also reflected in quality of life scores.  When linaclotide was stopped, patients reverted to similar stooling rates as placebo-treated patients but no rebound effects were noted.

Prior to approval of linaclotide, lubiprostone (Amitiza) had been the only FDA-approved medication for IBS-C.  For chronic constipation, polyethylene glycol is another approved treatment.

Related blog entries:

Acupuncture for irritable bowel syndrome

No medical therapy has been shown to alter the natural history of irritable bowel syndrome (IBS).  A number of therapies have been used to improve the symptoms.  More data has been published on whether acupuncture is an effective therapy (Am J Gastroenterol 2012; 107: 835-47)

A number of treatment approaches have shown that several medical treatments are more effective than placebo, including soluble fiber, some antispasmotics, peppermint oil, antidepressants, and agents that act on the 5-HT receptor.  In addition, cognitive-behavioral therapy and hypnotherapy seem to be more effective than placebo.  Dietary therapies (see blog links below) are helpful in some patients.  However, many patients have a poor response to all of these approaches.

To examine whether acupuncture may be effective for IBS, the authors of the current study reviewed 1421 citations and identified 17 eligible randomized controlled trials (RCTs) with >1800 patients.  Only trials that used accepted traditional Chinese medicine methods of acupuncture were included.

Key findings:

  • Among the five sham-controlled trials, there was no significant difference detected between true acupuncture and sham acupuncture in terms of effects on symptoms or quality of life.  The standardized mean difference in post-treatment between the groups was -0.11 (difference between two groups) –confidence limits -0.35 to 0.13 for symptom severity and -0.03 for quality of life –confidence limits -0.27 to 0.22.
  • A selected summary on this article in Gastroenterology (2012; 143: 1683-84) notes that the largest RCT in the U.S. found that sham acupuncture and true acupuncture were both superior to a control arm (Am J Gastroenterol 2009; 104: 1489-97).
  • When acupuncture was compared with medical therapies in 5 trials (4 with antispasmodic, 1 with sulfasalazine), acupuncture was more effective, RR=1.28 for symptom improvement.  These studies were non blinded and the overall effect was modest.
  • When acupuncture was added to traditional Chinese medicine in 4 RCTs, the addition of acupuncture improved the endpoints of IBS symptom severity (RR=1.17).

This study should reduce the stress of practitioners of acupuncture.  Whether they apply true acupuncture or sham acupuncture, the results may be equivalent.  In these studies, sham acupuncture did have a high “placebo effect.” At the same time, this study indicates that the comparison medical treatments (most in these RCTs are not used in Western medicine) were less effective than acupuncture.  So where does that leave us?

Related blog entries: