What Happens Four Years After Fecal Microbiota Transplantation?

A recent study (J Jalanka et al. AP&T 2018; 47: 371-9-thanks to Ben Gold for this reference) provide long-term data of fecal microbiota transplantation (FMT).

In this study of 84 adult patients who were treated for C difficile infection, 45 who had received FMT and 39 treated with antibiotics, the authors determined the frequency of adverse sequelae at 3.8 years using a retrospective questionnaire.

Key findings:

  • There were no difference in the development of severe diseases between FMT recipients and control patients (eg. IBD, cancer, autoimmune diseases, allergy, and neurological diseases)
  • There were no differences in weight gain
  • FMT patients reported faster improvements in bowel habits and reported that their mental health improved after treatment
  • FMT patients had fewer symptoms of functional gastrointestinal disorders than the control (antibiotic) patients

The authors note that FMT is frequently recommended based on three recurrences of C difficile infection and that their study would support using FMT earlier as a treatment option.

My take: Though a small study, these data suggest that FMT is effective and without long-term consequences.

Oral Capsules for Fecal Microbiota Transplantation

A recent study (D Kao et al.JAMA. 2017;318(20):1985-1993. doi:10.1001/jama.2017.17077showed that oral stool capsules are as effective as stool delivered via colonoscopy for recurrent C difficile infection (RCDI).  Thanks to Ben Gold for this reference.

Findings  In this noninferiority randomized clinical trial that included 116 adults with RCDI, the proportion without recurrence over 12 weeks was 96.2% after a single treatment in a group treated with oral capsules and in a group treated via colonoscopy, meeting the noninferiority margin of 15%.

My take: This study adds to the literature that oral delivery is effective in fecal microbiota transplantation and that capsules could be a convenient way to deliver.

Bright Angel Trail, Grand Canyon

Does Celiac Disease Increase the Likelihood of Clostridium difficile infections?

Thanks to Mike Hart for the following reference:  Risk of Clostridium difficile in patients with Celiac Disease: A Population-Based Study B Lebwohl et al. AJG 2017; doi:10.1038/ajg.2017.400



Patients with celiac disease are at increased risk for infections such as tuberculosis, influenza, and pneumococcal pneumonia. However, little is known about the incidence of Clostridium difficile infection (CDI) in patients with celiac disease.


We identified patients with celiac disease based on intestinal biopsies submitted to all pathology departments in Sweden over a 39-year period (from July 1969 through February 2008). We compared risk of CDI (based on stratified Cox proportional hazards models) among patients with celiac disease vs. without celiac disease (controls) matched by age, sex, and calendar period.


We identified 28,339 patients with celiac disease and 141,588 controls; neither group had a history of CDI. The incidence of CDI was 56/100,000 person-years among patients with celiac disease and 26/100,000 person-years among controls, yielding an overall hazard ratio (HR) of 2.01 (95% confidence interval (CI), 1.64–2.47; P<0.0001). The risk of CDI was highest in the first 12 months after diagnosis of celiac disease (HR, 5.20; 95% CI, 2.81–9.62; P<0.0001), but remained high, compared to that of controls, 1–5 years after diagnosis (HR, 1.85; 95% CI, 1.22–2.81; P=0.004). Among 493 patients with CDI, antibiotic data were available for 251; there were no significant differences in prior exposures to antibiotics between patients with celiac disease and controls.


In a large population-based cohort study, patients with celiac disease had significantly higher incidence of CDI than controls. This finding is consistent with prior findings of higher rates of other infections in patients with celiac disease, and suggests the possibility of altered gut immunity and/or microbial composition in patients with celiac disease.

Silver Bridge crossing Colorado River. Part of Grand Canyon’s Bright Angel Trail.

Briefly: Notable Recent IBD Publications

Vermeire S et al. Lancet 2017; 389: 266-75.  The “FITZROY ” study examined clinical remission in patients with moderate-to-severe Crohn’s disease treated with filgotinib, a orally administered selective JAK inhibitor.  This agent is 30 times more selective fo rJAK1 over JAK3. This study enrolled 174 patients in a phase II study. Key findings:

  • Among patients naive to anti-TNF agents, clinical remission (based on CDAI <150 at week 10) noted in 47% of filgotinib-treated compared with 23% of placebo group (P=.0077)
  • Among patients naive to anti-TNF agents, clinical response was noted in 67% of filgotinib-treated compared with 44% in the placebo group.

H Singh et al. Gastroenterol 2017; 153: 430-8.  Using the large Manitoba Epidemiology Database with 1.3 million population (2005-2014), the authors found that individuals with IBD had a 4.8 fold increase risk of Clostridium difficile infection.

T-D Kanneganti. NEJM 2017; 377: 694-6. This review examined the NLRP3 Inflammasome.  Neudecker et al (J Exp Med 2017; 214: 1737-52) identified microRNA miR-223 which functions “to suppress the Nlrp3 inflammasone during acute colitis.” Other useful points in this review of basic research:

  • “The majority of the immune cells in the body are located in the intestine, where they are spatially separated from more than 10 trillion microorganisms by a layer of mucus and a layer of epithelial cells.  Deterioration of this physical barrier …underlies inflammatory bowel disease.”
  • miR-223 is increased in the inflamed colon. “During inflammation, the expression of miR-223 is also upregulated..and the molecule binds to its complementary sequence in a regulatory part of Nlrp3 mRNA…lead[ing] to decreased Nlrp3 expression and the consequent dampening of interleukin-1β maturation and associated inflammation.”

Clostridium difficile Risk Factors in Children

From J Pediatr -full text: Risk Factors for Community-Associated Clostridium difficile Infection in Children  (DJ Adams J Pediatr 2017; 186: 105-9)

Methods: We performed a case-control study using billing records from the US military health system database

Results (from abstract):

A total of 1331 children with CA-CDI were identified and 3993 controls were matched successfully. Recent exposure to fluoroquinolones, clindamycin (OR 73.00; 95% CI 13.85-384.68), third-generation cephalosporins (OR 16.32; 95% CI 9.11-29.26), proton pump inhibitors (OR 8.17; 95% CI 2.35-28.38), and to multiple classes of antibiotics, each was associated strongly the subsequent diagnosis of CA-CDI. Recent exposure to outpatient healthcare clinics (OR 1.35; 95% CI 1.31-1.39) or to a family member with CDI also was associated with CA-CDI.

Table 2 lists other medications and their risks; for example, corticosteroids had adjusted OR of 1.22 and H2-receptor antagonists had adjusted OR of 3.33.  The OR of fluoroquinolone could not be calculated as 51 cases were exposed compared with 0 controls

In their discussion, the authors note the following:

Our study supports the occurrence of CDI among a population of children who were never hospitalized previously and provides a broad characterization of the medication and epidemiologic exposures associated with pediatric CA-CDI cases. Recent exposure to fluoroquinolones, clindamycin, third-generation cephalosporins, and to multiple classes of antibiotics was associated strongly with the subsequent diagnosis of CA-CDI in children; however, a sizeable minority had no preceding antibiotic exposure.

My take: This large study shows that CDI is more frequent after antibiotic usage and after usage of acid suppression (particularly with proton pump inhibitor) therapy.

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One Way Fecal Microbiota Transplant May Work: Changing Bile Acids

Breifly Noted:

From MedPage Today: Fecal transplant success may depend on bile acid metabolism

An excerpt:

the transplants change patterns of bile acid metabolism in the gut, making the environment inhospitable to C. diff colonization.

In three studies reported at Digestive Disease Week (DDW) 2017, it was demonstrated that individuals with C. diff who respond to fecal transplant showed a different pattern of microbiota species composition compared with baseline and/or with those who fail to respond. But that’s not all: the responders also showed distinct, altered profiles of those elements involved in bile acid metabolism.

Vincent Van Gogh; Hopital Saint-Paul (1889)


Another Shady Pharmaceutical Business Practice: Citizen’s Pathway to Delay Competition

First, a comment regarding yesterday’s post: The Truth About Probiotics: Constipation Version

Some readers took issue with my pessimism with probiotics in terms of their effectiveness for several conditions, their safety and the number needed to treat (NNT). It is noted that the number needed to treat (NNT) with probiotics is better than with many other conditions.  For example, the NNT for benefit with the influenza vaccine, Tamiflu for influenza, and mammography for preventing breast cancer are much worse than the NNT for benefit with probiotics for conditions like NEC, antibiotic-associated diarrhea, Clostridium difficile infection, and ulcerative colitis (with VSL#3). If one looks at multiple posts from this blog, there are plenty of posts supporting the use of probiotics (see some of the links yesterday or search “probiotics” on this blog.  Thus, it is important to not overlook the benefits of probiotics for many conditions and to not take a single study and extrapolate too much.

Now for today’s post -perhaps it will stir as much interest:

I must admit I’m fascinated with the way pharmaceutical companies operate and the creative ways they find to magnify their profits.  In previous posts, I’ve detailed how pharmaceutical companies will try to corner the generic market, increase the cost of liquid medicines, and package drugs in a way to force the purchase of additional vials of medicine among other tactics.  Now, a commentary (R Feldman, C Wang. NEJM 2017; 376: 1499-1501) details how pharmaceutical companies have increasingly used “the citizen-petition process that the Food and Drug Administration (FDA) implemented in the 1970s.”  This process was designed as “a way to voice concerns” by individual citizens.

Yet, this pathway is now being used to delay competition/entrance of generic drugs, mainly with frivolous claims.  In most cases, companies file these claims at the end of the approval process, almost always as a delaying tactic.  Approximately 80% of these actions by competitor drug companies are denied by the FDA.

Ultimately, these actions could be countered with antitrust actions; this, in fact, has occurred with Shire ViroPharma.  On February 7, 2017, the Federal Trade Commission filed an antitrust action “alleging that the company abused regulatory processes by filing 43 submissions with the FDA (including 24 meritless citizen-petition filings within one docket) in an effort to hold off generic competition for its gastrointestinal drug Vancocin (vancomycin).”  However, antitrust actions are typically difficult to pursue and expensive.

My take: I think these tactics (and others) will undermine the relationship of pharmaceutical companies with consumers. While their stock holders may see benefits in the short term, I expect that other stake holders will fight back.  There are several targets in that endeavor, including ending limits on Medicare negotiating for better prices.

Related blog posts: