Ketogenic Diets Alter Gut Microbiome in Humans and Mice

Ketogenic Diets Alter Gut Microbiome in Humans and Mice

Study Suggests Potential Anti-Inflammatory Properties of Ketone Bodies Via Effects on Gut Microbial Ecosystems

Low-carb, high-fat ketogenic diets, which have attracted public interest in recent years for their proposed benefits in lowering inflammation and promoting weight loss and heart health, have a dramatic impact on the microbes residing in the human gut, collectively referred to as the microbiome, according to a new UC San Francisco study of a small cohort of volunteer subjects.

Additional research in mice showed that so-called ketone bodies, a molecular byproduct that gives the ketogenic diet its name, directly impact the gut microbiome in ways that may ultimately suppress inflammation, suggesting evidence for potential benefits of ketone bodies as a therapy for autoimmune disorders affecting the gut.

In ketogenic diets, carbohydrate consumption is dramatically reduced in order to force the body to alter its metabolism to using fat molecules, rather than carbohydrates, as its primary energy source – producing ketone bodies as a byproduct – a shift that proponents claim has numerous health benefits.

“I got interested in this question because our prior research showed that high-fat diets induce shifts in the gut microbiome that promote metabolic and other diseases in mice, yet ketogenic diets, which are even higher in fat content, have been proposed as a way to prevent or even treat disease,” said Peter Turnbaugh, PhD, a UCSF associate professor of microbiology and immunology, member of the UCSF Benioff Center for Microbiome Medicine and a Chan Zuckerberg Biohub Investigator. “We decided to explore that puzzling dichotomy.”

In their new study, published May 20, 2020, in Cell, Turnbaugh and colleagues partnered with the nonprofit Nutrition Science Initiative to recruit 17 adult overweight or obese nondiabetic men to spend two months as inpatients in a metabolic ward where their diets and exercise levels were carefully monitored and controlled.

For the first four weeks of the study, the participants were given either a “standard” diet consisting of 50 percent carbs, 15 percent protein and 35 percent fat, or a ketogenic diet comprising 5 percent carbs, 15 percent protein and 80 percent fat. After four weeks, the two groups switched diets, to allow the researchers to study how shifting between the two diets altered participants’ microbiomes.

Analysis of microbial DNA found in participants’ stool samples showed that shifting between standard and ketogenic diets dramatically changed the proportions of common gut microbial phyla Actinobacteria, Bacteroidetes, and Firmicutes in participants’ guts, including significant changes in 19 different bacterial genera. The researchers focused in on a particular bacterial genus – the common probiotic Bifidobacteria – which showed the greatest decrease on the ketogenic diet.

To better understand how microbial shifts on the ketogenic diet might impact health, the researchers exposed the mouse gut to different components of microbiomes of humans adhering to ketogenic diets, and showed that these altered microbial populations specifically reduce the numbers of Th17 immune cells – a type of T cell critical for fighting off infectious disease, but also known to promote inflammation in autoimmune diseases.

Follow-up diet experiments in mice, in which researchers gradually shifted animals’ diets between low-fat, high-fat and low-carb ketogenic diets, confirmed that high-fat and ketogenic diets have opposite effects on the gut microbiome. These findings suggested that the microbiome responds differently as the level of fat in the animals’ diet increases to levels that promote ketone body production in the absence of carbs.

The researchers observed that that as animals’ diets were shifted from a standard diet towards stricter carbohydrate restriction, their microbes also began shifting, correlated with a gradual rise in ketone bodies.

“This was a little surprising to me,” Turnbaugh said. “As someone who is new to the keto field, I had assumed that producing ketone bodies was an all-or-nothing effect once you got to a low enough level of carb intake. But this suggests that you may get some of the effects of ketosis quite quickly.”

The researchers tested whether ketone bodies alone could drive the shifts they had seen in the gut’s microbial ecosystem by directly feeding ketone bodies to mice. They found that even in mice who were eating normal amounts of carbohydrates, the mere presence of added ketones was enough to produce many of the specific microbial changes seen in the ketogenic diet.

“This is a really fascinating finding because it suggests that the effects of ketogenic diets on the microbiome are not just about the diet itself, but how the diet alters the body’s metabolism, which then has downstream effects on the microbiome,” Turnbaugh said. “For many people, maintaining a strict low-carbohydrate or ketogenic diet is extremely challenging, but if future studies find that there are health benefits from the microbial shifts caused by ketone bodies themselves, that could make for a much more palatable therapeutic approach.”

