“An Allergic Basis for Abdominal Pain”

A recent post (Mechanisms of Postinfectious IBS & Functional Pain) reviewed a study which described how food antigens during an infectious process can result in meal-induced pain.

A recent review of this study (M Rothenberg. NEJM 2021; 384:2156-2158. An Allergic Basis for Abdominal Pain) provides more insight.

Key points:

  • “A peripheral immune mechanism involving local mast cells stimulated by food-induced local IgE may underlie the symptoms associated with IBS and functional abdominal pain; these findings prompt consideration of new therapeutic strategies to target mast cells and allergies.”
  • The article reviews the experimental methods/results used in both mice and humans. Mice that were treated with agents that interfered with allergy “including anti-IgE, mast-cell stabilizers, and histamine H1 receptor antagonists, attenuated the pathologic and symptomatic responses…mice [that were] deficient in mast cells or in histamine H1 receptor were protected” as well.
  • The study shows that a “bacterial infection can break oral tolerance to a dietary antigen…which in turn can lead to increased gut permeability.”
  • The findings in human “showed no evidence of systemic IgE against common foods” but localized reactions were identified in every IBS patient after allergen injection into rectal mucosa.

My take: This study adds to the evidence that specific foods can lead to localized tissue-specific allergic responses. Nevetheless, it is still a futile effort to look for systemic allergic food reactions in patients with IBS and functional GI disorders.

Related blog posts:

IBD-Like Microbiome in at-Risk Twins

Thus far, the relationship of the microbiome and inflammatory bowel disease has been a ‘chicken and the egg which came first’ conundrum. A new study (EC Brand, MAY Klaassen et al. Gastroenterol 2021; 160: 1970-1985. Full text pdf: Healthy Cotwins Share Gut Microbiome Signatures With Their Inflammatory Bowel Disease Twins and Unrelated Patients) offers some insight into this issue.

Methods: Fecal samples were obtained from 99 twins (belonging to 51 twin pairs), 495 healthy age-, sex-, and body mass index–matched controls, and 99 unrelated patients with IBD. Whole-genome metagenomic shotgun sequencing was performed.

Key findings:

  • No significant differences were observed in the relative abundance of species and pathways between healthy cotwins and their IBD-twins.
  • Compared with healthy controls, 13, 19, and 18 species, and 78, 105, and 153 pathways were found to be differentially abundant in healthy cotwins, IBD-twins, and unrelated patients with IBD, respectively.

Discussion: “The gut microbiome composition of individuals at increased risk of developing IBD (i.e. healthy cotwins from IBD-discordant twin pairs) displays IBD-like signatures on a species and pathway level…The overlap in gut microbial features between healthy cotwins at increased risk of developing IBD and related and unrelated IBD patients suggests that these IBD-like microbiome signatures might precede the onset of IBD. This potentially opens new avenues for diagnosis and therapy in individuals with pre-symptomatic IBD.”

My take This study indicates that the microbiome changes in persons with IBD are also found in their healthy twins. In many ways, this is similar to the frequent finding of abnormal serology in Crohn’s disease; ASCA antibodies were considered much less helpful as a diagnostic test after the realization that ~20% of healthy first degree relatives also have detectable levels.

Figure 4 (pg 1979) shows the relative abundance of a selection of IBD-associated species and highlights similarities between the healthy cotwins and IBD twins.

Related blog posts:

IBD Updates: Microbiome afer surgery, Anti-TNF agents NOT changing hospitalizations/surgeries, Biobanking Genetics

X Fang et al. Inflamm Bowel Dis 2021; 27: 603-616. Full Text: Gastrointestinal Surgery for Inflammatory Bowel Disease Persistently Lowers Microbiome and Metabolome Diversity

  • Methods: The UC San Diego IBD Biobank was used to prospectively collect 332 stool samples (every 6 months) from 129 subjects (50 ulcerative colitis; 79 Crohn’s disease). Of these, 21 with Crohn’s disease had ileocolonic resections, and 17 had colectomies.
  • Key finding: Intestinal surgeries in IBD patients seem to reduce the diversity of the gut microbiome and metabolome in IBD patients. Colectomy has a larger effect than ileocolonic resection.
  • Limitations: Confounding variables (eg. antibiotics) and selection bias (patients with more severe disease

C Verdon et al. Inflamm Bowel Dis 2021; 27: 655-661. No Change in Surgical and Hospitalization Trends Despite Higher Exposure to Anti-Tumor Necrosis Factor in Inflammatory Bowel Disease in the Québec Provincial Database From 1996 to 2015

Key findings:

  • 34,644 newly diagnosed patients with IBD (CD = 59.5%)
  • The probability of first and second hospitalizations remained unchanged in Québec and the probability of major surgery was low overall but did increase despite the higher and earlier use of anti-TNFs. However, the authors note that “in the present study, biologics use under the public reimbursement plan was 13% in patients with UC and 16% in patients with CD.”
  • My take: This study is provocative but probably misleading; it is quite likely that use of anti-TNF agents do lower the risk of hospitalization and surgery.

K Gettler et al. Gastroenterol 2021; 160: 1546-1557. Full text PDF: Common and Rare Variant Prediction and Penetrance of IBD in a Large, Multi-ethnic, Health System-based Biobank Cohort

  • Methods: The authors used the Mount Sinai BioMe Biobank, which contains genetic data on
    32,595 patients. After rigorous phenotype validation, 19,541 individuals were retained, of whom 339 were IBD patients (273 CD, 28 UC, and 37 individuals who were classified as both) and 19,202 were controls
  • Key findings: In this study, the authors identified several rare VEO-IBD variants with high genetic penetrance using the biobank samples and then replicated results in large case control African American and European data sets.
  • One of the variants with the highest genetic penetrance located in the gene LRBA was predicted to result in a deleterious change to the amino acid structure. Reduced expression of CTLA-4 secondary to the variants we identified in LRBA may result in autoinflammation that contributes to IBD. “Targeting reduced CTLA-4 expression is an exciting treatment venue, because expression of CTLA-4 has been shown to be increased by chloroquine treatment in vitro.”
  • Enteropathy is present in 63% of all known individuals with LRBA deficiency, with 27% having chronic diarrhea as the presenting symptom

Mangroves in John Pennekamp State Park (Key Largo)

How Important is Your Microbiome for Weight Loss?

Briefly noted: Z Jie et al. Gastroenterol 2021; 160: 2029-2042. Full text PDF: The Baseline Gut Microbiota Directs Dieting-Induced Weight Loss Trajectories

METHODS: A 6-month weight-reduction program with longitudinal collection of dietary, physical activity, body weight, and fecal microbiome data as well as single-nucleotide polymorphism genotypes in 83 participants was conducted, followed by integration of the high-dimensional data to define the most determining factors for weight loss in a dietician-guided, smartphone-assisted dieting program

Key findings:

  • 9 out of 83 subjects achieved long-term weight loss.
  • The baseline gut microbiota was found to outperform other factors as a predicting predictor of individual weight loss trajectories
  • Blautia wexlerae (MGS0575) and Bacteroides dorei (MGS0187) were the strongest predictors for weight loss when present in high abundance at baseline.
  • The microbiome features were more predictive of weight loss than diet, physical activity, and obesity-related host genotype (based on single-nucleotide polymorphism genotypes)

In the associated editorial by RA Reimer et al (pg 1933-1935, full text: Dieting for Success: What Baseline Gut Microbiota Can Tell You About Your Chances of Losing Weight), the authors state that this study supports considering the gut microbiome “as a key component of individual response to dietary interventions.

My take: Much more work is needed in this area to tease out confounding variables (like baseline diet). It is intriguing that our gut microbiome could be instrumental in diet success and perhaps many other characteristics (eg. mental health, longevity, and susceptibility to diseases).

Related blog posts:

Also NPR article (6/17/21): Bariatric Surgery Works, But Isn’t Offered To Most Teens Who Have Severe Obesity (at website, can also click link for 7 minute audio)

“Widely covered paper on ranitidine-cancer link retracted”

Retraction Watch: Widely covered paper on ranitidine-cancer link retracted Thanks to Bryan Vartabedian’s twitter feed for this reference.

An excerpt:

“A paper linking the use of a wildly popular drug for heartburn to cancer has been retracted after the authors concluded that their widely touted finding appears to have resulted from a hiccup in the way they conducted their testing. 

The 2016 article, in Carcinogenesis, has played a minor role in an ongoing class action lawsuit against the makers of ranitidine (sold as Zantac, among other brand names) claiming that use of the medication has caused cancer in more than 100,000 plaintiffs. And it was a key citation in a 2019 petition to the FDA urging that such drugs be recalled….

[From one of the authors of the retracted study] As far as I know, the detections of NDMA in ranitidine tablets remain an issue (detections by LC/MS, which should not be affected by this artefact).

Related blog posts:

Disclaimer: This blog, 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. These blog posts are for educational purposes only. Specific dosing of medications (along with potential adverse effects) should be confirmed by prescribing physician.  Because of rapid advances in the medical sciences, the gutsandgrowth blog 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.  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

Sunset at Islamorada, FL

Long-term Safety of Fecal Microbiota Transplantations

S Saha et al. Gastroenterol 2021; 160: 1961-1969. Full text PDF: Long-term Safety of Fecal Microbiota Transplantation for Recurrent Clostridioides difficile Infection

In this prospective study (2012-2018) with 609 patients (median age 56 years), the authors studied long-term outcomes. Key findings:

  • At 1 year, 9.5% reported additional CDI episodes. Diarrhea occured in more than half of all patients, although it lasted for than a week in most patients.
  • Among 477 with long-term data, 188 patients post-FMT developed new medical conditions/symptoms.
  • Weight gain was reported by 46 patients (10.3%) post-FMT. In these patients, the median weight gained was 30 pounds (range, 10–70). Of these patients, 11 (23%) had
    preexisting obesity.
  • Approximately 3% of patients each reported new-onset diabetes mellitus and dyslipidemia,
    whereas 2.3% reported thyroid disease.
  • Gastrointestinal symptoms were the second most frequently reported (13.4%). New-onset IBS was reported by 4%, IBD by 0.3%, chronic diarrhea by 5.0%, and chronic constipation by 1.6% of patients.
  • Serious infections were reported by 11.8% of patients: CDI in 5.7%, Pneumonia in 4.5%, UTI in 1.8% and Sepsis in 1.2%. Median time to the infections was 29 months (range, 0–73) following FMT; only 1 patient reported an infection (CDI) within the first month after FMT.
  • No deaths were considered related to FMT
  • Limitation: no control group

My take (borrowed from authors): “FMT appears safe and effective, both in the
short-term and long-term. Several new medical conditions were reported post-FMT, in particular, weight gain and IBS.”

Related blog posts:

For the Next Insurance Appeal: Therapeutic Drug Monitoring in Adalimumab Treatment (Pediatrics) & Satire on Prior Authorizations

There is a lot of data supporting the use of therapeutic drug monitoring (TDM) for anti-TNF agents. A recent study (MJ Kim et al. JPGN 2021; 72: 870-876. Therapeutic Drug Monitoring of Adalimumab During Long-term Follow-up in Paediatric Patients With Crohn Disease) adds to this data and supports increased adalimumab (ADL) dosing if below target values.

In this prospective study of 31 pediatric patients with Crohn’s disease, the authors found correlations between ADL values and the endpoints of clinical remission (CR) and mucosal healing (MH). The authors checked TLs at 4 months, 1, 2, and 3 years. Key findings:

  • The median trough levels (TLs) of ADL were higher in patients in CR (7.6 ± 3.5 μg/mL) than in patients with active disease (5.1 ± 2.2 μg/mL).
  • ADL TLs were significantly higher in patients who achieved MH than in those who did not (14.2 ± 7.6 vs 7.8 ± 5.2 μg/mL). 
  • The optimal cut-point for predicting MH at 1 year of ADL treatment was 8.18 μg/mL
  • MH was noted in 42% at 4 months and 55% at 1 yr; CR was noted in 90% at 4 months and 84% at 1 yr. ADL treatment was associated with positive effects on growth indicators as well.

The authors discuss TDM for anti-TNF therapy, noting that for infliximab, the AGA recommends values >5 mcg/mL and the ACG >7.5 mcg/mL. There are fewer studies of ADL TDM -prior studies have indicated goals of >5.8, >7.1, >8, and >8.1; thus, this study is in agreement with these prior studies.

My take: This study further supports the value of TDM; better drug levels correlate with better outcomes.

Related blog posts:

Fort Jefferson, Dry Tortugas. The fort has reportedly 16 million bricks (I didn’t confirm this figure).

