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)

Alterations in Microbes and Impaired Psychological Function in Patients with Inflammatory Bowel Disease

Briefly noted: F Humbel et al. Clin Gastroenterol Hepatol 2020; 18: 2019-2029. Association of Alterations in Intestinal Microbiota With Impaired Psychological Function in Patients With Inflammatory Bowel Diseases in Remission

In a prospective study with 171 adults with IBD in remission, the authors combined

  1. measures of psychological comorbidities and quality of life (QoL)
  2. microbial analysis with 16S rRNA high-throughput sequencing

Key findings:

  • Microbiomes of patients with higher perceived stress had significantly lower alpha diversity
  • Anxiety and depressive symptoms were significantly associated with beta diversity

My take: This study adds another dimension to the idea of bidirectionality between psychological well-being and course of inflammatory bowel disease.  The microbiome may directly influence both psychological well-being and IBD activity.

Related blog posts:

Healthy Microbiome: A Work in Progress, Plus Microbiome-Drug Metabolism

A recent study (G Galazzo, N Van Best, et al. Gastroenterol 2020; 158: 1584-96) highlights the changes in microbiota diversity from birth until 11 years of age.

Full text: Development of the Microbiota and Associations With Birth Mode, Diet, and Atopic Disorders in a Longitudinal Analysis of Stool Samples, Collected From Infancy Through Early Childhood

Methods: We collected 1453 stool samples, at 5, 13, 21, and 31 weeks postpartum (infants), and once at school age (6–11 years), from 440 children (49.3% girls, 24.8% born by cesarean delivery; all children except for 6 were breastfed for varying durations; median 40 weeks; interquartile range, 30–53 weeks).

Key findings:

  • Most bacteria within the Bacteroidetes and Proteobacteria phyla were already present at 5 weeks after birth, whereas many bacteria of the Firmicutes phylum were acquired at later times in infancy.
  • At school age, many new Actinobacteria, Firmicutes, and Bacteroidetes bacterial taxa emerged.
  • The largest increase in microbial diversity occurred after 31 weeks of life.
  • Vaginal, compared with cesarean delivery, was most strongly associated with an enrichment of Bacteroides species at 5 weeks through 31 weeks.
  • From 13 weeks onward, diet became the most important determinant of microbiota composition; cessation of breastfeeding, rather than solid food introduction, was associated with changes.
  • When we adjusted for confounding factors, we found fecal microbiota composition to be associated with development of atopic dermatitis, allergic sensitization, and asthma. Members of the Lachnospiraceae family, as well as the genera Faecalibacterium and Dialister, were associated with a reduced risk of atopy.

My take: We are still learning a lot about the microbiome.  Though a ‘healthy’ microbiome is still not straight-forward determination, a good diet with plenty of fruits and vegetables has been associated with more favorable attributes.

Plus One: Bahar Javdan, et al. Personalized Mapping of Drug Metabolism by the Human Gut MicrobiomeCell, 2020; DOI: 10.1016/j.cell.2020.05.001

In this study, the authors found how variations in the microbiome had unique effects on drug metabolism.  From ScienceDaily, Can gut microbiome alter drug safety and efficacy?  The authors tested 575 FDA-approved drugs to see if they are chemically modified by one of the 21 cultured microbiomes, and then tested a subset of the drugs with all the cultured microbiomes. Here, they found microbiome-derived metabolites that had never been previously reported

Related blog posts:

 

Not Curing Obesity with Fecal Microbiota Transplantation & More on Remdesivir

A recent pilot (n=22) double-blind study (JR Allegrett et al. Clin Gastroenterol Hepatol 2020; 18: 855-63) pours cold water on the idea that repopulating one’s microbiome would be helpful in treating obesity.

In this study, the authors examined obese patients without diabetes, nonalcoholic steatohepatitis, or metabolic syndrome.  In the treatment group, patients received FMT by capsules: 30 capsules at week 4 and then a maintenance dose of 12 capsules at week 8.  All FMT was derived from a single lean donor.

Key findings:

  • There were no significant changes in mean BMI at week 12 in either group.
  • Patients in the FMT group had sustained shifts in microbiomes associated with obesity toward those of the donor (P<.001).  In addition, bile acid profiles became more similar to the donor.

My take: Though this was a small study, it suggests that changing the microbiome by itself is likely insufficient to result in significant weight loss.

