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)

 

Fecal Transplantation: “Frozen is as Good as Fresh”

Besides pointing out that someone could make $13,000 per year selling their stool, a recent Washington Post story summarized a JAMA study (JAMA. 2016;315(2):142-149. doi:10.1001/jama.2015.18098) which indicated that frozen stool works as well as fresh stool in treating Clostridium difficile infection.

In this study:

Design: Randomized, double-blind, noninferiority trial enrolling 232 adults with recurrent or refractory CDI, conducted between July 2012 and September 2014 at 6 academic medical centers in Canada.

Key finding: In the per-protocol population, the proportion of patients with clinical resolution was 83.5% for the frozen FMT group and 85.1% for the fresh FMT group

Washington Post Summary In fecal matter transplants, frozen is as good as fresh

Here’s an excerpt:

The new study, led by McMaster University’s Christine H. Lee and published Tuesday in JAMA, found that patients given donations that had been frozen for up to 30 days fared just as well as those given fresh samples…

Lee and her colleagues administered one or two FMT enemas to 178 patients, splitting them into two groups to compare freshly-harvested samples and ones that had been frozen and defrosted. Thirteen weeks later, 85 percent of the fresh patients were diarrhea-free. In the frozen group, the success rate reached 83.5 percent – a margin that allows Lee and her team to dub the treatment “noninferior.”

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Bryce Canyon

Bryce Canyon.  This is where I was told to beware of ‘poison rock’ —  one drop can kill you

Nutrition Symposium Georgia AAP (Part 2)

Last week I summarized an excellent talk by Ronald Kleinman.  For me, I had never heard such a concise and definitive rebuttal of the claims of those fearful of food biotechnology.  There were three other lectures at the symposium.  These three lectures covered areas that are well-known to pediatric gastroenterologists but less familiar to general pediatricians.  The full set of slides are available at the Georgia AAP Symposium Website.

Jeff Lewis had an excellent lecture that tied together gluten and our microbiome: Gluten – Eat not, suffer not and Microbiome 101: Waste Not, Want Not

After reviewing celiac disease and other wheat-related disorders (eg. wheat intolerance syndrome, and wheat allergy), he summarized a great deal of information regarding the human microbiome and which factors influence this. In addition, he had the opportunity to briefly present data from his research on fecal microbiota transplantation (for C diff) and its influence on the microbiome over time. Here are a couple of slides from his talk:

 

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Key points:

  • “It is hard to communicate science to families. It is a huge challenge for us.”
  • Dermatitis herpetiformis (rare in kids), a rash associated with celiac disease, can be treated with Dapsone. This rash has caused such severe itching that there are cases of suicide that have been reported.
  • For celiac disease, Dr. Lewis recommends testing of 1st degree relatives but this needs to be after gluten exposure and before gluten-free diet.
  • Wheat allergy reviewed. Skin test positivity does not prove that you are allergic to food. IgG based testing is worthless –it means you have been exposed to a food, but is not an indication of food allergy.
  • Nonceliac gluten sensitivity (aka. wheat intolerance syndrome): need to test for celiac first. No tests/biomarker that can confirm this diagnostic. This appears to be a true disease; there is a small subset of patients who develop symptoms with a double-blind challenge.
  • Microbiome –more bacterial DNA in us than human DNA. New organisms –archaea kingdom.  Now a specimen of a person’s microbiome can be run for <$50.
  • Microbiome terms: Richness, Diversity, and Dysbiosis. Many diseases are associated with dysbiosis (obesity, IBD), but there is a ‘chicken and the egg’ problem. Is dysbiosis a causal factor or a secondary factor?
  • Xyloglucans (in lettuce) –not broken down by humans and affected by gut bacteria.
  • Mice given stool from fat mice or fat person become heavy.

Rejected! Most Stool is Not Good Enough for FMT

I found a recent study (Paramsothy S. Inflamm Bowel Dis 2015; 21: 1600-06) interesting in that it shows how few individuals would qualify as long-term stool donors for fecal microbiata transplantation (FMT).  In previous discussions with colleagues, I’ve thought that getting paid to donate stool would be a pretty sweet deal.