More satireOn Prior Authorizations:

Identifying BAD (bile acid diarrhea) in IBS-D

BC Beinvogl et al. JPGN 2021; 72: 859-865. Markers of Bile Acid Metabolism in Pediatric Diarrhea Predominant Irritable Bowel Syndrome and Healthy Controls

Background: Up to ~30% of adults with IBS-D may have bile acid diarrhea (BAD); however, identification has been hampered by cumbersome testing. In the U.S., the most reliable test has been a 48-hr fecal bile acid (FBA) level of >2337 micromol/48 h. Alternatively, blood tests have been used:

  1. 7alpha-hydroxy-4-cholesten-3-one (C4)–a direct measure of BA production
  2. Fibroblast growth factor-19 (FGF-19)–an indirect measure of ileal BA resorption

This prospective cross-sectional study of adolescents (n=26 and 56 healthy controls) examined these blood tests and 48-h FBA . Key findings:

  • 20% of IBS-D patients had elevated C4 levels based on 90% of serum C4 in healthy controls (HC). Mean value in HC was 12 and mean value in IBS-D was 16; 90th% was 22 in HC.
  • 28% had decreased fasting serum FGF-19 based on 10% of HC. Mean value in HC was 128 pg/mL compared with 93 in IBS-D; 10th% was 45 in HC.
  • There was good correlation between C4 and 48-h FBA and there was an inverse relationship between serum C4 and FGF-19. Mean value for 48-h FBA in HC was 490 micromol/48 h compared with 824 in IBS-D; 90th% was 972 in HC.

The authors argue that a definitive diagnosis of BAD is beneficial compared to empiric use of bile acid sequestrants. They point to studies showing that treatment is more effective in those with known BAD, up to 75% response rate. In addition, the use of empiric treatment “has not been validated as a diagnostic test for BAD.” Furthermore, definitive diagnosis would help with adherence to long-term treatment and avoid drug interactions/side effects in those who are unlikely to respond to treatment.

My take: This study shows that C4 could help identify BAD in IBS-D in adolescents and is in agreement with studies in adults (Mayo Clinic labs does run this test: Mayo Clinic: 7AC4, Bile Acid Synthesis, Serum).

Related blog posts:

Below is a sign from the broadwalk in Hollywood, FL. Watch out if you are eating something!

Is the Rectal Exam Obsolete?

A recent review (S Rajindrajith et al. JPGN 2021; 72: 794-801. Functional Fecal Incontinence in Children: Epidemiology, Pathophysiology, Evaluation, and Management) provides a quick review of fecal incontinence in children but one part left me unsettled.

Under the section titled, “Clinical Evaluation,” the authors state the following:

Digital examination of the rectum is not needed as general history and examination reveal the diagnosis in most cases; however, in case of diagnostic uncertainty, digital examination should be performed and can provide information about the integrity of the spincter complex…the presence of a large fecal mass helps to differentiate between constipation-associated FI [fecal incontinence] and FNRFI [functional nonretentive fecal incontinence].”

Of course, there are many situations in which a rectal exam should be deferred. But I think it is a big mistake to state in a leading pediatric GI journal that the default position is that a rectal exam is unnecessary. Here’s why:

  1. A rectal exam is the best way to determine if a patient needs a ‘cleanout’ prior to a routine management plan.
  2. A rectal exam can help avoid unnecessary hospitalizations. I have been made aware of patients in the inpatient setting who have been subjected to cleanouts when they did not need this. Unnecessary cleanouts for outpatients also happen. This can occur in children with irritable bowel syndrome who are having regular bowel movements and are told by practitioners that they are backed up due to flimsy evidence (like a normal abdominal xray).
  3. A rectal exam does not add any additional costs to the evaluation. Later in this same review the authors describe many potential expensive investigations including colonic transit studies, anorectal or colonic manometry, and MRI of lower spine. Is it really a good idea to order any of these tests without completing a rectal exam first?
  4. The article also reviews potential treatments beyond fiber and pharmacology including psychological interventions, transanal irrigation, botulinum toxin injection, antegrade continence enemas, bowel resection and neuromodulation. In my view, none of these should be undertaken prior to a rectal exam.

The review does state that guidelines recommend against using plain abdominal X-ray for evaluation for defecation disorders, noting that “the sensitivity and specificity are not sufficient to provide the required diagnostic accuracy.”

My take: I fundamentally disagree with the premise that a rectal exam is NOT part of the routine evaluation of children with defecation disorders.

Related blog posts:

Picture below from “Robert Is Here” Fruitstand (Homestead, FL)

New Guidelines from AGA for Crohn’s Disease

Summary from AGA website: New AGA guidelines on the medical management of moderate-to-severe Crohn’s disease (see below for main takeaways). These guidelines are for adults.

Fulltext Guideline: JD Feuerstein et al. AGA Clinical Practice Guidelines on the Medical Management of Moderate to Severe Luminal and Perianal Fistulizing Crohn’s Disease. DOI:https://doi.org/10.1053/j.gastro.2021.04.022

Resources: