Crohn’s disease driven by inflammation – not genetics
Lilly drug scores in Phase 2 Crohn’s study
Dive Brief:
- An experimental immunology drug from Eli Lilly has scored positive data in a mid-stage study of Crohn’s disease patients.
- The study enrolled 180 participants, who received either placebo or one of three doses of Lilly’s mirikizumab. After 12 weeks of treatment, all three doses of mirikizumab significantly outperformed placebo on the study’s primary endpoint, which was a 50% or greater reduction in the severity of each patient’s Crohn’s disease.
- Specifically, 26% of the 200 mg group, 38% of the 600 mg group, and 44% of the 1,000 mg group achieved a response, versus 11% of the placebo arm. Five of the patients receiving mirikizumab had at least one serious adverse event, while 81 — or 64% — had a treatment emergent adverse event during the trial’s induction phase. Lilly intends to push mirikizumab into late-stage testing for Crohn’s disease.
Crohn’s disease driven by inflammation – not genetics, reports study
Inflammation — not genetic susceptibility — drives the growth of intestinal bacteria and invasive E. coli linked to Crohn’s disease (CD), reports a new Cornell study.
Scientists have long wondered about the role of bacteria in CD. Recent studies have shown marked changes in the composition of the intestinal bacteria in people with CD, leading researchers to ask: Are microbial abnormalities a direct consequence of genetic abnormalities linked to Crohn’s and precede and initiate inflammation, or does intestinal inflammation bring on the bugs?
Inflammation, in fact, drives microbial imbalances (dysbiosis) and the proliferation of a specific type of E. coli that is adherent, invasive and found in the ileum, reported Cornell researchers July 31 in PLoS (7[7]). And genetics, they said, do play a role in determining the threshold and magnitude of dysbiosis in response to acute inflammation induced by environmental triggers.
This study also reports that a common therapy directed against intestinal inflammation decreases dysbiosis. In addition, the study found that the lack of a receptor that helps recruit T cells, which are needed for cell-mediated immunity, to the gut also decreases inflammation and dysbiosis, offering a new option for therapeutic intervention.
“Today, remission is our mission,” said Kenneth Simpson, professor of small animal medicine at Cornell’s College of Veterinary Medicine and principal investigator. “Crohn’s disease is a highly complex condition that finds its strength in the combination of negatives: environmental factors, genetic mutations and immune system malfunctions. Ultimately, there may be a cure. Until then, we need to find ways to relieve suffering.”
CD is a chronic debilitating inflammatory bowel disease that involves a complex interaction of host genes, the immune system, the intestinal microbiome and the environment. Afflicting more than half a million people in North America, CD can trigger mild to severe diarrhea, fever, fatigue, anemia, reduced appetite and weight loss.
To mirror the complex nature of the disease, Simpson’s team designed a study that incorporated inflammatory triggers related to relapse of CD and ileal inflammation. Unlike previous studies that have focused on colonic or fecal dysbiosis, the team focused on ileal dysbiosis, which is prevalent in 70 percent of CD cases. Also novel to this study, the team used a variety of contemporary techniques to generate a comprehensive picture of the composition and spatial distribution of the ileal microbiome. Particular attention was paid to pinpointing the number, pathotype and location of E. coli associated with intestinal inflammation in people, dogs and mice.
“Our findings clearly demonstrate that inflammation drives ileal dysbiosis and proliferation of CD-associated adherent invasive E. coli. Further, in the context of a patient with Crohn’s, we found that the host genotype and therapeutically blocking inflammation both impact the onset and extent of ileal dysbiosis. These novel findings are of high relevance to Crohn’s disease.”
The investigation leveraged the knowledge and resources of researchers in the labs of Erik Denker, Dwight Bowman and Sean McDonough labs. Building on findings in patients with Crohn’s disease evaluated by Dr. Ellen Scherl’s group at Weill Cornell Medical College, this collaboration shed new light on this debilitating disease.
“It appears that we harbor our own powder keg,” said Simpson. “The bacteria are already seeded. It’s what controls the relative balance between the different species of bacteria and their numbers, relative proportions, our ability to deal with them, and the cross-talk between the bacteria and host that is important.”
This work was supported by NewYork-Presbyterian Hospital/Weill Cornell Medical Center, the Jill Roberts Center for Inflammatory Bowel Disease and the National Institutes of Health.
http://www.news.cornell.edu/stories/Aug12/Inflammation.html
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The GI tract, particularly in the small intestines is the largest lymphoid organ in the body, classical related to the “Bursa of Fabricious” and B-type lymphocyte immunity (cell-mediated immune system). The T-cells are derived from thymus, which atrophies as a distinct organ, and accounts for antibody mediated second response immunity.
Bacteria, like the gut residing E. coli, may cross the fut barrier. The bacteria may be carried to regional splanchnic lymph nodes. They reside there for incubating any length of time. What brings on pathogenicity? It was a prominent surgeon at the Schriner’s burn unit in Cincinatti, some 15-20 years ago who carried out important studies that indicated major trauma, burns, or other challenge brings out activation of the inflammatory response, and this could in a final stage lead to bacteremia, MOF, shock and cardiovascular collapse.
The inflammatory response, as highlighted by Yves Ingenbleek and Larry Bernstein, goes in three stages. The initial phase activates the local response, and releases cytokine driven – fever, chills, neutrophilia, and catecholamines release. The second stage lasts about 48 hours. Liver glycogen is depleted, and there is release of fatty acids from fat stores. The third stage is cortisol driven at first (also related to the lypolysis), and involves peripheral proteolysis (gluconeogenic conversion of muscle and of serum proteins to provide glucose precursors, large by way of branched chain amino acids). This is accompanied by the reprioritization of protein synthesis in the liver. This is highlighted by the events in acute medical conditions.
The link between this and more chronic conditions hasn’t been made, except that we now look at type 2 DM as an inflammatory condition.
Transthyretin: its response to malnutrition and stress injury. clinical usefulness and economic implications.
L Bernstein, Y Ingenbleek
Clin Chem Lab Med 2002; 40(12):1344-1348
ICID: 636205
Article type: Original article
The nutritionally dependent adaptive dichotomy (NDAD) and stress hypermetabolism
Yves Ingenbleek, Larry Bernstein
JOURNAL OF CLINICAL LIGAND ASSAY 1999; 22(3):259-267
ICID: 841561
Article type: Original article
The stressful condition as a nutritionally dependent adaptive dichotomy.
Y Ingenbleek, L Bernstein
Nutrition 1999; 15(4):305-320
ICID: 627568
Article type: Original article
The Transthyretin Inflammatory State Conundrum
Larry H. Bernstein
Current Nutrition & Food Science, 2012, 8, 00-00
Keywords: Tranthyretin (TTR), systemic inflammatory response syndrome (SIRS), protein-energy malnutrition (PEM), C- reactive protein, cytokines, hypermetabolism, catabolism, repair.
There are a number of physiologic changes associated with SIRS and the injury/repair process that will affect TTR and will be put in the context of this review. In the context of an ICU setting, the contribution of TTR is significant. Despite the complexity of the situation, TTR is not to be considered a test “for all seasons”. In the context of age, prolonged poor meal intake, chronic or acute illness, TTR needs to be viewed in a multivariable lens, along with estimated lean body mass, C-reactive protein, the absolute lymphocyte count, presence of neutrophilia, and perhaps procalcitonin if there is remaining uncertainty. Furthermore, the reduction of risk of associated complication requires a systematized approach to timely identification, communication, and implementation of a suitable treatment plan.
Manuscript Number: NUT-12-8802 (31 May 2012 ■ 1-9)
Title: The Automated Malnutrition Assessment
Article Type: Original Article
Accepted 29 April 2012. http://www.nutritionjrnl.com. Nutrition (2012), doi:10.1016/j.nut.2012.04.017.
Keywords: Network Algorithm; unsupervised classification; malnutrition screening; protein energy
malnutrition (PEM); malnutrition risk; characteristic metric; characteristic profile; data
characterization; non-linear differential diagnosis
Corresponding Author: Dr Larry Howard Bernstein, MD
First Author: Gil David, PhD
Order of Authors: Gil David, PhD; Larry Howard Bernstein, MD; Ronald R Coifman, PhD
We propose an automated nutritional assessment (ANA) algorithm that provides a method for malnutrition risk prediction with high accuracy and reliability. The problem of rapidly identifying risk and severity of malnutrition is crucial for minimizing medical and surgical complications. These are not easily performed or adequately expedited. We characterized for each patient a unique profile and mapped similar patients into a classification. We also found that the laboratory parameters were sufficient for the automated risk prediction.
Metabolomics, Metabonomics and Functional Nutrition: The Next Step in Nutritional Metabolism and Biotherapeutics
Larry H. Bernstein
Journal of Pharmacy and Nutrition Sciences, 2012, 2, 000-000
2012 Lifescience Global. ISSN: 2223-3806 / E-ISSN: 1927-5951/12
Keywords: Genomics, Functional genomics, Proteomics, Metabolic Pathways, Metabolome, Metabonomics,
Metabolic Syndrome, Inflammatory Process, Cancer, Iron Metabolism, Obesity, Fat Metabolism.
Metabolomics is a part of an integrated approach to biological sciences that is grouped with an “OMICS” family of genomics, proteomics, transcriptomics, translational medicine, and pharmacogenomics. This is a challenge to our knowledge comprehension with an explosive development in the computational technology for modeling biological systems and studying the interaction between the genome, the ribosome, protein synthesis, protein folding, and metabolic regulation
Dr. Larry,
Thank you for your comment.
Please convert this comment into a post with live linkS, connect to groups on linkedIn AND DO MENTION MY POST ABOVE WITH Thr LINK TO GET TO INTO YOUR NEW POST on Chron’s disease. PLease cover Meds in use for Crohn’s and a discussion on pain Meds in Crohn’s chronic maintenance regimen.
Researchers at Baylor College of Medicine and Texas Children’s Hospital have identified commensal bacteria in the human intestine that produce a neurotransmitter that may play a role in preventing or treating inflammatory bowel diseases such as Crohn’s disease.
GABA is one of the chief inhibitory neurotransmitters in the human central nervous system. It plays a role in regulating pain and some pain relieving drugs currently on the market act by targeting GABA receptors on neural cells.
In addition to its pain modulating properties, GABA may also be capable of inhibiting inflammation. Recent studies have shown that immune cells called macrophages also possess GABA receptors. When these receptors were activated on the macrophages there was a decrease in the production of compounds responsible for inflammation.
Read more at:
http://www.dddmag.com/news/2012/06/neurotransmitter-linked-inflammation?et_cid=2825738&et_rid=45527476&linkid=http%3a%2f%2fwww.dddmag.com%2fnews%2f2012%2f06%2fneurotransmitter-linked-inflammation
Dr. Karra
Thank .you for the comment above.
May I suggest to have stand alone post reviewing GABA derived Meds:
Lyrica and Neurontin presented with a review of chlorine channel GABA with pictures of synaptic. Linking that with your post on Genetics of pain.
Thank you
Dr. Larry,
Have you addressed my comment above?
Did I miss it?
Few recent searches by the Search engine fetched this post.
Please, do convert-your comment above into a post. We have a Metabolic disease Research category, needs more entries.
THANK YOU