Does Irritable Bowel Syndrome Occur More Commonly in the Setting of Endometriosis?

According to a recent study (AD DiVasta et al. Clin Gastroenterol Hepatol 2021; 19: 528-537. Overlap Between Irritable Bowel Syndrome Diagnosis and Endometriosis in Adolescents), adolescents with surgically-confirmed endometriosis are at increased risk for irritable bowel syndrome.

This study derived data from a longitudinal cohort; the sample for this study followed women with and without endometriosis who completed extensive surveys (n=323) and excluded women with celiac disease or inflammatory bowel disease. Cases of IBS were based on patient reports of Rome IV criteria, though 81% were confirmed via medical record review.

Key findings:

  • “More adolescents with endometriosis (54 of 224; 24%) had comorbid IBS compared with adolescents without endometriosis (7 of 99; 7.1%). The odds of IBS was 5.26-fold higher among participants with endometriosis than without (95% CI, 2.13–13.0).”
  • “For participants with endometriosis, each 1-point increase in acyclic pain severity increased the odds of IBS by 31% (adjusted odds ratio, 1.31; 95% CI, 1.18–1.47).”

The association of endometriosis with IBS was based on Rome IV criteria, as such, the authors assert that this is “not merely a diagnostic bias” However, some of the increase may be related to referral patterns.

Useful points:

  • “In the adult literature, pain in the pelvis, menstrual-related symptoms, symptoms related to sexual intercourse, ovarian cysts, and subfertility seem to distinguish women with endometriosis from other GI conditions.”
  • “Chronic pain syndromes were more prevalent in girls with endometriosis and IBS. Rates of migraine headaches, sleep disturbance, and urinary symptoms were higher…[and] had higher prevalence rates of mood disturbance.”

Why is there overlap between these disorders?

  • The authors speculate that “the inflammatory process likely plays a role…and central pain sensitization may play a crucial role in the two diseases”

My take: Adolescents with endometriosis have a higher likelihood of IBS. Acyclic pain is a strong predictor of IBS.

Related blog posts:

Related humor: YouTube Link: SNL IBS Ad (4/10/21) Very funny!

FMT Research & The Shawshank Redemption

In The Shawshank Redemption, Andy Dufresne (Tim Robbins) manages to escape prison by crawling through 500 yards of a filthy sewage pipe. It seems like a similar effort will be needed to find out how to benefit from fecal transplantation when given for problems like irritable bowel syndrome and metabolic disease/obesity. Some recent studies and associated editorials are noted below.

T Holvoet et al. Gastroenterol 2021; 160: 145-157. Fecal Microbiota Transplantation Reduces Symptoms in Some Patients With Irritable Bowel Syndrome With Predominant Abdominal Bloating: Short- and Long-term Results From a Placebo-Controlled Randomized Trial

  • Key finding: At week 12, 56% of patients given donor stool reported improvement in both primary endpoints compared with 26% of patients given placebo (P = .03).
  • Commentary: PW O’Toole, F Flanahan. Gastroenterol 2021; 160: 15-17. Full Text: Transplanting Microbes for Irritable Bowels or Irritated Microbes or Both?
    • This editorial stresses that trials of FMT in IBS have had inconsistent results and risks are unclear. “How many clinicians inform patients receiving FMT that the donor microbiota might include components that increase (or decrease) one’s risk of colorectal cancer?” Part of the problem is “due, in part, because a normal microbiome has not been defined.”

E Rinott et al. Gastroenterol 2021; 160: 158-173. Full text Effects of Diet-Modulated Autologous Fecal Microbiota Transplantation on Weight Regain

Key findings:

  • In this randomized controlled trial with 90 participants, autologous FMT (aFMT) significantly attenuated weight regain in the green-Mediterranean group (aFMT, 17.1%, vs placebo, 50%; P = .02) and improved insulin resistance: insulin rebound (aFMT, –1.46 ± 3.6 μIU/mL vs placebo, 1.64 ± 4.7 μIU/mL; P = .04) (Graphical abstract below)
  • In mice, Mankai-modulated aFMT in the weight-loss phase compared with control diet aFMT, significantly prevented weight regain and resulted in better glucose tolerance during a high-fat diet–induced regain phase (all, P < .05).

