Type I Diabetes: The Gut Microbiota Connection

By Mikael Häggström.When using this image in external works, it may be cited as:Häggström, Mikael (2014). "Medical gallery of Mikael Häggström 2014". WikiJournal of Medicine 1 (2). DOI:10.15347/wjm/2014.008. ISSN 2002-4436. Public Domain.orBy Mikael Häggström, used with permission. - See above. All used images are in public domain., Public Domain, https://commons.wikimedia.org/w/index.php?curid=6055517

The connection between gut microbiota and type 2 diabetes is known, and makes sense, as the long-term effects of the microbiota on the GI tract, food processing, secretion of factors inflammation, etc. can reasonably be seen as contributing to metabolic syndrome, insulin resistance, and, eventually, full-fledged type 2 diabetes. What is less well known is the link between intestinal bacteria and type 1 diabetes.  A review article has looked into this and concluded that two mechanisms may link the gut microbiota to type 1 diabetes.  First, if the infant has its GI tract colonized by sup-optimal bacteria, this will negatively affect the “education” of the immune system, resulting in a child vulnerable to immune system related diseases (e.g., autoimmune problems), including type 1 diabetes.  Note that type 1 diabetes results from autoimmune destruction if insulin-producing cells of the pancreases; therefore, an immune system not properly “trained” to distinguish “self” from “non-self” is “primed” to possibly result in attack against the targeted pancreatic cells.  Second, thus vulnerability, this predisposition, then develops into actual diabetes through the development of the antibodies that attack the pancreatic cells, and this development is associated with decreased diversity of the bacterial population of the gut, accompanied by an increase of certain bacterial species.  Protection against type 1 diabetes may therefore include modulating the colonization of the young intestinal tract to promote those bacterial species that would assist in normal immune function.  Abstract.

PURPOSE OF REVIEW:

The purpose of this review is to summarize potential modulations of the intestinal microbiome aimed at preventing or delaying progression to overt type 1 diabetes in the light of recently identified perturbations of the gut microbiota associated with the development of type 1 diabetes.

RECENT FINDINGS:

Accumulated data suggest that the gut microbiota is involved at two different steps in the evolution of type 1 diabetes. At the first step, the intestinal tract is colonized by a microbial community unable to provide an adequate education of the immune system. As a consequence, the infant acquires susceptibility to immune-mediated diseases, type 1 diabetes included. At the other step, the young child seroconverts to positivity for diabetes-associated autoantibodies. This is preceded or accompanied by a decrease in the diversity of the intestinal microbiota and an increased abundance of Bacteroides species. These changes will affect the disease process promoting progression toward overt type 1 diabetes. By providing specific probiotics, one can affect the colonization of the intestinal tract in the newborn infant or strengthen the immune education in early life. Human milk oligosaccharides function as nutrients for "healthy" bacteria. Dietary interventions applying modified starches can influence the numbers and activities of both autoreactive and regulatory T cells and provide protection against autoimmune diabetes in non-obese diabetic mice. Modulation of the intestinal microbiome holds the promise of effective protection against human type 1 diabetes.

Evolution Of Resistance Training

Here is an article reviewing the evolution of resistance training over time; therefore, originally, it was all about just strength and muscle development and today it is a more integrated system encompassing many aspects of human health.  Abstract:

The history of resistance training research began with anecdotal ideas and a slow growth of research from the late 1890s through the 1970s. The mid-1970s were a nexus point when resistance training studies evolved from just strength assessments to importance in physiological systems, physical health, and physical performance capabilities for individuals interested in physical fitness through to those seeking elite athletic performances. The pursuit of understanding program design and what mediated successful programs continues today as new findings, replication of old concepts, and new visions with the latest technologies fuel both our understanding and interest in this modality. This brief review highlights some of the important scientific contributions to the evolution of our scientific study of resistance training and provides a literature base analysis for greater quantification of the origins and expanse of such investigations.

Not diagnosed? Search CrowdMed

I have previously written about sourcing of diagnosis, but this recent post came out and I decided that the idea is worth sharing again.

