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Archive for the ‘microbiome’ Category


Reporter and Curator: Dr. Sudipta Saha, Ph.D.

 

When a baby is born through its mother’s birth canal, it is bathed in a soup of microbes. Those born by caesarean section (C-section) miss out on this bacterial baptism. The differences in microbe exposure at birth and later health could be caused by other factors, such as whether a mother takes antibiotics during her surgery, and whether a baby is breastfed or has a genetic predisposition to obesity. So, the researchers are sharply split on whether or not this missing of bacterial exposure increases the risk of chronic health problems such as obesity and asthma.

 

Researchers found that babies delivered surgically harboured different collections of bacteria than did those born vaginally. C-section babies, which comprise more than 30% of births in the United States, are also more prone to obesity and immune diseases such as diabetes. Experiments show that mice born by C-section are more prone to obesity and have impaired immune systems. There are fewer factors that could account for these differences in the rodents, which can be studied in controlled conditions, than in people.

 

A wave of clinical trials now under way could help to settle the question — and feed into the debate over whether seeding babies born by C-section with their mother’s vaginal bacteria is beneficial or potentially harmful. Several groups of researchers will be swabbing hundreds of C-section babies with their mother’s microbes, while comparing them to a control group. Each team plans to monitor its study participants over several years in the hope of learning more about how the collection of microbes in their bodies might influence weight, allergy risk and other factors.

 

But some scientists say that the trials could expose C-section babies to infection, or encourage mothers to try do-it-yourself swabbing, without much evidence that there is a benefit or risk. Moreover, there is no evidence that differing exposure to vaginal microbes at birth can help explain variation in people’s health over time. Presently the whole concept is in very much a state of uncertainty.

 

Researchers in near future will compare swabbed C-section babies with a placebo group and with infants delivered vaginally. They confirmed that their protocols will not increase the risk of infection for C-section babies. Scientists will also rigorously screen mothers participating in these trials for microbes such as HIV and group B streptococcus — a common vaginal bacterium that causes respiratory problems in newborns.

 

References:

 

https://www.nature.com/articles/d41586-019-02348-3?utm_source=Nature+Briefing

 

https://www.ncbi.nlm.nih.gov/pubmed/31431742

 

https://www.ncbi.nlm.nih.gov/pubmed/20566857

 

https://www.ncbi.nlm.nih.gov/pubmed/25452656

 

https://www.ncbi.nlm.nih.gov/pubmed/22939691

 

https://www.ncbi.nlm.nih.gov/pubmed/24030708

 

https://pharmaceuticalintelligence.com/2017/02/22/babys-microbiome-changing-due-to-caesarean-birth-and-formula-feeding/

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The Journey of Antibiotic Discovery

Reporter and Curator: Dr. Sudipta Saha, Ph.D.

 

The term ‘antibiotic’ was introduced by Selman Waksman as any small molecule, produced by a microbe, with antagonistic properties on the growth of other microbes. An antibiotic interferes with bacterial survival via a specific mode of action but more importantly, at therapeutic concentrations, it is sufficiently potent to be effective against infection and simultaneously presents minimal toxicity. Infectious diseases have been a challenge throughout the ages. From 1347 to 1350, approximately one-third of Europe’s population perished to Bubonic plague. Advances in sanitary and hygienic conditions sufficed to control further plague outbreaks. However, these persisted as a recurrent public health issue. Likewise, infectious diseases in general remained the leading cause of death up to the early 1900s. The mortality rate shrunk after the commercialization of antibiotics, which given their impact on the fate of mankind, were regarded as a ‘medical miracle’. Moreover, the non-therapeutic application of antibiotics has also greatly affected humanity, for instance those used as livestock growth promoters to increase food production after World War II.

 

Currently, more than 2 million North Americans acquire infections associated with antibiotic resistance every year, resulting in 23,000 deaths. In Europe, nearly 700 thousand cases of antibiotic-resistant infections directly develop into over 33,000 deaths yearly, with an estimated cost over €1.5 billion. Despite a 36% increase in human use of antibiotics from 2000 to 2010, approximately 20% of deaths worldwide are related to infectious diseases today. Future perspectives are no brighter, for instance, a government commissioned study in the United Kingdom estimated 10 million deaths per year from antibiotic resistant infections by 2050.

 

The increase in antibiotic-resistant bacteria, alongside the alarmingly low rate of newly approved antibiotics for clinical usage, we are on the verge of not having effective treatments for many common infectious diseases. Historically, antibiotic discovery has been crucial in outpacing resistance and success is closely related to systematic procedures – platforms – that have catalyzed the antibiotic golden age, namely the Waksman platform, followed by the platforms of semi-synthesis and fully synthetic antibiotics. Said platforms resulted in the major antibiotic classes: aminoglycosides, amphenicols, ansamycins, beta-lactams, lipopeptides, diaminopyrimidines, fosfomycins, imidazoles, macrolides, oxazolidinones, streptogramins, polymyxins, sulphonamides, glycopeptides, quinolones and tetracyclines.

 

The increase in drug-resistant pathogens is a consequence of multiple factors, including but not limited to high rates of antimicrobial prescriptions, antibiotic mismanagement in the form of self-medication or interruption of therapy, and large-scale antibiotic use as growth promotors in livestock farming. For example, 60% of the antibiotics sold to the USA food industry are also used as therapeutics in humans. To further complicate matters, it is estimated that $200 million is required for a molecule to reach commercialization, with the risk of antimicrobial resistance rapidly developing, crippling its clinical application, or on the opposing end, a new antibiotic might be so effective it is only used as a last resort therapeutic, thus not widely commercialized.

 

Besides a more efficient management of antibiotic use, there is a pressing need for new platforms capable of consistently and efficiently delivering new lead substances, which should attend their precursors impressively low rates of success, in today’s increasing drug resistance scenario. Antibiotic Discovery Platforms are aiming to screen large libraries, for instance the reservoir of untapped natural products, which is likely the next antibiotic ‘gold mine’. There is a void between phenotanypic screening (high-throughput) and omics-centered assays (high-information), where some mechanistic and molecular information complements antimicrobial activity, without the laborious and extensive application of various omics assays. The increasing need for antibiotics drives the relentless and continuous research on the foreground of antibiotic discovery. This is likely to expand our knowledge on the biological events underlying infectious diseases and, hopefully, result in better therapeutics that can swing the war on infectious diseases back in our favor.

 

During the genomics era came the target-based platform, mostly considered a failure due to limitations in translating drugs to the clinic. Therefore, cell-based platforms were re-instituted, and are still of the utmost importance in the fight against infectious diseases. Although the antibiotic pipeline is still lackluster, especially of new classes and novel mechanisms of action, in the post-genomic era, there is an increasingly large set of information available on microbial metabolism. The translation of such knowledge into novel platforms will hopefully result in the discovery of new and better therapeutics, which can sway the war on infectious diseases back in our favor.

 

References:

 

https://www.mdpi.com/2079-6382/8/2/45/htm

 

https://www.ncbi.nlm.nih.gov/pubmed/19515346

 

https://www.ajicjournal.org/article/S0196-6553(11)00184-2/fulltext

 

https://www.ncbi.nlm.nih.gov/pubmed/21700626

 

http://www.med.or.jp/english/journal/pdf/2009_02/103_108.pdf

 

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Celiac Disease Breakthrough: (1) 472 genes regulated differently in organoids reflecting celiac disease than in non-celiac control organoids (2) bio-products derived from gut microorganisms can be employed to modify the epithelial response to gluten, a finding that could lead to future treatment strategies.

 

Reporter: Aviva Lev-Ari, PhD, RN

“These results confirm our hypothesis that genes and exposure to gluten are necessary but not sufficient, since changes in both the composition and function of the gut microbiome are also needed to switch from genetic predisposition to clinical outcome, as shown by our data,” said Alessio Fasano, HMS professor of pediatrics at Mass General, director of MIBRC and co-senior author of the paper.

https://hms.harvard.edu/news/major-shift?utm_source=Silverpop&utm_medium=email&utm_term=field_news_item_3&utm_content=HMNews05132019

 

 

Image Source: iStock/wildpixel

Article OPEN Published: 

Human gut derived-organoids provide model to study gluten response and effects of microbiota-derived molecules in celiac disease

Scientific Reports volume 9, Article number: 7029 (2019Download Citation

Abstract

Celiac disease (CD) is an immune-mediated disorder triggered by gluten exposure. The contribution of the adaptive immune response to CD pathogenesis has been extensively studied, but the absence of valid experimental models has hampered our understanding of the early steps leading to loss of gluten tolerance. Using intestinal organoids developed from duodenal biopsies from both non-celiac (NC) and celiac (CD) patients, we explored the contribution of gut epithelium to CD pathogenesis and the role of microbiota-derived molecules in modulating the epithelium’s response to gluten. When compared to NC, RNA sequencing of CD organoids revealed significantly altered expression of genes associated with gut barrier, innate immune response, and stem cell functions. Monolayers derived from CD organoids exposed to gliadin showed increased intestinal permeability and enhanced secretion of pro-inflammatory cytokines compared to NC controls. Microbiota-derived bioproducts butyrate, lactate, and polysaccharide A improved barrier function and reduced gliadin-induced cytokine secretion. We concluded that: (1) patient-derived organoids faithfully express established and newly identified molecular signatures characteristic of CD. (2) microbiota-derived bioproducts can be used to modulate the epithelial response to gluten. Finally, we validated the use of patient-derived organoids monolayers as a novel tool for the study of CD.

Mass. General researchers develop 3D “mini-gut” model to study autoimmune response to gluten in celiac and non-celiac patient tissue

Gene expression of intestinal organoids reflects functional differences found in celiac disease

In pursuit of a novel tool for the research and treatment of celiac disease, scientists at the Mucosal Immunology and Biology Research Center (MIBRC) at Massachusetts General Hospital (MGH) have validated the use of intestinal organoids. These three-dimensional tissue cultures are miniature, simplified versions of the intestine produced in vitro. Taking tissue from duodenal biopsies of celiac and non-celiac patients, researchers created the “mini-guts” to explore how the gut epithelium and microbiota-derived molecules respond to gluten, a complex class of proteins found in wheat and other grains.

“We currently have no animal model that can recapitulate the response to gluten that we see in humans,” says Stefania Senger, PhD, co-senior author of the study published in Scientific Reports this week. “Using this human tissue model, we observed that intestinal organoids express the same molecular markers as actual epithelium in the celiac tissue, and the signature gene expression reflects the functional differences that occur when epithelia of celiac disease patients are exposed to gliadin.” Gliadin and glutenin proteins are main components of gluten.

Celiac disease is triggered when genetically predisposed individuals consume gluten. The condition affects approximately 1 percent of the U.S. population. Based on current data, the onset of celiac disease is thought to be preceded by the release of the protein zonulin, which is triggered by the activation of undigested gliadin to induce an autoimmune response. This leads to increased intestinal permeability and a disrupted barrier function. Novel evidence suggests that the microorganisms in the gastrointestinal tract may play a role in the onset of celiac disease.

Earlier studies from the MIBRC group and others have shown that human organoids “retain a gene expression that recapitulates the expression of the tissue of origin, including a diseased state,” the authors write. Through RNA sequencing, the new findings validate the organoid model as a “faithful in vitro model for celiac disease,” Senger says.
Using whole-transcriptome analysis, the researchers identified 472 genes regulated differently in organoids reflecting celiac disease than in non-celiac control organoids. These included novel genes associated with epithelial functions related to the pathogenesis of celiac disease – including gut barrier maintenance, stem cell regeneration and innate immune response. A second finding of the study shows that bioproducts derived from gut microorganisms can be employed to modify the epithelial response to gluten, a finding that could lead to future treatment strategies.