Commentary: M Nieurdorp, K Madsen. Gastroenterol 2021; 160: 17-19. Full text The Promise of Maintaining Diet-Induced Weight Loss by Swallowing One’s Own Feces: Time to Provide a Do-It-Yourself Manual?

  • “These findings add support to the current body of evidence that the gut microbiota have a role in weight gain and metabolism. However, many questions remain. Indeed, although studies have shown varying degrees of effectiveness of FMT in the improvement of metabolic parameters in human participants, there has been no evidence yet that FMT can induce weight loss in obese patients.”
  • “The finding that maintenance of weight loss was only seen in the one dietary group consuming the Mediterranean diet plus green tea and Mankai supplement who received autologous FMT, would suggest that specific microbial profiles may be involved and that weight loss per se may not result in the required microbial profiles.”
Figure 1 from editorial: Challenges associated with the use of fecal microbial transplantation (FMT) as treatment

My take: Both of these studies show that modulation of the fecal microbiome may be helpful under the right set of circumstances to help with both irritable bowel syndrome and metabolic syndrome. However, ‘hundreds of yards’ of more research is needed to determine if this is really feasible and to assure that the benefits outweigh the potential risks.

Related blog posts:

Mechanisms of Postinfectious Irritable Bowel Syndrome & Functional Disorders

Aguilera-Lizarraga, J., Florens, M.V., Viola, M.F. et al. Local immune response to food antigens drives meal-induced abdominal painNature (2021). https://doi.org/10.1038/s41586-020-03118-2 (Thanks to Ben Gold’s twitter feed for this reference)

Background: “Up to 20% of people worldwide develop gastrointestinal symptoms following a meal, leading to decreased quality of life, substantial morbidity and high medical costs”

“Here we show that a bacterial infection and bacterial toxins can trigger an immune response that leads to the production of dietary-antigen-specific IgE antibodies in mice, which are limited to the intestine. Following subsequent oral ingestion of the respective dietary antigen, an IgE- and mast-cell-dependent mechanism induced increased visceral pain. This aberrant pain signaling resulted from histamine receptor H1-mediated sensitization of visceral afferents. Moreover, injection of food antigens (gluten, wheat, soy and milk) into the rectosigmoid mucosa of patients with irritable bowel syndrome induced local oedema and mast cell activation.”

My take: This study shows how innocuous food can trigger pain after an intestinal infection.

Related blog posts:

Potential Efficacy of Ondansetron for Irritable Bowel -More Studies Needed

A recent correspondence letter (CJ Black, AC Ford. AJG 2020; doi: 10.14309/ajg.0000000000000932. Full text: Efficacy of Ondansetron for Irritable Bowel Syndrome With Diarrhea) shows that ondansetron could be an effective option for irritable bowel syndrome with diarrhea. Thanks to Ben Gold for this reference.

IB-Stim (Neuro-Stim) for Adolescents with Irritable Bowel

A recent study (A Krasaelap et al. Clin Gastroenterol Hepatol 2020; 18: 1987-1994.  Efficacy of Auricular Neurostimulation in Adolescents With Irritable Bowel Syndrome in a Randomized, Double-Blind Trial) with data from a double-blind trial provides evidence of short-term (4 week) efficacy of auricular neurostimulation therapy (aka. IB-Stim or Neuro-Stim).