In this study, the authors examined 116 potential donors.  The donor screening protocols and donor inclusion/exclusion criteria were similar to many others (outlined in their Tables 1, 2 and 3 & noted in previous gutsandgrowth blog post on FMT). What the researchers found is that 47 prospective donors declined to participate after learning the requirements and only 12 of the remaining 69 (17%) remained eligible after concluding screening; this represents only 10% of the initial cohort.  A large proportion of healthy asymptomatic donors failed stool testing –40% of those tested. The next most common reasons for rejection were medication comorbidities (n=13) or risk factors for Creutzfeldt-Jakob disease (n=6).

Bottomline: Now, I realize how these stool donors should be justifiably proud of their carefully-balanced uncontaminated microbiome.  The difficulty in identifying suitable donors further reinforces the value of human stool banks.

Briefly noted:

Vandenplas Y, et al. “Fecal Microbiota Transplantation: Just a Fancy Trend? JPGN 2015; 61: 4-7.  Brief overview which includes screening protocol used in Brussels.  One of the recommendations is to conserve a sample of the donated stool for >30 years.

Related blog posts:

Disclaimer: These blog posts are for educational purposes only. Specific dosing of medications/diets (along with potential adverse effects) should be confirmed by prescribing physician/nutritionist.  This content is not a substitute for medical advice, diagnosis or treatment provided by a qualified healthcare provider. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a condition.

Cumberland Island

Cumberland Island -Main Road

Keeping Up with Clostridium Difficile

It is difficult to keep up with all of the relevant publications regarding Clostridium difficile–there are so many.  This likely reflects its emergence as a frequent and important pathogen.

Recent references:

  1. Sandberg KC et al. “Disproportionate Rise in Clostridium difficile Associated Hospitalizations Among US Youth with Inflammatory Bowel Disease, 19978-2011.” JPGN 2015; 60: 486-92 (editorial 421-22).
  2. Leffler DA, Lamont JT. NEJM 2015; 372: 1539-48.

In the first study, the researchers note that there has been a 5-fold increase in inflammatory bowel disease (IBD) hospitalizations with concomitant Clostridium difficile infection (CDI).  Whereas, the hospitalization without CDI increased 2-fold.  Associated with this 5-fold increase in hospitalizations, there were increased costs and longer length of stays.  Interestingly, IBD patients with CDI had a  lower likelihood (OR 0.31) of colectomy in this study. This epidemiology yields more questions than answers.  Certainly, a significant fraction of this increase is due to the use of more sensitive PCR-based assay. In addition, many of these patients may not be symptomatic due to CDI; it can be difficult to determine if IBD symptoms are due to IBD or due to CDI. Even treatment with antibiotics like vancomycin does not fully differentiate as the response could be nonspecific.

In the second review, severe useful points were made.

Risk factors:

  • Antibiotics –this remains most important risk factor
  • Older age (especially if >65 years)
  • Possible acid suppression -not confirmed in some studies when adjusting for coexisting conditions
  • Inflammatory bowel disease
  • Immunosuppression
  • Chronic kidney disease

Diagnosis:

  • Use of DNA assays has allowed for detection of “low levels of toxigenic organisms of uncertain clinical significance.”  Thus, these assays may detect clinically-insignificant infections.
  • Endoscopy is rarely needed, but sometimes helpful in ovelapping conditions like coexistent CDI from IBD
  • Negative PCR assay has a negative predictive value of “more than 95% in average-risk groups.”
  • Testing and treating persons with solid stools is not recommended

Prevention:

  • Probiotics “have an uncertain effect on the prevention of C difficile infection, and their routine use for the prevention or treatment of active infection is not recommended.”  The authors note that initial favorable studies of antibiotic-associated diarrhea were underpowered and that more recent studies have shown mixed results.  In studies of patients with unusually high rates of CDI, probiotics were shown to confer benefit.

Treatment:

  • Metronidazole and vancomycin remain 1st line treatments.
  • Fidaxomicin use has been limited due to expense, but has been shown to reduce recurrence of CDI in those who do not have the b1/NAP1/027 strain.
  • Alternative antimicrobials, including rifaximin, nitazoxanide and others, are “not recommended except in cases of unacceptable adverse effects.”
  • For recurrent infection, 1st line approach is retreatment with either metronidazole & vancomycin. Second recurrences are often treated with fidaxomicin or tapered vancomycin course.
  • Fecal microbial transplantation –noted to be highly effective and safe as salvage therapy. The precise components that are important are uncertain; however, “the phyla Bactteroidetes and Firmicutes are thought to comprise critical components.”  “More work is neede to understand the possible role for fecal microbial transplantation for primary CDI”

Bottomline: CDI remains an important pathogen and significantly complicates the management of IBD.