Related blog posts:

JH Beigel et al. NEJM DOI: 10.1056/NEJMoa2007764 (May 22, 2020): Full text: Remdesivir for the Treatment of Covid-19 — Preliminary Report

This was a a double-blind, randomized, placebo-controlled trial of intravenous remdesivir in adults hospitalized with Covid-19 with evidence of lower respiratory tract involvement (n=1063).

Key findings:

  • Faster recovery for remdesivir recipients: 11 days vs 15 days
  • Lower mortality rate: 7.1% with remdesivir and 11.9% with placebo (hazard ratio for death, 0.70, 95% CI, 0.47 to 1.04) (mortality difference did not reach statistical significance)

 

 

Bigger Data Needed and Other IBD Updates April 2020

R Pittayanon et al. Gastroenterol 2020; 158: 930-46.  In this systematic review of the relationship between gut microbiota and inflammatory bowel disease, 48 studies and 45 articles were included from a total of 2631 citations.  Overall, the authors found inconsistent results with differences in the abundances of some bacteria in IBD. My take: These microbiota studies use ‘big data’ to look for abnormal patterns in patients with IBD.  Overall, most of these studies support a reduced diversity among patients with IBD.  Specific variation in microbes varies widely and remains unclear if they are a cause or a consequence of IBD.

J Piercy et al. JPGN 2020; 70: 318-23. Among 90 adolescents with IBD, “perfectionistic concerns (self-critical and socially prescribed perfectionism) were associated with higher rates of adolescent-reported externalizing symptoms” Thus, perfectionism may help with self-management but lead to more stress and psychosocial symptoms.

S Jardine et al. Gastroenterol 2020; 158: 1000-15. This study used both TTC7A-knockout cells and a zebrafish model to screen compounds that have been FDA approved for treatment of inflammatory bowel disease caused by TTC7A deficiency.  The authors identified leflunomide that reduces apotosis and levels of active caspase 3 in TTC-7A-knockout cells and restored gut motility along with improvement of intestinal cell survival in zebrafish. This study has some amazing figures detailing the changes induced by leflunomide. My take: Although some centers have offered hematopoetic stem cell transplant (with dismal results), there is NOT a currently accepted treatment for TTC7A deficiency-induced IBD.  This study suggests an agent which may help.

CLD Prevost et al. AP&T 2020. https://doi.org/10.1111/apt.15681 Key finding:  Among patients exposed to anti‐TNF, the Lémann Index was lower in those who were exposed in the first 2 years of their disease (P = 0.015).  My take: Early treatment with anti-TNF agents can reduce risk of permanent bowel damage. This was seen as well in the RISK study which showed that anti-TNF therapy reduced the development of penetrating disease. (Related post: CCFA Update 2017, Part 3)

Full link: Bowel damage and disability in Crohn’s disease: a prospective study in a tertiary referral centre of the Lémann Index and Inflammatory Bowel Disease Disability Index

Why Stool Diversity is a Crappy Argument for Drinking Red Wine

A recent study (C Le Roy et al.  Gastroenterol 2020; 158: 270-2) has indicated that red wine (& to a lesser extent white wine) can improve the intestinal microbiome diversity.

A recent AGA blog provides some insight into this study: Is Red Wine Consumption Good For Your Intestinal Microbiome?

An excerpt:

Consumption of red wine polyphenols has been previously associated with health benefits ranging from reducing cardiovascular disease risk factors, metabolic syndrome, and depression to improving cognition…

Le Roy et al compared the effects of beer and cider, red wine, white wine, spirits, and sum of all alcohols on the α-diversity of the intestinal microbiota (determined from 16s ribosomal RNA sequence data) in discovery cohort of 916 women (from a study of twins in the United Kingdom) and 2 replication cohorts (in Europe and North America) using a linear mixed-effect model adjusted for age, body mass index, Healthy Eating Index scores, education, and family structure…

LeRoy et al found that red wine consumption was associated, in a frequency-dependent manner, with α-diversity—even rare consumption had an effect. White wine was associated with α-diversity to a lesser extent, and there was no association with other alcohol categories…

LeRoy et al also observed a direct association between red wine consumption and blood level of insulin and high-density lipoprotein.

[Limitations] this was a cross-sectional and observational study; randomized studies would be needed to determine whether red wine drinking has direct effects on composition of the intestinal microbiome and health outcomes…

My view: If you like to drink red wine, that’s fine but I would be reluctant to expect a health benefit –no matter how great your poop is.  As the associated editorial notes, “high consumption of alcohol has many adverse health effects, including development of cirrhosis. So, it remains to be determined whether long-term trials of red wine can be safely managed in an ethically responsible manner. It will be important to identify doses that provide beneficial health effects without reducing gut barrier integrity.”

Related blog posts

#NASPGHAN19 Annual Meeting -Plenary Session

Here are some notes and a few slides from NASPGHAN’s plenary session.  There could be errors of transcription in my notes.

Benjamin Gold, NASPGHAN president and part of our GI group, GI Care For Kids, welcomed everyone to the meeting.

Link to NASPGHAN_Annual_Meeting_Program 2019

The first speaker, Jack Gilbert, gave the William F Balistreri lecture.  Dr. Gilbert has written a book on the topic of our ‘magnificent microbiome,’ Dirt is Good.  Here are a few slides:

Related study (not discussed in the talk): A recent study (R Vasapolli et al. Gastroenterology 2019; 157: 1081-91) provided data from 21 healthy adults. Using biopsies from panendoscopy and saliva/fecal samples, the authors found that the fecal microbiome is not representative of the mucosal microbiome.  In addition, each GI region had a different bacterial community.

Christopher Forrest gave the keynote lecture on pediatric learning health systems. By collating data from large pediatric health systems, the researchers can determine more quickly how effective treatments are in all pediatric specialties.

Melvin Heyman, editor of JPGN, provided a good year in review. I only capture a few images.

Those Probiotics May Actually Be Hurting Your ‘Gut Health’

A very readable article in the Wall Street Journal: Those Probiotics May Actually Be Your ‘Gut Health’ –may be behind a paywall. (Thanks to Ben Enav for sharing)

This study makes the following key points:

  • “In a landmark paper by my colleague Dr. Jennifer Wargo at the University of Texas MD Anderson Cancer Center that was published in Science last year, melanoma patients with the healthiest gut microbiomes—that is, the greatest diversity of microorganisms—showed enhanced systemic and antitumor immunity as well as significantly increased odds of responding to immunotherapy.”
  • “The preliminary results [from an MD Anderson Study] showed that patients who reported taking an over-the-counter probiotic supplement had a lower probability of responding to immunotherapy as well as lower microbiome biodiversity. But those eating a high-fiber diet were about five times more likely to respond to immunotherapy and had high gut bacteria diversity, including bacteria previously linked to a strong immunotherapy response.”
  • “The cheapest and safest way to improve our microbiome and gut health is to make simple dietary changes to feed the development of good bacteria and crowd out the bad. There is no pill, special food, unique diet or quick fix for what ails our health and diet. The key is simply to focus on eating a diverse, whole-food, plant-centered, high-fiber diet.”

More information on studies alluded to above:

Related blog posts:

CCFA: Updates in IBD Conference (part 2)

My notes from Georgia Chapter of CCFA’s conference. There could be errors of omission, transcription and/or errors in context based on my understanding.

Sandy Kim, MD –Children’s Hospital of Pittsburgh

Diet in Inflammatory Bowel Disease: Food for Thought

This was a terrific lecture –though much of the topic has been reviewed recently in this blog: Dietary Therapy for Inflammatory Bowel Disease.

Key points:

  • Changes in diet can change microbiome quickly, within 24 hrs
  • Some diets (eg. more fruit/vegetables/fish) may help lower risk of developing IBD
  • Dietary therapy, especially exclusive enteral nutrition (EEN), is effective therapy for Crohn’s disease
  • Why does EEN work?  It is not clear.  There are some changes in microbiome but decrease or little change overall in microbial diversity
  • Reviewed newer dietary approaches: SCD (www.nimbal.org), CD-TREAT, Crohn’s Disease Exclusion Diet

Related blog posts:

Frank Farraye, MD –Mayo Clinic

Health Maintenance in the Adult Patient with IBD

  • Good Practice: Update Vaccinations in IBD population
  • Recent concerns include measles outbreak, and frequent occurrence of Herpes zoster
  • No evidence that vaccination exacerbates IBD
  • New Hepatitis B Recombination Vaccine (Heplisa-B) -2 doses given over one month (for patients older than 18 years. Seroprotective anti-HBs after two doses: 95.4%
  • Shingrix -new recombinant Zoster vaccine.  Overall efficacy 97.2%.  Frequent adverse reactions
  • Women with IBD should undergo annual cervical cancer screening
  • IBD patients should be seen by dermatology
  • Consider depression screening in IBD patients
  • Counsel patients to quit smoking
  • Consider bone density screening in at risk patients

One audience member (Jeff Lewis, MD) pointed out that more attention needs to be paid to depression and anxiety which are much more common and more frequently health-threatening than issues like vaccination.

Related blog posts:

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.