New Breast Cancer Risk Gene Variants

Below we see some new studies in which new genetic variants that increase breast cancer risk have been discovered.  Such findings have multiple long-term benefits.  First, to identify at-risk patients, who can then have additional screenings, earlier screening, etc.  Second, to understand the mechanisms by which these variants, or the genes linked to them (if the variants themselves are just "markers" of risk), affect breast cancer, so as to devise new preventive and therapeutic approaches.  Third, to combine points one and two, to devise individualized screening and prevention (and therapy?) regimens for specific individuals.

Paper one; abstract:

Most common breast cancer susceptibility variants have been identified through genome-wide association studies (GWAS) of predominantly estrogen receptor (ER)-positive disease. We conducted a GWAS using 21,468 ER-negative cases and 100,594 controls combined with 18,908 BRCA1 mutation carriers (9,414 with breast cancer), all of European origin. We identified independent associations at P < 5 × 10-8 with ten variants at nine new loci. At P < 0.05, we replicated associations with 10 of 11 variants previously reported in ER-negative disease or BRCA1 mutation carrier GWAS and observed consistent associations with ER-negative disease for 105 susceptibility variants identified by other studies. These 125 variants explain approximately 16% of the familial risk of this breast cancer subtype. There was high genetic correlation (0.72) between risk of ER-negative breast cancer and breast cancer risk for BRCA1 mutation carriers. These findings may lead to improved risk prediction and inform further fine-mapping and functional work to better understand the biological basis of ER-negative breast cancer.

Paper two; abstract:

Breast cancer risk is influenced by rare coding variants in susceptibility genes, such as BRCA1, and many common, mostly non-coding variants. However, much of the genetic contribution to breast cancer risk remains unknown. Here we report the results of a genome-wide association study of breast cancer in 122,977 cases and 105,974 controls of European ancestry and 14,068 cases and 13,104 controls of East Asian ancestry. We identified 65 new loci that are associated with overall breast cancer risk at P < 5 × 10-8. The majority of credible risk single-nucleotide polymorphisms in these loci fall in distal regulatory elements, and by integrating in silico data to predict target genes in breast cells at each locus, we demonstrate a strong overlap between candidate target genes and somatic driver genes in breast tumours. We also find that heritability of breast cancer due to all single-nucleotide polymorphisms in regulatory features was 2-5-fold enriched relative to the genome-wide average, with strong enrichment for particular transcription factor binding sites. These results provide further insight into genetic susceptibility to breast cancer and will improve the use of genetic risk scores for individualized screening and prevention.

Cancer Stem Cell Switch

By Philippe Hupé - Emmanuel Barillot, Laurence Calzone, Philippe Hupé, Jean-Philippe Vert, Andrei Zinovyev, Computational Systems Biology of Cancer Chapman & Hall/CRC Mathematical & Computational Biology , 2012, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=18530796

The cancer stem cell hypothesis postulates that at least some cancers are driven by carcinogenic stem cells, that are resistant to treatment.  Forcing those cancer stem cells to stop proliferating (stopping self-renewal) and differentiate (become a more specialized cell type with decreased or no ability to reproduce) is a possible therapeutic approach.  A small RNA that affects gene expression (micro-RNA) called miR-600 can promote a “switch” between self-renewal and proliferation of these cancer stem cells; an example of basic science discoveries that one day can be used for cancer therapy.  Abstract:

Tumors are organized in a cellular hierarchy with a population of cancer stem cell (CSC) driving cancer progression and resistance to treatment. Recently, we identified miR-600 as a bimodal switcher that balances breast CSC-fate from a self-renewing to a differentiation state, with a direct impact on tumor progression.

Yet More On The Microbiota Colon Cancer Connection

A review paper asserts, from the abstract:

From the abstract:

Colorectal cancer (CRC) is the third most common cancer and the fourth most common cause of cancer-related death. Most cases of CRC are detected in Western countries, with its incidence increasing year by year. The probability of suffering from colorectal cancer is about 4%-5% and the risk for developing CRC is associated with personal features or habits such as age, chronic disease history and lifestyle. In this context, the gut microbiota has a relevant role, and dysbiosis situations can induce colonic carcinogenesis through a chronic inflammation mechanism. Some of the bacteria responsible for this multiphase process include Fusobacterium spp, Bacteroides fragilis and enteropathogenic Escherichia coli.

It is becoming increasingly clear that modification of gut microbiota, possibly through diet and/or probiotics, will become an important tool in the prevention and treatment of many diseases, including CRC.

HMGB Proteins, Wnt Signaling, And Arthritis

HMGB proteins bind DNS to affect gene expression, and are associated with arthritis.  HMGB1 has been linked to inflammation in rheumatoid arthritis, and HMGB2 is associated with age-related osteoarthritis.  Effects of HMGB2 on bone is related to Wnt signaling, which is also often deregulated in cancer. These findings may lead to novel therapies for arthritis, particularly, with respect to Wnt signaling, for osteoarthritis. Abstract: 

The high-mobility group box (HMGB) family includes four members: HMGB1, 2, 3 and 4. HMGB proteins have two functions. In the nucleus, HMGB proteins bind to DNA in a DNA structure-dependent but nucleotide sequence-independent manner to function in chromatin remodeling. Extracellularly, HMGB proteins function as alarmins, which are endogenous molecules released upon tissue damage to activate the immune system. HMGB1 acts as a late mediator of inflammation and contributes to prolonged and sustained systemic inflammation in subjects with rheumatoid arthritis. By contrast, Hmgb2 -/- mice represent a relevant model of aging-related osteoarthritis (OA), which is associated with the suppression of HMGB2 expression in cartilage. Hmgb2 mutant mice not only develop early-onset OA but also exhibit a specific phenotype in the superficial zone (SZ) of articular cartilage. Given the similar expression and activation patterns of HMGB2 and β-catenin in articular cartilage, the loss of these pathways in the SZ of articular cartilage may lead to altered gene expression, cell death and OA-like pathogenesis. Moreover, HMGB2 regulates chondrocyte hypertrophy by mediating Runt-related transcription factor 2 expression and Wnt signaling. Therefore, one possible mechanism explaining the modulation of lymphoid enhancer binding factor 1 (LEF1)-dependent transactivation by HMGB2 is that a differential interaction between HMGB2 and nuclear factors affects the transcription of genes containing LEF1-responsive elements. The multiple functions of HMGB proteins reveal the complex roles of these proteins as innate and endogenous regulators of inflammation in joints and their cooperative roles in cartilage hypertrophy as well as in the maintenance of joint tissue.

Protein Types And Muscle Building

By Adrem68 at Dutch Wikipedia - Transferred from nl.wikipedia to Commons., Public Domain, https://commons.wikimedia.org/w/index.php?curid=3224328

Aging individuals lose muscle mass for a variety of reasons, one of which is reduced muscle protein being synthesized after ingestion of dietary protein.  A study has shown that animal proteins are more anabolic (muscle building) than plant proteins.  However, as the authors seem to have social and political motivations here (e.g., environmental concerns), they state mechanism whereby plant-based proteins can be more effective for muscle building: ingestion of a greater amount of protein, combining plant proteins to get a better intake of amino acids (“the mixing plant foods for a complete protein profile,” I assume), leucine co-ingestion, and “prior exercise or n-3 fatty acid supplementation” can better sensitize muscle to the protein. Abstract:

The age-related loss of skeletal muscle mass and function is caused, at least in part, by a reduced muscle protein synthetic response to protein ingestion. The magnitude and duration of the postprandial muscle protein synthetic response to ingested protein is dependent on the quantity and quality of the protein consumed. This review characterises the anabolic properties of animal-derived and plant-based dietary protein sources in older adults. While approximately 60 % of dietary protein consumed worldwide is derived from plant sources, plant-based proteins generally exhibit lower digestibility, lower leucine content and deficiencies in certain essential amino acids such as lysine and methionine, which compromise the availability of a complete amino acid profile required for muscle protein synthesis. Based on currently available scientific evidence, animal-derived proteins may be considered more anabolic than plant-based protein sources. However, the production and consumption of animal-derived protein sources is associated with higher greenhouse gas emissions, while plant-based protein sources may be considered more environmentally sustainable. Theoretically, the lower anabolic capacity of plant-based proteins can be compensated for by ingesting a greater dose of protein or by combining various plant-based proteins to provide a more favourable amino acid profile. In addition, leucine co-ingestion can further augment the postprandial muscle protein synthetic response. Finally, prior exercise or n-3 fatty acid supplementation have been shown to sensitise skeletal muscle to the anabolic properties of dietary protein. Applying one or more of these strategies may support the maintenance of muscle mass with ageing when diets rich in plant-based protein are consumed.

An Unusual Case With A Positive Ending

By Ildar Sagdejev (Specious) - Own work, GFDL, https://commons.wikimedia.org/w/index.php?curid=4428926

We all need to be thankful that surgeons and emergency medicine doctors exist and can deal with problems such as that described here.  Abstract:

Background  Transorbital intracranial penetrating injury is rare. Damage caused by a huge metallic foreign body is very critical and life-threatening. Method  We report an extremely rare case of transorbital intracranial penetrating metal strip (a car windshield wiper), which has not previously been reported in the literature. Results  Emergency craniotomy was performed; the object was removed successfully, and the patient's life was saved. Conclusion  With the life-threatening penetrating brain injury caused by a huge foreign body, prompt surgical treatment and comprehensive postoperative treatment are important to save patients' lives.

Stress, Dopamine, Wnt signaling, And Myelin Loss

Dopamine is related to major aspects of behavior, and abnormal regulation of the dopamine system is linked to depression and other mental disorders. Mice with knocked out dopamine receptors display increased anxiety and depression when confronted with chronic stress. Loss of myelin occurs with multiple sclerosis, and this study shows that chronic stress causes myelin loss in wild-type mice, while the dopamine receptor mutant mice have lower baseline (starting) levels of myelin, but in these mutant mice, myelin levels are not further decreased by stress.  Wnt signaling, which is abnormally regulated in different forms of cancer, is downregulated in the brains of stressed mice; this effect is reversed by lithium treatment (lithium can upregulate Wnt signaling), which normalizes myelin and behavior in stressed wild-type mice.  However, this effect of lithium did not occur in dopamine receptor-mutant mice.  This links the dopamine system with Wnt signaling affecting myelin levels and behavior in mice; the possibility exists that the same association occurs in humans. Stress has previously been linked to multiple sclerosis – with inflammation being one possible mechanism – but the dopamine pathway is another possibility, one that requires further consideration and study. Abstract:

Dopaminergic systems play a major role in reward-related behavior and dysregulation of dopamine (DA) systems can cause several mental disorders, including depression. We previously reported that dopamine D2 receptor knockout (D2R-/-) mice display increased anxiety and depression-like behaviors upon chronic stress. Here, we observed that chronic stress caused myelin loss in wild-type (WT) mice, while the myelin level in D2R-/- mice, which was already lower than that in WT mice, was not affected upon stress. Fewer mature oligodendrocytes (OLs) were observed in the corpus callosum of stressed WT mice, while in D2R-/- mice, both the control and stressed group displayed a decrease in the number of mature OLs. We observed a decrease in the number of active β-catenin (ABC)-expressing and TCF4-expressing cells among OL lineage cells in the corpus callosum of stressed WT mice, while such regulation was not found in D2R-/- mice. Administration of lithium normalized the behavioral impairments and myelin damage induced by chronic stress in WT mice, and restored the number of ABC-positive and TCF4-positive OLs, while such effect was not found in D2R-/- mice. Together, our findings indicate that chronic stress induces myelin loss through the Wnt/β-catenin signaling pathway in association with DA signaling through D2R.