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No Habla Appendicitis

Before today’s blog, I wanted to state that our physicians now can treat Clostridium difficile with fecal microbiota transplant (would have been more relevant to yesterday’s blog: “Gut Microbiome”) :

GI Care for Kids is one of the few places in the region to offer this capability for children (thanks to Jeff Lewis for working to navigate the logistics/regulatory burdens).

Today’s blog: Though physicians make efforts to combat language barriers with translators, the personal connection between physicians and patients is undoubtedly weakened in those with limited English proficiency LEP).  Recently, one of my emergency room colleagues explained that he had ordered a CT scan on a young man in part due to his hispanic ethnicity and concern that this would lead him to overlook a diagnosis of appendicitis.  According to a recent study, my emergency room colleague was right –hispanic ethnicity and language barriers increased the risk for appendiceal perforation (J Pediatr 2014; 164: 1286-91).

The researchers performed a secondary analysis of a prospective, cross-sectional, multi center study of children aged 3-18 years who presented with abdominal pain/possible appendicitis (2009-2010) at 10 tertiary care pediatric emergency departments in the U.S.

Results:

  • Of the 2590 patients enrolled, 1001 (38%) had appendicitis.
  • Hispanics with LEP had an odds ratio of 1.44 of having appendiceal perforation.  In addition, these patients were less likely to undergo advanced imaging (OR 0.64)

Bottomline: Patients/families who speak English are more likely to communicate the severity of their medical problem.  Those with limited English proficiency are at increased risk for complications and this extends beyond perforation with appendicitis.

Related blog postHow much radiation from your CT scanner? | gutsandgrowth

CCFA Conference Notes 2014 (part 2)

Yesterday’s notes highlighted the most useful discussion at this year’s meeting regarding mucosal healing (MH) in inflammatory bowel disease.

Many points were intriguing but often at odds. For example, the speakers noted that symptoms and scoring systems like CDAI are unreliable in establishing remission.  It was noted that the FDA is mandating more objective measures (like endoscopic improvement) in future studies. Yet, the studies cited for their arguments often were derived from studies which did not use objective endpoints. Similarly, some of the arguments were based on small studies and yet experts often caution to use evidence-based medicine.

Bo Shen (Cleveland Clinic) “Surgerical Options in IBD”

  • 50-71% of CD patients require some type of surgery within 10 years of diagnosis
  • End-ileostomy may be a cure for some CD patients,  For UC, end-ileostomy 98% are cured.  2% develop enteritis.
  • Can use infliximab after surgery.  Immune system different after surgery and may work even
  • ‘Don’t operate until a CD patient develops a complication. But, don’t wait until further complications develop.’

Different type strictures –web-like strictures are suitable for dilatation, others are more difficult: spindle-like (longer) , ulcerated stricture, and anastomotic.

  • Classification: Gast Endosc 2013; 78: 8181-35.
  • Etiology: primary, secondary (anastomotic), benign, malignant
  • Short-long: Length (<4cm) if dilating
  • Degree: high-grade, low-grade
  • Number: single, multiple
  • Associated conditions: abscess, others

Determining resection margin –does not depends on absence of histologic activity (Ann Surg 1996; 224: 563-71).  Try to save as much bowel as possible, often based on how thick bowel is rather than histologic margins.

Save the gut –stricturoplasty.  1st surgery –usually is a resection rather than stricture plasty.  Heineke-Mikulicz (most common) <10 cm for short , Finney for strictures 10-20 cm, Michelassi >20 cm (sid-to-side isoperistaltic). (Dis Colon Rectum 2007) Stricturoplasty –best for mid small bowel, minimum inflammation, no fistula

Fistula –Hollow-organ to hollow-organ fistula –treat surgically. Whereas if fistula is perianal, start with medical treatment. Perianal fistulas often treated with seton; seton often kept in place for a long time (“forever if not bothering patient”).

Abscess—avoid surgical drainage if possible.  Delineate anatomy and consider elective surgery later.  If less than 3 cm, could aspirate and not leave in drain. If >3 cm, start with interventional radiology

Post-op management –Ruttgerts score.  Rescope 6 months post-op to determine if needs more aggressive treatment.

UC Surgery: issues: preoperative biologics, 2- or 3-stage operations, what type of pouch

  • There may be increased risk with biologics (studies have not shown this consistently) –depends on type of surgery.  If very sick, use 3-stage rather than 2-stage operation.  Don’t do pouch at time of 1st operation if very sick DCR 2013; 56: 1243-52).
  • J-pouch now standard.  Kock pouch –catheterize pouch/no ostomy.  S-pouch –problemswith mechanical obstruction.
  • Even with mucosectomy (vs. stapler/no mucosectomy)–can still develop cuffitis and malignancy.  Mucosectomy may increase risk of incontinence.

Edward Loftus (Mayo Clinic) “Optimizing Biologic Therapy: Maximizing Benefit and Minimizing Risk”

Is azathioprine an effective drug? Should we be using biologics sooner?

Key points:

  • ACT1 and ACT2 were pivotal studies for infliximab approval for UC.  1/3rd chance of going into full remission, 1/3rd chance of response, 1/3rd chance of not responding.  Infliximab lowers risk of colectomy.  Favorable studies of other anti-TNFs as well: adalimumab (Gastroenterol 2012; 142: 257-65) and golimumab (Gastroenterol 2014; 46: 85-95 & 96-109). No head-to-head anti-TNF trials.
  • Crohn disease:  5-ASA products don’t work for Crohn disease.  Reviewed pivotal trials of anti-TNF agents (infliximab, adalimumab, certolizumab)-30% in remission.
  • Natalizumab (anti-alpha 4 integrin) for refractory disease was discussed (NEJM 2005; 353: 1912-25).  Takes longer to work then anti-TNFs but maintenance data look good. PML risk: 395 cases among 118,100 patients treated as of August 2013.  Lots of paperwork and physicians have to be certified.  If you are JC virus serology is negative, “your risk is about 1 in one million in the next year. If you are positive, about a 1% risk in the following year.”
  • Azathioprine (AZA) not very effective (Gastroenterol 2013; 145: 766-74 & 758-65).  Prospective double-blind Spanish study (n=131) –no statitistical benefit.  2nd reference is French study. N=132. No significant difference at 36 months in patients with added AZA.  In U.S., most “thought leaders” going straight to anti-TNFs.
  • Combination therapy works best in adults (SONIC study for Crohn disease, UC Success for UC).  UC Success only studied 16 weeks, no maintenance therapy trial.  However, methotrexate (MTX) with anti-TNFs combination has not been proven to be effective (Gastroenterol 2014; 146: 681-8).  Reason this was a negative study, per lead author, may have been related to steroid use.

Other pointers:

  • Don’t rely on symptoms alone.  Symptoms/CDAI do not correlate with CDEIS (endoscopic improvement).  FDA mandating all future trials have an endoscopic endpoint and not rely on use of CDAI alone. Other factors cause symptoms including IBS, infections, and bacterial overgrowth. Take-home point: Need to look (endoscopy) if someone is not doing well.
  • In the SONIC trial –if there was inflammation on endoscopy, there was an impressive 30% delta in response to treatment (with combination therapy compared with AZA monotherapy). Whereas if you have no lesions, combination therapy no more effective than either monotherapy agent.  Patients whose complaints are due to irritable bowel rather than inflammation do not respond well to treatment.
  • OLD paradigm –treat based on symptoms.  NEW paradigm–treat based on biologic/radiographic markers or endoscopic findings.  “Treat to target” has been approach used by Dr. Sandborn. Target mucosal healing and then assess mucosal healing every 6 months until target achieved, then less frequently.  Yet mucosal healing cannot be achieved in many/most patients.
  • Therapeutic drug monitoring.  For example, 6-TGN >235 associated with better response to AZA (OR 5.0)
  • Pharmacokinetics of anti-TNFs: lower clearance if concomitant use of immunomodulators, increased clearance if high CRP, higher BMI
  • New drugs: Ustekinumab –three phase 3 trials underway.  Should be available in about 2 yrs for Crohn disease. Vedolizumab –under FDA review (NEJM 2013; 369: 699-710).  Infusion (similar to remicade frequency). Blocks lymphocyte homing in the gut. UC data much more robust than with CD, but probably will be approved for both.  Rate of adverse events were low. Etrolizumab—similar to Vedolizumab, but SC administered. Currently, this drug is in phase 2 studies.