“These results confirm our hypothesis that genes and exposure to gluten are necessary but not sufficient, since changes in both the composition and function of the gut microbiome are also needed to switch from genetic predisposition to clinical outcome, as shown by our data,” says Alessio Fasano, MD, director of the Mucosal Immunology and Biology Research Center and co-senior author.

Senger adds, “We believe our observations represent a major shift in the study of celiac disease. We are confident that with adequate funding we could achieve major goals that include the development and implementation of high-throughput drug screenings to quickly identify new treatments for patients and expand the organoid repository to develop more complex models and pursue personalized treatment.”
Additional co-authors of the paper are first author Rachel Freire, PhD, along with Laura Ingano and Gloria Serena, PhD, of the MGH MIBRC; Murat Cetinbas, PhD, and Ruslan Sadreyev, PhD, MGH Department of Molecular Biology; Anthony Anselmo, PhD, formerly of MGH Molecular Biology and now with PatientsLikeMe, Cambridge, Mass.; and Anna Sapone, MD, PhD, Takeda Pharmaceuticals International. Support for the study includes National Institutes of Health grants RO1 DK104344-01A1 and 1U19 AI082655-02 and the Egan Family Foundation.

SOURCE

https://www.massgeneral.org/about/pressrelease.aspx?id=2403

 

Other related articles and e-Books by LPBI Group’s Authors published on this Open Access Online Scientific Journal include the following:

 

Series D: e-Books on BioMedicine – Metabolomics, Immunology, Infectious Diseases

  • Metabolomics 

VOLUME 1: Metabolic Genomics and Pharmaceutics. On Amazon.com since 7/21/2015

http://www.amazon.com/dp/B012BB0ZF0

Gluten-free Diets

Writer and Curator: Larry H. Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2015/03/01/gluten-free-diets/

 

Breakthrough Digestive Disorders Research: Conditions affecting the Gastrointestinal Tract.

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2012/12/12/breakthrough-digestive-disorders-research-conditions-affecting-the-gastrointestinal-tract/

 

Collagen-binding Molecular Chaperone HSP47: Role in Intestinal Fibrosis – colonic epithelial cells and subepithelial myofibroblasts

Curators: Larry H Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2016/01/25/collagen-binding-molecular-chaperone-hsp47-role-in-intestinal-fibrosis-colonic-epithelial-cells-and-subepithelial-myofibroblasts/

Expanding area of Tolerance-inducing Autoimmune Disease Therapeutics: Key Players

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2017/01/17/expanding-area-of-tolerance-inducing-autoimmune-disease-therapeutics-key-players/

 

What is the key method to harness Inflammation to close the doors for many complex diseases?

Author and Curator: Larry H Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2014/03/21/what-is-the-key-method-to-harness-inflammation-to-close-the-doors-for-many-complex-diseases/

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Reporter and Curator: Dr. Sudipta Saha, Ph.D.

 

The bacterial makeup of human milk is influenced by the mode of breastfeeding, according to a new study. Although previously considered sterile, breast milk is now known to contain a low abundance of bacteria. While the complexities of how maternal microbiota influence the infant microbiota are still unknown, this complex community of bacteria in breast milk may help to establish the infant gut microbiota. Disruptions in this process could alter the infant microbiota, causing predisposition to chronic diseases such as allergies, asthma, and obesity. While it’s unclear how the breast milk microbiome develops, there are two theories describing its origins. One theory speculates that it originates in the maternal mammary gland, while the other theory suggests that it is due to retrograde inoculation by the infant’s oral microbiome.

 

To address this gap in knowledge scientists carried out bacterial gene sequencing on milk samples from 393 healthy mothers three to four months after giving birth. They used this information to examine how the milk microbiota composition is affected by maternal factors, early life events, breastfeeding practices, and other milk components. Among the many factors analyzed, the mode of breastfeeding (with or without a pump) was the only consistent factor directly associated with the milk microbiota composition. Specifically, indirect breastfeeding was associated with a higher abundance of potential opportunistic pathogens, such as Stenotrophomonas and Pseudomonadaceae. By contrast, direct breastfeeding without a pump was associated with microbes typically found in the mouth, as well as higher overall bacterial richness and diversity. Taken together, the findings suggest that direct breastfeeding facilitates the acquisition of oral microbiota from infants, whereas indirect breastfeeding leads to enrichment with environmental (pump-associated) bacteria.

 

The researchers argued that this study supports the theory that the breast milk microbiome is due to retrograde inoculation. Their findings indicate that the act of pumping and contact with the infant oral microbiome influences the milk microbiome, though they noted more research is needed. In future studies, the researchers will further explore the composition and function of the milk microbiota. In addition to bacteria, they will profile fungi in the milk samples. They also plan to investigate how the milk microbiota influences both the gut microbiota of infants and infant development and health. Specifically, their projects will examine the association of milk microbiota with infant growth, asthma, and allergies. This work could have important implications for microbiota-based strategies for early-life prevention of chronic conditions.

 

References:

 

https://www.genomeweb.com/sequencing/human-breast-milk-microbiome-affected-mode-feeding#.XIOH0igzZPY

 

http://childstudy.ca/2019/02/13/breastmilk-microbiome-linked-to-method-of-feeding/

 

https://gizmodo.com/pumping-breast-milk-changes-its-microbiome-1832568169

 

https://www.sciencedaily.com/releases/2019/02/190213124445.htm

 

https://www.cell.com/cell-host-microbe/fulltext/S1931-3128(19)30049-6

 

https://www.unicef.org.uk/babyfriendly/news-and-research/baby-friendly-research/infant-health-research/epigenetics-microbiome-research/

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Reporter and Curator: Dr. Sudipta Saha, Ph.D.

 

The relationship between gut microbial metabolism and mental health is one of the most intriguing and controversial topics in microbiome research. Bidirectional microbiota–gut–brain communication has mostly been explored in animal models, with human research lagging behind. Large-scale metagenomics studies could facilitate the translational process, but their interpretation is hampered by a lack of dedicated reference databases and tools to study the microbial neuroactive potential.

 

Out of all the many ways, the teeming ecosystem of microbes in a person’s gut and other tissues might affect health. But, its potential influences on the brain may be the most provocative for research. Several studies in mice had indicated that gut microbes can affect behavior, and small scale studies on human beings suggested this microbial repertoire is altered in depression. Studies by two large European groups have found that several species of gut bacteria are missing in people with depression. The researchers can’t say whether the absence is a cause or an effect of the illness, but they showed that many gut bacteria could make substances that affect the nerve cell function—and maybe the mood.

 

Butyrate-producing Faecalibacterium and Coprococcus bacteria were consistently associated with higher quality of life indicators. Together with DialisterCoprococcus spp. was also depleted in depression, even after correcting for the confounding effects of antidepressants. Two kinds of microbes, Coprococcus and Dialister, were missing from the microbiomes of the depressed subjects, but not from those with a high quality of life. The researchers also found the depressed people had an increase in bacteria implicated in Crohn disease, suggesting inflammation may be at fault.

 

Looking for something that could link microbes to mood, researchers compiled a list of 56 substances important for proper functioning of nervous system that gut microbes either produce or break down. They found, for example, that Coprococcus seems to have a pathway related to dopamine, a key brain signal involved in depression, although they have no evidence how this might protect against depression. The same microbe also makes an anti-inflammatory substance called butyrate, and increased inflammation is implicated in depression.