DOI: https://doi.org/10.1016/j.cell.2020.04.027

 


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Gut microbiome linked to efficacy of PD-1-inhibitor therapy for solid cancers

Gut microbiome linked to efficacy of PD-1-inhibitor therapy for solid cancers

In patients with solid cancers, the concentration of fecal short-chain fatty acids (SCFA) may be a biomarker of the efficacy of the programmed cell death 1 (PD-1) checkpoint inhibitors nivolumab and pembrolizumab, according to researchers in Japan.

Immune-checkpoint inhibitors have been remarkably effective across multiple cancer types, note Dr. Motoo Nomura of Kyoto University and colleagues in JAMA Network Open. However, for solid cancers the response rate to PD-1 inhibitors has been relatively low, they add.

Thus, a biomarker of efficacy “is critically needed for clinical decision-making,” they say, and the gut microbiome profile could be one such factor.

To investigate, the researchers prospectively studied 52 cancer patients with a median age of 67 years who were scheduled to be treated with nivolumab or pembrolizumab. Concentrations of SCFAs in fecal and plasma samples were determined before PD-1 inhibitor administration.

The overall response rate was 28.8% and the median follow-up of survivors was for two years. There were no significant differences between responders and nonresponders in patient characteristics,

However, concentrations of fecal and plasma SCFAs were higher in the responder than nonresponder group, and high concentrations of some SCFAs were significantly associated with longer progression-free survival. These included fecal acetic acid (hazard ratio, 0.29), propionic acid (HR, 0.08) and butyric acid (HR, 0.31). This was also the case for plasma isovaleric acid (HR, 0.38).

The results, the researchers say, “showed that high frequencies of intake of several sources of dietary fiber, such as green vegetables, cabbage, and mushrooms, were associated with high concentrations of fecal SCFAs.”

There was no significant association between green vegetable or cabbage intake and progression-free survival. However, Dr. Nomura told Reuters Health by email, “A high frequency of mushroom intake during the one year preceding the onset of their current cancer was significantly associated with longer progression-free survival (HR, 0.40) in patients with solid cancer tumors treated with programmed cell death-1 inhibitors.”

However, he and his colleagues stress that the dietary information used in their study was collected before it started.

The researchers call for further studies but suggest that SCFAs may be the link between the gut microbiota and PD-1-inhibitor efficacy.

“Because fecal examinations are completely noninvasive, they may be applicable for routine monitoring of patients,” they say.

DOI: 10.1001/jamanetworkopen.2020.2895


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Gut bacteria’s interactions with immune system mapped

Gut bacteria’s interactions with immune system mapped

Cell atlas could reveal why some gut diseases affect specific areas

The first detailed cell atlas of the immune cells and gut bacteria within the human colon has been created by researchers. The study from the Wellcome Sanger Institute and collaborators revealed different immune niches, showing changes in the bacterial microbiome and immune cells throughout the colon.  As part of the Human Cell Atlas initiative to map every human cell type, these results will enable new studies into diseases which affect specific regions of the colon, such as ulcerative colitis and colorectal cancer.

Published today in Nature Immunology, this study revealed the interaction between the microbiome and our immune cells. These results form an important resource, which will help scientists to understand how these microbial cells are tolerated by the immune system in health.

The gut microbiome is a complex ecosystem composed of millions of microbes, and these bacteria are thought to play important roles in digestion, in regulating the immune system and in protecting against disease. They are essential to human health, and imbalances in our gut microbiome can contribute to autoimmune diseases such as inflammatory bowel diseases and asthma.

The gut also has a rich community of immune cells, which help to repair tissues and defend against infection. However, there is little detailed information on how the microbiome interacts with the gut resident immune cells, which immune cells co-exist with bacteria in different locations, and why different diseases affect distinct areas of the gut.

To shed light on this, researchers studied three different parts of the healthy colon from organ donors, simultaneously analysing the immune cells and the bacterial microbiome from each area. By sequencing the active genes of 41,000 individual immune cells, they were able to identify cell type specific genes that were switched on in different immune cell populations in each location. They also identified the bacteria present in the same colon region, to reveal how the immune system and bacteria interact.

The study revealed that not only were there differences between the immune cells in different parts of the colon, but that the microbiome also subtly changed, with a broader range of bacteria further down the colon.

Previous work on mice had shown that immune cells in lymph nodes could be targeted to particular destinations – like an immune satnav. For the first time, this study showed that regulatory immune cells, which dampen down an immune response, moved from lymph nodes to the colon.  This could be one way the intestine tolerates or even welcomes the microbiome.

Story source: https://www.sanger.ac.uk/news_item/gut-bacterias-interactions-with-immune-system-mapped/

More information: Kylie James et al. (2020). Distinct microbial and immune niches of the human colon. Nature Immunology. DOI: 10.1038/s41590-020-0602-z


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Microbial DNA in patient blood may be tell-tale sign of cancer

Microbial DNA in patient blood may be tell-tale sign of cancer

When Gregory Poore was a freshman in college, his otherwise healthy grandmother was shocked to learn that she had late-stage pancreatic cancer. The condition was diagnosed in late December. She died in January.

“She had virtually no warning signs or symptoms,” Poore said. “No one could say why her cancer wasn’t detected earlier or why it was resistant to the treatment they tried.” As Poore came to learn through his college studies, cancer has traditionally been considered a disease of the human genome — mutations in our genes allow cells to avoid death, proliferate and form tumors.

But when Poore saw a 2017 study in Science that showed how microbes invaded a majority of pancreatic cancers and were able to break down the main chemotherapy drug given to these patients, he was intrigued by the idea that bacteria and viruses might play a bigger role in cancer than anyone had previously considered.

Poore is currently an MD/PhD student at University of California San Diego School of Medicine, where he’s conducting his graduate thesis work in the lab of Rob Knight, PhD, professor and director of the Center for Microbiome Innovation.

Together with an interdisciplinary group of collaborators, Poore and Knight have developed a novel method to identify who has cancer, and often which type, by simply analyzing patterns of microbial DNA — bacterial and viral — present in their blood.

The study, published March 11, 2020 in Nature, may change how cancer is viewed, and diagnosed.

“Almost all previous cancer research efforts have assumed tumors are sterile environments, and ignored the complex interplay human cancer cells may have with the bacteria, viruses and other microbes that live in and on our bodies,” Knight said.

“The number of microbial genes in our bodies vastly outnumbers the number of human genes, so it shouldn’t be surprising that they give us important clues to our health.”

Cancer-associated microbial patterns

The researchers first looked at microbial data available from The Cancer Genome Atlas, a database of the National Cancer Institute containing genomic and other information from thousands of patient tumors. To the team’s knowledge, it was the largest effort ever undertaken to identify microbial DNA in human sequencing data.

From 18,116 tumor samples, representing 10,481 patients with 33 different cancer types, emerged distinct microbial signatures, or patterns, associated with specific cancer types. Some were expected, such as the association between human papillomavirus (HPV) and cervical, head and neck cancers, and the association between Fusobacterium species and gastrointestinal cancers. But the team also identified previously unknown microbial signatures that strongly discriminated between cancer types. For example, the presence of Faecalibacterium species distinguished colon cancer from other cancers.

Armed with the microbiome profiles of thousands of cancer samples, the researchers then trained and tested hundreds of machine learning models to associate certain microbial patterns with the presence of specific cancers. The machine learning models were able to identify a patient’s cancer type using only the microbial data from his or her blood.

The researchers then removed high-grade (stage III and IV) cancers from the dataset and found that many cancer types were still distinguishable at earlier stages when relying solely on blood-derived microbial data. The results held up even when the team performed the most stringent bioinformatics decontamination on the samples, which removed more than 90 percent of the microbial data.

Applying the microbial DNA test

To determine if these microbial patterns could be useful in the real world, Knight, Poore and team analyzed blood-derived plasma samples from 59 consenting patients with prostate cancer, 25 with lung cancer and 16 with melanoma, provided by collaborators at Moores Cancer Center at UC San Diego Health. Employing new tools they developed to minimize contamination, the researchers developed a readout of microbial signatures for each cancer patient sample and compared them to each other and to plasma samples from 69 healthy, HIV-negative volunteers, provided by the HIV Neurobehavioral Research Center at UC San Diego School of Medicine.

The team’s machine learning models were able to distinguish most people with cancer from those without. For example, the models could correctly identify a person with lung cancer with 86 percent sensitivity and a person without lung disease with 100 percent specificity. They could often tell which participants had which of the three cancer types. For example, the models could correctly distinguish between a person with prostate cancer and a person with lung cancer with 81 percent sensitivity.

“The ability, in a single tube of blood, to have a comprehensive profile of the tumor’s DNA (nature) as well as the DNA of the patient’s microbiota (nurture), so to speak, is an important step forward in better understanding host-environment interactions in cancer,” said co-author Sandip Pravin Patel, MD, a medical oncologist and co-leader of experimental therapeutics at Moores Cancer Center at UC San Diego Health.

“With this approach, there is the potential to monitor these changes over time, not only as a diagnostic, but for long-term therapeutic monitoring. This could have major implications for the care of cancer patients, and in the early detection of cancer, if these results continue to hold up in further testing.”

Comparison to current cancer diagnostics

According to Patel, diagnosis of most cancers currently requires surgical biopsy or removal of a sample from the suspected cancer site and analysis of the sample by experts who look for molecular markers associated with certain cancers. This approach can be invasive, time-consuming and costly.

Several companies are now developing “liquid biopsies” — methods to quickly diagnose specific cancers using a simple blood draw and technologies that allow them to detect cancer-specific human gene mutations in circulating DNA shed by tumors. This approach can already be used to monitor progression of tumors for some types of already-diagnosed cancers, but is not yet approved by the U.S. Food and Drug Administration (FDA) for diagnostic use.

“While there has been amazing progress in the area of liquid biopsy and early cancer detection, current liquid biopsies aren’t yet able to reliably distinguish normal genetic variation from true early cancer, and they can’t pick up cancers where human genomic alterations aren’t known or aren’t detectable,” said Patel, who also serves as the deputy director of the San Diego Center for Precision Immunotherapy.

That’s why there’s often a risk that current liquid biopsies will return false-negative results in the setting of low disease burden. “It’s hard to find one very rare human gene mutation in a rare cell shed from a tumor,” Patel said. “They’re easy to overlook and you might be told you don’t have cancer, when you really do.”

According to the researchers, one advantage of cancer detection based on microbial DNA, compared to circulating human tumor DNA, is its diversity among different body sites. Human DNA, in contrast, is essentially the same throughout the body. By not relying on rare human DNA changes, the study suggests that blood-based microbial DNA readouts may be able to accurately detect the presence and type of cancers at earlier stages than current liquid biopsy tests, as well as for cancers that lack genetic mutations detectable by those platforms.

Limitations and cautions

The researchers are quick to point out that there’s still the possibility blood-based microbial DNA readouts could miss signs of cancer and return a false-negative result. But they expect their new approach will become more accurate as they refine their machine learning models with more data.

And while false negatives may be less common with the microbial DNA approach, false positives — hearing you have cancer when you don’t — are still a risk.

Patel said that just because a cancer is detected early, it doesn’t mean it always requires immediate treatment. Some DNA changes are non-cancerous, changes related to aging, harmless or self-resolve. You would never know about them without the test. That’s why more screening and more cancer diagnoses might not always be a good thing, Patel said, and should be determined by expert clinicians.

The team also cautioned that even if a microbial readout indicates cancer, the patient would likely require additional tests to confirm the diagnosis, determine the stage of the tumor and identify its exact location.

Looking ahead

Knight said many challenges still lay ahead as his team further develops these initial observations into an FDA-approved diagnostic test for cancer. Most of all, they need to validate their findings in a much larger and more diverse patient population, an expensive undertaking. They need to define what a “healthy” blood-based microbial readout might look like among many, diverse people. They’d also like to determine whether the microbial signatures they can detect in human blood are coming from live microbes, dead microbes or dead microbes that have burst open, dispersing their contents — an insight that might help them refine and improve their approach.

To advance blood-based microbial DNA readouts through the next steps toward regulatory approval, commercialization and clinical application of a diagnostic test, Knight and Poore have filed patent applications and they founded a spinout company called Micronoma, with co-author Sandrine Miller-Montgomery, PhD, professor of practice in the Jacobs School of Engineering and executive director of the Center for Microbiome Innovation at UC San Diego.

The latest study may prompt important shifts in the field of cancer biology, Poore said.

“For example, it’s common practice for microbiologists to use many contamination controls in their experiments, but these have historically been rarely used in cancer studies,” he said. “We hope this study will encourage future cancer researchers to be ‘microbially conscious.'”

The researchers also suggest cancer diagnostics may only be the beginning for the newly discovered cancer-associated blood microbiome.

“This new understanding of the way microbial populations shift with cancer could open a completely new therapeutic avenue,” Miller-Montgomery said. “We now know the microbes are there, but what are they doing? And could we manipulate or mimic these microbes to treat cancer?”

Additional co-authors include: Qiyun Zhu, Carolina Carpenter, Serena Fraraccio, Stephen Wandro, Tomasz Kosciolek, Stefan Janssen, Se Jin Song, Jad Kanbar, Robert Heaton, Rana McKay, Austin D. Swafford, UC San Diego; Evguenia Kopylova, formerly of UC San Diego, now at Clarity Genomics; and Jessica Metcalf, formerly of UC San Diego, now at Colorado State University, Fort Collins.


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Caloric restriction mimetics enhance anti-tumor efficacy

Caloric restriction mimetics enhance anti-tumor efficacy

We’re happy to announce that the Seerave Fellow Dr. Jonathan Pol published part of his work entitled “A synergistic triad of chemotherapy, immune checkpoint inhibitors, and caloric restriction mimetics eradicates tumors in mice” in the journal OncoImmunology.

The lab of Professor Guido Kroemeber has recently shown that chemotherapy with agents inducing immunogenic cell death (ICD), such as anthracyclines (e.g. mitoxantrone) or the platinum salt oxaliplatin, can be advantageously combined with fasting or caloric restriction mimetics (CRMs) to reach a better control of tumor growth (1-3). The antitumor activity of the treatment depended on immune actors, particularly on CD8+ T cells. Among these CRMs, Jonathan Pol was particularly interested in further studying hydroxycitrate (HC) and spermidine (SPD). In this follow up study, Jonathan Pol and colleagues revealed that the myeloid immune compartment is also required for the efficacy of this therapeutic combination (4). Indeed, blocking of the integrin CD11b, which participates in the extravasation of myeloid cells, abrogated the benefit of CRMs to chemotherapy. In-depth characterization of the myeloid and lymphoid immune subpopulations infiltrated into the tumor bed allowed a better understanding of the underlying immune mechanisms. In particular, when combined with chemotherapy, HC and fasting amplified a population of dendritic cells derived from monocytes (moDCs, Ly6ChiLy6G+CD11c+CD11b+) and displaying an activated phenotype (CD80+MHC-IIint/hi). In contrast, complementation with SPD was responsible for an increased infiltration of inflammatory macrophages (F4/80+CD11b+CD11cCD38+).

These moDCs and macrophages participate in cancer immunosurveillance by promoting the activation of CD8+ T lymphocytes able to eliminate malignant cells. Interestingly, chemotherapy alone doubled the influx of CD8+ T cells into the tumor. In combination with fasting, their infiltration was further increased but was accompanied by a more pronounced exhaustion phenotype, as shown by the expression of the negative immune feedback molecule PD-1 at the surface of CD8+ T cells. In comparison, the introduction of CRMs maintained a CD8+ T cell population of comparable size to chemotherapy alone but less exhausted than with fasting. In contrast, the CRM HC appeared to induce a rise in activated CD8+ T lymphocytes, characterized by the expression of the surface marker ICOS.

In parallel, Jonathan Pol and colleagues found that chemotherapy was inducing the overexpression of PD-L1 (PD-1 ligand) on both cancer cells and leukocytes (typically the myeloid compartment). Thus, the detection of PD-1 and PD-L1, both inhibiting the antitumor activity, on multiple cellular components of the tumor environment prompted us to introduce an immunotherapy blocking the PD-1/PD-L1 axis. The latter treatment relies on the administration of an antibody targeting PD-1 that prevents the interaction with its ligand PD-L1. Three anti-PD-1 immunotherapies are nowadays approved into the clinic: Nivolumab (Opdivo, BMS), Pembrolizumab (Keytruda, MSD), and Cemiplimab (REGN-2810, Sanofi). In our mouse fibrosarcoma model, treatment with anti-PD1 alone or in combination with fasting or CRMs had no significant antitumor effect. In contrast, the combination of anti-PD-1 with chemotherapy provided a benefit comparable to that of CRMs. However, complete regression of the majority of tumors was obtained only by a triple therapy combining (i) ICD-inducing chemotherapy, in this case mitoxantrone or oxaliplatin, (ii) a CRM such as HC or SPD, and substitutable by fasting, and (iii) an antibody blocking PD-1 and PD-L1 interaction. (4).

Overall, these results suggest the possibility of synergistic interactions between distinct classes of anticancer agents. Clinical trials are in preparation to evaluate this therapeutic triad against different malignant indications.

Full article: https://doi.org/10.1080/2162402X.2019.1657375

References:

  1. F. Pietrocola*, J. Pol*, E. Vacchelli, S. Rao, D. P. Enot, E. E. Baracco, S. Levesque, F. Castoldi, N. Jacquelot, T. Yamazaki, L. Senovilla, G. Marino, F. Aranda, S. Durand, V. Sica, A. Chery, S. Lachkar, V. Sigl, N. Bloy, A. Buque, S. Falzoni, B. Ryffel, L. Apetoh, F. Di Virgilio, F. Madeo, M. C. Maiuri, L. Zitvogel, B. Levine, J. M. Penninger, G. Kroemer, Caloric Restriction Mimetics Enhance Anticancer Immunosurveillance. Cancer Cell 30, 147-160 (2016).
  2. F. Pietrocola*, J. Pol* E. Vacchelli, E. E. Baracco, S. Levesque, F. Castoldi, M. C. Maiuri, F. Madeo, G. Kroemer, Autophagy induction for the treatment of cancer. Autophagy 12, 1962-1964 (2016).
  3. F. Pietrocola*, J. Pol*, G. Kroemer, Fasting improves anticancer immunosurveillance via autophagy induction in malignant cells. Cell Cycle 15, 3327-3328 (2016).
  4. S. Levesque, J. Le Naour, F. Pietrocola, J. Paillet, M. Kremer, F. Castoldi, E. E. Baracco, Y. Wang, E. Vacchelli, G. Stoll, A. Jolly, P. De La Grange, L. Zitvogel, G. Kroemer, J. G. Pol, A synergistic triad of chemotherapy, immune checkpoint inhibitors, and caloric restriction mimetics eradicates tumors in mice. Oncoimmunology 8, e1657375 (2019).

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Human microbiome-derived bacterial strains with antitumor activity

Human microbiome-derived bacterial strains with antitumor activity

Vedanta Biosciences, a clinical-stage company developing a new category of therapies for immune-mediated diseases based on rationally defined consortia of human microbiome-derived bacteria, today announced a publication in Nature reporting a newly discovered mechanism underlying antitumor immunity that involves human microbiota-driven induction of interferon-gamma-producing (IFNy+) CD8+ T cell accumulation in the gut and tumors.

Led by Vedanta’s scientific co-founder Kenya Honda, M.D., Ph.D., of Keio University School of Medicine, the research also led to the identification and selection of a defined consortium of human microbiome-derived bacterial strains that harnesses this mechanism of antitumor activity and cooperatively potentiates responses to checkpoint inhibitor therapies and immune challenges in general. Based on this research, Vedanta is advancing VE800, a proprietary clinical candidate designed to enhance immune responses against cancer. Vedanta plans to initiate clinical studies in 2019 to evaluate VE800 in combination with Bristol-Myers Squibb’s checkpoint inhibitor OPDIVO (nivolumab).

“This research demonstrates that specific, human microbiome-derived bacteria assembled rationally into consortia can cooperatively enhance the responses to immune checkpoint inhibitors, which supports our hypothesis that modulating the gut microbiota could be a powerful tool for potentiating immune responses that help fight cancer and infection,” said Bernat Olle, Ph.D., Chief Executive Officer of Vedanta Biosciences. “This work also builds upon Dr. Honda’s previous groundbreaking research on the role of the human microbiome in modulating a range of immune responses and provides a robust scientific foundation for our proprietary lead cancer candidate, VE800.”

The authors of the Nature paper sought to understand the previously poorly characterized relationship between the human microbiota and intestinal IFNy+ CD8 T cells, which are critical to innate and adaptive immune responses. In preclinical models, they were able to establish that the number and frequency of these immune cells in the gut depend on the presence of a gut microbiota and are plastic, with specific members of the microbiota promoting their intestinal accumulation in an inducible and reversible manner. The authors went on to identify specific commensal bacterial strains from healthy human donors that spurred the production of IFNy+ CD8+ T cells.