Eva Szigethy (Pittsburgh Pediatrics) “Psychological evaluation and assessment in IBD”

Key points:

  • Anxiety/depression ~25-40% of pediatric IBD.  Occurs in both active and inactive disease.
  • IBD effects on brain: inflammation, drugs (steroids, biologics)–both have direct effects on brain.
  • 15% of kids and 25% of adults are having thoughts of death on screening tools. Pain is frequent trigger for suicidal thoughts.
  • Simple depression screen: Mood, Energy, Sleep, Suicide/Self-esteem, Anhedonia (lack of pleaure), Guilt, Eating (change in appetite)
  • We should not ignore adjustment disorders.  We may be able to prevent a full-blown psychiatric disorder.  Each time we let problems like anxiety or depression go untreated, this can leave long-term changes in brain.
  • Anxiety screen: Tense, Tired, Recurrent worries/fear, Restless, Avoidance, Poor sleep/nightmares, Poor concentration
  • Important to look at patient perspective of their disease: identity (what they see as their symptoms), cause/etiology, timeline (how long the patient believes that the illness will last), consequences, cure/control.
  • Catastrophizing –more persistent pain and increased visceral hyperalgesia.  Abnormal brain activation. Poor coping drives development of depression and anxiety.
  • With adult IBD, 20% of patients consume up to 80% of medical costs.  Chronic pain and depression are key factors (Binion et al 2010).
  • Management of anxiety/depression: Cognitive Behavioral therapy –changing behaviors and thinking, problem-solving. ACT –activities, calm (relaxation, guided imagery, hypnosis), think positive (cognitive reframing). Antidepressants: TCA, SSRI, SNRI.  SSRI/SNRI –few side effects or drug interactions.  Overdose risk is highest with TCA (but typically using low doses of these agents).  No pediatric studies in IBD and only small studies in adults. If inactive IBD, SSRI often 1st line. If active IBD, Bupropion often used as 1st line.
  • For anxiety, most likely use SSRI if comorbid anxiety
  • For pain, most likely use SNRI  or low dose TCA
  • Opiates are problematic due to psychological/physical dependence, increased mortality/infection risk, narcotic bowel
  • Sleep –don’t go to bed if not tired, aim for consistency, if not asleep in 20 minutes, then do something else.  1st line pharmacology: consider antihistamines or melatonin.

Sachin Kunde (Michigan State University, Helen DeVos Children’s Hospital) “FMT for IBD”

Key points:

  • Microbial diversity altered in IBD –can we modulate dysbiosis to treat IBD?
  • Issues with cause and effect.  Is dysbiosis due to IBD or causing IBD.
  • FMT –“the ultimate probiotic.” Application of FMT.  For recurrent C difficile, cure rate nearly 90% –?better with lower GI route. For any indication besides C difficile infection (CDI), can only be given through clinical trials (FDA IND).  Currently 9 ongoing trials for IBD (1 pediatric, 3 in U.S).

FMT in IBD: Studies:

  1. -Anderson et al.  Aliment Phar Ther 2012: 13/18 without CDI had some resolution of IBD symptoms.
  2. -Kunde et al JPGN 2013: n=10. PUCAI decrease by 15 indicated response found in 78% (7/9) at 1 week, and 67% (6/9) at 1 month, 3 (33%) went into remission.
  3. -Kump et al IBD 2013: n=6. FMT for UC was not effective.  Transient improvement in 2/6 patients, 1/6 improved on Mayo sub score.

Bottomline for FMT & IBD: More questions than answers: efficacy, route of administration, # of infusions needed, fresh vs. frozen, adverse effects, best donor, etc.

For today’s post today and yesterday’s post, I may have made some transcription errors and these notes were not reviewed with the speakers.  Also, due to brevity, some useful information was not included.  Thus, the disclaimer with these posts is particularly important.

Disclaimer: These blog posts are for educational purposes only. Specific dosing of medications (along with potential adverse effects) should be confirmed by prescribing physician.  This content is not a substitute for medical advice, diagnosis or treatment provided by a qualified healthcare provider. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a condition.

Related blog posts: