“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.
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.
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.
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
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.
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)
“The U.S. Food and Drug Administration approved Wegovy (semaglutide) injection (2.4 mg once weekly) for chronic weight management in adults with obesity or overweight with at least one weight-related condition (such as high blood pressure, type 2 diabetes, or high cholesterol), for use in addition to a reduced calorie diet and increased physical activity…The drug is indicated for chronic weight management in patients with a body mass index (BMI) of 27 kg/m2 or greater who have at least one weight-related ailment or in patients with a BMI of 30 kg/m2 or greater… The largest placebo-controlled trial enrolled adults without diabetes. Individuals who received Wegovy lost an average of 12.4% of their initial body weight compared to individuals who received placebo”
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
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)
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).
“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).
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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.”
In this single-center prospective study, the authors show that pantoprazole (40 mg daily for 4 weeks) improves symptoms and duodenal eosinophilia in adults with functional dyspepsia (FD).
Symptoms and duodenal eosinophils, mast cells (all, P < .0001), and paracellular passage (P = .02) were significantly higher in FD-starters (patients new to PPI treatment) vs HVs and reduced with PPI therapy.
The authors note that systemic inflammation, subjective stress and salivary cortisol were also higher in patients with FD vs controls (off PPI).
My take: This study indicates that improvement in symptoms in FD related to PPIs is likely often due to improvement in duodenal mucosal inflammation and barrier dysfunction rather than by changing acidity.
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.
AGA 2017 Guidelines on Therapeutic Monitoriing Proactive drug monitoring: “careful and selective use of proactive TDM could be beneficial, but current evidence for its routine use is limited and its overall benefits remain uncertain”
Fort Jefferson, Dry Tortugas. The fort has reportedly 16 million bricks (I didn’t confirm this figure).
A Louvet et al. Hepatology 2021; 73: 1945-1955. Acute Liver Injury With Therapeutic Doses of Acetaminophen: A Prospective StudyThis prospective study (2002-2019) showed that 89 of 400 adult patients with acetaminophen-induced acute liver injury (ALI) had received therapeutic doses of acetaminophen (<6 g). Especially in individuals with underlying alcoholic liver disease or fasting, acetaminophen (more than 2 gm/day) can trigger liver injury.
JE Eaton et al. Hepatology 2021; 73:1868-1881.Early Cholangiocarcinoma Detection With Magnetic Resonance Imaging Versus Ultrasound in Primary Sclerosing Cholangitis This multicenter retrospective study showed that MRI is superior to ultrasound for the detection of early-stage CCA in patients with PSC. Identification of CCA before the onset of symptoms with MRI is associated with improved outcomes. The authors note that individuals diagnosed with CCA while asymptomatic had a 36% reduction in 5-year mortality and that MRI allowed for a 77% reduction in 5-year mortality among asymptomatic persons. One important limitation of this study would be lead-time bias; that is, those with disease detected at an earlier stage will live longer than those detected at a later stage and thus earlier diagnosis may be ascribed as conferring a greater longevity even with no intervention.