Key findings:

  • The IB-Stim group (n=27, median age 15 years) had a ≥30% reduction in abdominal pain in 59% compared to 26% of the sham group (n=23)
  • A symptom response scale score of 2 or more was observed in 82% of patients who received IB-Stim vs 26% of patients in the sham group ( P ≤ .001)

Discussion points:

  • The authors indicate that the NNT for IB-Stim is 3 compared to 6-14 for other medical therapies (lubiprostone, linaclotide, and rifaximin)
  • The effects of IB-Stim were NOT sustained at follow-up 8-12 weeks and there was no significant improvment in functional disability or anxiety.  “The lack of long-term effect…likely reflects insufficient statistical power.”  The authors indicate that longer or repeated courses could be needed

My take: This study indicates that IB-Stim can be helpful, at least in the short term, for adolescents with IBS.  More studies showing long-term benefit would be helpful.

Related blog posts:

Myth or Fact: Joint Hypermobility is Related to Pediatric Functional Abdominal Pain & Dr. Roy Link

According to a recent study (RJ Shulman et al. J Pediatri 2020; 222: 134-40), the prevalence of joint hypermobility does NOT differ in children with irritable bowel syndrome, functional abdominal pain, or healthy control children.

Methods (to reach this conclusion):

  • Children (median age ~9.5 years) with irritable bowel syndrome (n=109), functional abdominal pain (n=31), and healthy controls (n=69) completed a prospective 2-week pain and stooling diaries.  In addition, children and parents reported on measures of anxiety, depression, and somatization. Children were recruited from both primary care and tertiary care settings
  • Joint hypermobility was determined using Beighton criteria using a goniometer and examined cutoffs at both ≥4 or ≥6).

Key findings:

  • Beighton scores were similar between the groups, as was the proportion with joint hypermobility.  Beighton scores were not related to abdominal pain or stooling characteristics.
  • Beighton score ≥4: IBS 35%, FAP 36%, healthy controls 36%.
  • Beighton score ≥6: IBS 12%, FAP 13%, healthy controls 9%.
  • Children reported depression more frequently in those with Beighton scores ≥6 and somatization was greater in those with a score ≥4.

Discussion:

  • “It is well-recognized that patients with joint hypermobility syndromes (eg, Ehlers-Danlos syndrome, Marfan) commonly have GI symptoms.” However, joint hypermobility is common —in this study’s healthy control group 36% had a score ≥4 and 9% had a score ≥6.
  • This study is in agreement with a school-based study (n=136) (M Saps et al. JPGN 2018; 66: 387-90).
  • Limitations: This study population had a median age of ~9.5 years; thus, these findings need to be determined in an older children

My take: There does not appear to be an increased risk of functional GI disorders in children with joint hypermobility. Thus, looking for joint laxity/hypermobility in children with abdominal pain is not needed.

Related blog posts:

Also, a link to Dr. Roy (Benaroch).  Roy is an Atlanta pediatrician and he explains, with the help of Batman and Luigi, the term ‘index’ case and when one is considered exposed: Dr. Roy Covid Pathway

AGA Practice Guidelines: Probiotics NOT Helpful for Most GI Conditions

Here is a link to the EPUB draft of AGA clinical report (G Su et al. Gastroenterology DOI: https://doi.org/10.1053/j.gastro.2020.05.059): AGA Clinical Practice Guidelines on the Role of Probiotics in the Management of Gastrointestinal Disorders

Here is a link to the pre-draft technical review by GA Preidis et al. Gastroenterology DOI: https://doi.org/10.1053/j.gastro.2020.05.060 AGA Technical Review on the Role of Probiotics in the Management of Gastrointestinal Disorders

  • The report recommends NOT using probiotics outside of clinical trials for irritable bowel syndrome, Clostridium difficile infection treatment, Crohn’s disease, and gastroenteritis.
  • It recommends a specific probiotic for pouchitis and for prevention of necrotizing enterocolitis in preterm infants <37 weeks and 3 probiotics for patients who are receiving antibiotics (to prevent Clostridium difficile infection)

CNN summary: Probiotics don’t do much for most people’s gut health despite the hype, review finds

“While our guideline does highlight a few use cases for probiotics, it more importantly underscores that the public’s assumptions about the benefits of probiotics are not well-founded,” said Dr. Grace L. Su, a professor of medicine and chief of gastroenterology at the University of Michigan, Ann Arbor, in a news statement. She was the chair of the panel that issued the new guidance….

“The industry is largely unregulated and marketing of product is often geared directly at consumers without providing direct and consistent proof of effectiveness,” said the new guidelines. “This has led to widespread use of probiotics with confusing evidence for clinical efficacy,” it said…

“Not all probiotics are created equal. Some probiotic strains and mixtures are very effective for some types of diseases and should not be overlooked due to studies that lump all probiotics together as one”

My take: Probiotics are overhyped and underperform for most conditions. This report suggests that most people should NOT be taking probiotics.

Related blog posts:

#NASPGHAN19 Postgraduate Course (Part 3)

Here are some selected slides and notes from this year’s NASPGHAN’s postrgraduate course. There may be some errors of omission or transcription.

Link to the full NASPGHAN PG Syllabus 2019 (Borrowed with permission)

Functional/Motility Session

95 Carlo Di Lorenzo, MD, Nationwide Children’s Hospital. Evaluation Testing for functional disorders: The indispensable, the useless, the dangerous and treatment strategies in NERD and functional dyspepsia.

This was the best lecture of the day!!! (Hence a lot of slides follow)

  • Families never complain about doctors missing irritable bowel syndrome and anxiety. They may complain about missing diagnosis which are controversial with regarding to chronic pain (‘chronic appendicitis, gallbladder dyskinesia, ‘mild’ IBD, median arcuate ligament syndrome, and food allergies)
  • Functional disorders, but not organic disorders, can cause ‘constant’ pain. “Tried everything.”  Functional disorder patients frequently have side effects with everything.
  • Listen to patient and sit while listening.
  • Early diagnosis of functional disorder associated with higher long-term resolution
  • Testing –only tests that are cost-effective: celiac disease and stool calprotectin.  “Don’t get KUB for constipation.”
  • Endoscopy does not improve outcomes in children with functional GI disorder (FGID)
  • Eosinophilic esophagitis (EoE) treatment does not help abdominal pain but can help if patient has dysphagia
  • Abdominal wall pain is often overlooked.  Check Carnett sign.

 

112 Peter Kahrilas, MD, Northwestern Medicine  Achalasia

  • Achalasia likely develops after an infection in a susceptible host
  • Discussed POEM as newer treatment. It appears to be more effective than either Heller myotomy or pneumatic dilatation in adults.  So far, there is limited experience in pediatrics though it appears to mirror adult experience

124 Julie Khlevner, MD, Morgan Stanley Children’s Hospital Evaluation and treatment strategies in NERD and functional dyspepsia

  • In patients with NERD, hypermetabolizers of PPIs may need higher dosing.
  • Neuromodulators (not FDA approved) used for PPI-nonresponders.  Cognitive behavioral therapies may be helpful as well.
  • Functional dyspepsia with reflux symptoms are more likely to respond to PPIs than those with dyspepsia symptoms
  • A Japanese herb, rikkunshito, may be helpful for functional dyspepsia

136 Robert J. Shulman, MD, Children’s Nutrition Research Center Role of diet in managing of IBS

Key points:

  • Vast majority of low FODMAPs studies show “too much bias” due to lack of blinding in study designs.
  • Nutritionists are needed to guide diet.  Kids (families) do not follow these diets well.
  • Most who are going to respond to diet will do so within 7-10 days.

Disclaimer: NASPGHAN/gutsandgrowth assumes no responsibility for any use or operation of any method, product, instruction, concept or idea contained in the material herein or for any injury or damage to persons or property (whether products liability, negligence or otherwise) resulting from such use or operation. The discussion, views, and recommendations as to medical procedures, choice of drugs and drug dosages herein are the sole responsibility of the authors. Because of rapid advances in the medical sciences, the Society cautions that independent verification should be made of diagnosis and drug dosages. The reader is solely responsible for the conduct of any suggested test or procedure. Some of the slides reproduced in this syllabus contain animation in the power point version. This cannot be seen in the printed version.

 

Fecal Microbial Transplantation -Evidence for Use Beyond Recurrent Clostridium Difficile

Briefly noted: GR D’Haens, C Jobin. Gastroenterol 2019; 157: 624-36. This review sums up the emerging evidence for use of fecal microbial transplantation for conditions besides recurrent Clostridium difficile infection.

Table 2 succinctly provides list of disease, types of study/evidence, and potential effect.

  • Among gastrointestinal diseases, the authors note that there is an “overall positive” effect for ulcerative colitis, “suggestive” benefits for IBS, GVHD, post-antibiotic diarrhea, constipation, and hepatic encephalopathy.  No effect has been evident with Crohn’s disease or pouchitis.
  • Among nongastrointestinal diseases, the authors note a “suggestive” benefit in autism and metabolic syndrome and “unknown” effect with psoriasis and multiple sclerosis.

My take: The review indicates a need for more studies and the need to define which factors in fecal material mediate the therapeutic effects.

Related article: OC Aroniadis. Lancet Gastroenterology and Hepatology; 2019. https://doi.org/10.1016/S2468-1253(19)30198-0. In this double-blind, randomized, placebo-controlled crossover trial in patients aged 18–65 years with moderate-to-severe IBS-D with 48 patients, FMT (capsule study) was safe, but did not induce symptom relief at 12 weeks compared with placebo.

Related blog posts:

AGA Guidelines for Evaluation of Functional Diarrhea and IBS-D

W Smalley et al. Gastroenterol 2019; 157: 851-54. Full Text Link: AGA Clinical Practice Guidelines on the Laboratory Evaluation of Functional Diarrhea and Diarrhea-Predominant Irritable Bowel Syndrome in Adults (IBS-D)

Clinical support tool on pg 855, Patient Summary 856-57, and Technical Review 859-80.

These guidelines/recommendations (listed below) do NOT apply to patients with any of the following:

  • Alarm features such as gross blood, weight loss, anemia, and hypoalbuminemia
  • Family history of of IBD, colon cancer, or celiac disease
  • Travel to areas with high prevalence of infectious diarrhea
  • Immune suppression
  • Ingestion of medications or substances known to cause diarrhea

 

Table 3  Summary of Recommendations of the American Gastroenterological Association on the Laboratory Evaluation of Functional Diarrhea and Diarrhea-Predominant Irritable Bowel Syndrome in Adults
Statement Strength of recommendation Quality of evidence
Recommendation 1: In patients presenting with chronic diarrhea, the AGA suggests the use of either fecal calprotectin or fecal lactoferrin to screen for IBD. Conditional Low
Recommendation 2: In patients presenting with chronic diarrhea, the AGA suggests against the use of ESR or CRP to screen for IBD. Conditional Low
Recommendation 3: In patients presenting with chronic diarrhea, the AGA recommends testing for Giardia. Strong High
Recommendation 4: In patients presenting with chronic diarrhea with no travel history to or recent immigration from high-risk areas, the AGA suggests against testing stools for ova and parasites (other than Giardia). Conditional Low
Recommendation 5: In patients presenting with chronic diarrhea, the AGA recommends testing for celiac disease with IgA-tTG and a second test to detect celiac disease in the setting of IgA deficiency Strong Moderate
Recommendation 6: In patients presenting with chronic diarrhea, the AGA suggests testing for bile acid diarrhea. Conditional Low
Recommendation 7. In patients presenting with chronic diarrhea, the AGA makes no recommendation for the use of currently available serologic tests for diagnosis of IBS None Knowledge gap

For recommendation #6, the authors note that tests for bile acid mediated diarrhea in the U.S. include total bile acid in a 48-hour stool collection and serum fibroblalt growth factor 19.

Image available online: