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The intestinal microbiome as a tool for regenerative medicine; New approach piloted by GN Corp Japan with potential in neurological diseases

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Regenerative medicine uses tools that include cells (stem cells, progenitors, mature adult cells), cell-derived factors (cytokines), and scaffolds (extracellular matrices for cell transplantation). This news is published by Index of Sciences Ltd.

YAMANASHI, Japan, May 6, 2022 /PRNewswire/ — However, there is another tool involving the gut microbiome (GM) that plays an important role in directly and indirectly supporting all MR tools (http://dx.doi.org/10.3233/ JAD-220313). In neurological diseases, one of the main causes is the aggregation of abnormal proteins causing inflammation and neurological dysfunction. A standard RM approach may have limited success unless aggregations are cleaned up. The enhancement of microglia through GM recovers and resumes homeostasis in the brain. The results are based on clinical research (http://dx.doi.org/10.1136/bmjno-2021-000203) which established the influence of biological response modifying glucans (BRMGs) to control GMs, preventing the aggregation and therefore the spread of abnormal proteins to the brain (https://doi.org/10.1101/2021.10.26.21265505).

Extensive research by the European Metagenomics of the Human Intestinal Tract (MetaHIT) and the NIH-funded Human Microbiome Project (HMP), which studied the intestinal metagenomes of 1,070 individuals, revealed that the human gut had 30 times more genes than the human genome. Thus, GM is considered to be the second genome in the body due to its breadth of functionality.

Investigative procedures such as sequencing of the gene encoding 16S rRNA as well as metagenomic and microbial analyzes of the transcriptome, proteome and metabolome have increased knowledge about the human microbiome, including the gut. Healthy adults have over 1,000 species of bacteria, with Bacteroidetes and Firmicutes being the dominant phyla. However, the health of GMs differs between patients. Gut microbes release short-chain fatty acids (SCFAs) from indigestible dietary fiber. SCFAs are the energy source of the intestinal mucosa and are essential for regulating both immunity and tumorigenesis in the gut. Besides SCFAs, GM produces many other microbial products such as uremic toxins, bile acids, trimethylamine N-oxide (TMAO), SCFAs, lipopolysaccharides (LPS), nitric oxide, vitamin K, vitamin B complex, gut hormones and neurotransmitters that modulate metabolism and bodily function.

Studies have found a synergy between the gut microbiome and MSC-based regeneration, particularly in the case of inflammatory bowel disease (IBD). Intestinal bacterial secretions control cytokine gene transcription and surface protein expression in MSCs. They also alter the differentiation potentials and enhance the immunomodulatory capacity of bone marrow MSCs. Nagashima and colleagues reported the symbiotic relationship between a subepithelial population of MSCs and the gut microbiome, with the former facilitating microbiome diversity and regulating IgA production. Other means of restoring the Bacteroidetes/Firmicutes ratio, hepatocyte repair, and intestinal epithelial cell regeneration include MSC infusion and NOD2 sensors. Conditioning treatments such as hematopoietic stem cell transplantation (HSCT), chemotherapy, radiation therapy, and immunosuppressive therapy disrupt the gut microbiome. Valid strategies that work to counter side effects include administration of lactobacilli, probiotics, prebiotics, and fecal microbiota transplantation (FMT).

Additionally, a balanced GM is important for cardiac repair. Certain metabolites and microorganisms have been linked to the development of coronary artery disease (CAD) and atherosclerosis. A comparison between healthy adults and coronary patients revealed the presence of Helicobacter pylori, cytomegalovirus, hepatitis C virus, Chlamydia pneumoniae and Porphyromonas gingivalis in affected individuals. In addition, the population profile of gut microbes changes depending on the type of disease. For example, asymptomatic plaques had an abundance of Porphyromonadaceae, Bacteroidaceae, Micrococcacaea, and Streptococcacaea, and symptomatic atherosclerotic plaques showed elevated levels of Helicobacteraceae, Neisseriaceae, and Thiotrichacaea. Other microbes that cause heart disease are Escherichia coli, Klebsiella penumoniae and Streptococcus viridans. While higher HDL has been associated with Firmicutes, Eggerthella is associated with lower HDL cholesterol. Experimental studies in mouse models have demonstrated that a reduction in Lactobacillus causes myocardial infarction (MI). Similar results were found in mice treated with dose-dependent antibiotics, and dietary SCFA supplementation improved physiological status and survival of mice. Post-stroke recovery improved with a healthy gut microbiome, possessing a greater abundance of SCFA-producing bacteria (eg, Bifidobacterium longum, Clostridium symbiosum, and Lactobacillus fermentum).

The state of GM is reflected in the quality of bone health. Experimental studies in mice have demonstrated a 99% decrease in gut microbes, resulting in increased trabecular bone mass compared to control mice. The Lactobacillus reuteri probiotic treatment protected the mice from bone mass loss. Bifidobacterium longum and Lactobacillus plantarum treatment have been shown to reverse blunted skeletal development in germ-free mice. Similarly, Pstpip2cmo mice predisposed to autoinflammatory osteomyelitis did not develop osteomyelitis through dietary modification of the gut microbiota.

An imbalance in the GM can negatively affect the kidneys. Metabolites from an imbalanced gut including urea, indoxyl sulfate (IS) and p-cresyl sulfate (PCS) cause abnormal activation of immune cells, and overproduction of antibodies, immune complexes and inflammatory factors can damage the renal parenchyma. Administration of the probiotic L. Casei restores the SCFA-producing gut microbiome and nicotinamide metabolism lowered blood pressure, improved kidney failure, and prevented complications in patients with chronic kidney disease (CKD). Studies have shown a strong correlation between gut flora and diabetes, with an effective treatment strategy for diabetes being restoration of the gut microbiome.

To conclude, MR methodologies have developed new strategies, ranging from cell-derived factors to pluripotent stem cells, that promote the paracrine effect by stimulating the regeneration of damaged cells. Donor cells do not have to persist to ensure disease-free status.

Managing the gut microbiome should be an essential part of any MR process, as it prepares the system to exploit the full potential of sophisticated MR tools. The gut microbiome represents a group of cells that influence treatment outcomes. It not only plays a role in cell differentiation, proliferation and paracrine effects, but also influences tissue repair and regeneration. The gut microbiome even affects organs at a distant site, via its inter-organ axes such as the gut-brain, gut-lung, and gut-skin axis, to name a few. Simple strategies such as dietary interventions, lifestyle modifications, and safe dietary supplements such as probiotics and prebiotics can work wonders to promote regeneration. The gut microbiome works endlessly from tissue repair, inflammation, and regeneration, and it continues to be present even after tissues have matured for homeostasis. It makes GM management essential to the success of any RM tool.

About the corresponding author:

Dr. Samuel JK Abraham, after medical training and training in pediatric surgery in India, joined Yamanashi University for postgraduate training in pediatric cardiac surgery and earned a Ph.D. Founded GN Corporation (GNC) in 2002 in Yamanashi, Japan, and in collaboration with Japanese institutes in the field of biomaterials and tissue engineering, in 2005 founded the Nichi-In Center for Regenerative Medicine and initiated stem cell research producing cell therapy solutions in the specialties of ophthalmology, orthopedics and urology. In 2010, began multidisciplinary clinical research on new strains of biological response modifying glucans produced by Aureobasidium Pullulans to address unmet needs and rare diseases, including neurodevelopmental conditions such as autism, genetic diseases such than Duchenne muscular dystrophy. GNC undertakes translational research that complements MR with a focus on neurodegenerative diseases such as Parkinson’s disease, Alzheimer’s disease, and neuroinflammatory diseases such as multiple sclerosis.

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