 

Still, it is very much unclear that how microbial compounds made in the gut might influence the brain. One possible channel is the vagus nerve, which links the gut and brain. Resolving the microbiome-brain connection might lead to novel therapies. Some physicians and companies are already exploring typical probiotics, oral bacterial supplements, for depression, although they don’t normally include the missing gut microbes identified in the new study.

 

References:

 

https://www.sciencemag.org/news/2019/02/evidence-mounts-gut-bacteria-can-influence-mood-prevent-depression?utm_source=Nature+Briefing

 

https://www.nature.com/articles/s41564-018-0337-x

 

https://www.ncbi.nlm.nih.gov/pubmed/22968153

 

https://www.ncbi.nlm.nih.gov/pubmed/24888394

 

https://www.ncbi.nlm.nih.gov/pubmed/27067014

 

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The second annual PureTech Health BIG (Brain-Immune-Gut) Summit 2019 – By invitation only –

Selected Tweets from  #BIGAxisSummit

by @pharma_BI @AVIVA1950

for @pharmaceuticalintelligence.com

Reporter: Aviva Lev-Ari, PhD, RN

 

January 30 – February 1, 2019

The second annual PureTech Health BIG Summit brings together an elite ensemble of leading scientific researchers, investors, and CEOs and R&D leaders from major pharmaceutical, technology, and biotech companies.

The BIG Summit is designed to stimulate ideas that will have an impact on existing pipelines and catalyze future interactions among a group of delegates that represent leaders and innovators in their fields.

Please follow the discussion on Twitter using #BIGAxisSummit

By invitation only; registration is non-transferable.

For more information, please contact PureTechHealthSummit@PureTechHealth.com

 

HOST COMMITTEE

Participants

 

BIG SUMMIT AGENDA

(Subject to Change)

PureTech Health BIG Summit 2019 Agenda_FINALv2_WEBSITE.jpg

“Almost starting to understand immunology at this thought-provoking @PureTechh #BIGAxisSummit. Great Speakers.”

-tweet by Simone Fishburn, BioCentury @SimoneFishburn

SOURCE

https://bigsummit2019.com/agenda/

 

Selected Tweets from  #BIGAxisSummit

by @pharma_BI @AVIVA1950

for @pharmaceuticalintelligence.com

Gail S. Thornton Selections

Luke Timmerman‏ @ldtimmerman 7h7 hours ago

Back for final sessions at #BIGAxisSummit. @PureTechH Jim Harper of Sonde Health talking about how voice data — pacing, fine motor articulation, oscillation — can point the way to objective, quantitative measures for detecting and monitoring depression.

 

Eddie Martucci

 @EddieMartucci 5h5 hours ago

Paul Biondi at #BIGAxisSummit : What makes big deals happen is financial, and *deep conviction* of a big future fit. Disproportionate valuation from bidders is expected.

Love this. We often reduce everything to mathematical analyses to champion or ridicule deals. Not that simple

 

PureTech Health Plc‏ @PureTechH Jan 31

Bob Langer (@MIT) asks how #lymphatics affected by #aging. Santambrogio: typically blame aging #immune cells for increased disease, but aging affects lymphatics too (less efficient trafficking shown). Rejuvenating these could affect several aging-related diseases #BigAxisSummit

 

PureTech Health Plc‏ @PureTechH Jan 31

Viviane Labrie (@VAInstitute) discusses why the appendix has been identified as a potential starting point for #parkinsons #BIGAxisSummit

 

PureTech Health Plc‏ @PureTechH Jan 31

Chris Porter (@MIPS_Australia) notes #lymphatics is major route for trafficking #immune cells that surveil gut and respond to immune & #autoimmune stimuli. This is key in #BIGAxis interactions and why lymphatics-targeted therapies could enhance #immunomodulation #BIGAxisSummit

 

Dr. Stephen J. Williams Selections

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Dr. Irina Robu Selection

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Dr. Sudipta Saha Selection

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