Through rigorous selection, the authors isolated a defined consortium of commensal bacteria derived from the human microbiome that proved most effective at inducing rapid and persistent accumulation of IFNy+ CD8+ T cells. Mice colonized with the defined bacterial consortium demonstrated enhanced therapeutic efficacy in a range of tumor models when given in conjunction with PD-1 or CTLA4 immune checkpoint inhibitors. The strains identified are primarily rare, low-abundance components of the human microbiome, representing a significant opportunity for amplification as a therapeutic strategy.

The research demonstrates for the first time that human microbiome-derived bacterial consortia that cooperatively enhance the responses of immune checkpoint inhibitors can be identified. The authors addressed the challenge of reducing a complex community of human microbiome bacteria down to a few, rationally defined members that can induce a robust immune potentiation response necessary for an effective cancer immune therapy, and directly linking their activity to pathways that promote antitumor immunity.

The Nature paper also found that human stool samples showed considerable variability in their ability to induce colonic IFNy+ CD8+ T cells. Vedanta’s development process is designed to bypass this variability by using pure, clonal cell banks of well-characterized bacterial strains isolated from healthy humans to produce defined consortia of uniform composition. This eliminates the need to rely on direct sourcing of fecal donor material of inconsistent composition. Vedanta sources bacteria from a vast, extensively characterized collection of 80,000 bacterial isolates obtained from human donors from four continents, which is believed to be the largest collection of human-gut associated bacteria. It then designs high-throughput assays to screen product candidates against a given disease target.

VE800 is Vedanta Biosciences’ proprietary oral immuno-oncology product candidate. It consists of a rationally defined bacterial consortium that activates cytotoxic CD8+ T cells, a type of white blood cell that is the predominant effector in cancer immunotherapy. In preclinical studies, VE800 has been shown to enhance the ability of these T cells to infiltrate tumors, thereby promoting suppression of tumor growth and enhancing survival. Data also suggest that VE800 may enhance the effects of checkpoint inhibitors. Vedanta is evaluating VE800 alone and in combination with checkpoint inhibitors as a potential treatment for patients with advanced or metastatic cancers. In December 2018, Vedanta entered into a clinical trial collaboration to evaluate Bristol-Myers Squibb’s programmed death-1 (PD-1) immune checkpoint inhibitor OPDIVO (nivolumab) in combination with Vedanta’s VE800, in patients with advanced or metastatic cancers. Clinical trials are expected to begin in 2019.

Story Source: medicalexpress.com

More information: https://doi.org/10.1038/s41586-019-0878-z


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Gut microbiome regulates the intestinal immune system

Gut microbiome regulates the intestinal immune system

A new study in mice unveils the role of vitamin A in immune system regulation, a finding that could assist in developing treatments for autoimmune and inflammatory diseases as well as vitamin A deficiency.

PROVIDENCE, R.I. [Brown University] — Scientists have long known that bacteria in the intestines, also known as the microbiome, perform a variety of useful functions for their hosts, such as breaking down dietary fiber in the digestive process and making vitamins K and B7.

Yet a new study unveils another useful role the microbiome plays. A team of researchers from Brown University found that in mice, the gut microbiome regulates the host’s immune system — so that rather than the host’s defense system attacking these helpful bacteria, the bacteria can coexist peacefully with the immune system.

What’s the trick to the microbiome’s work with the immune system? Vitamin A — the bacteria moderate active vitamin A levels in the intestine, protecting the microbiome from an overactive immune response.

That insight may prove important for understanding and treating autoimmune and inflammatory diseases, said Shipra Vaishnava, an assistant professor of molecular microbiology and immunology at Brown.

“A lot of these diseases are attributed to increased immune response or immune activation, but we’ve found a new way that bacteria in our gut can dampen the immune response,” Vaishnava said. “This research could be critical in determining therapies in the case of autoimmune diseases such as Crohn’s disease or other inflammatory bowel diseases, as well as vitamin A deficiency.”

The study was published on Tuesday, Dec. 18, in the journal Immunity.

Microbiomes of mice and men

The gut microbiome is an ecosystem made of 100 trillion bacteria that have evolved to live in the special conditions of the intestines, Vaishnava said. The vast majority of these bacteria are helpful rather than harmful. A healthy microbiome, just like a healthy forest, has many species coexisting together and can fend off hostile intruders — such as disease-causing bacteria or invasive species.

In both humans and mice, the phyla Firmicutes and Bacteroidetes comprise the majority of the gut microbial community. To play their part in regulating their hosts’ immune systems, the bacteria in the microbiome fine-tune the levels of a protein responsible for the conversion of vitamin A to its active form in their hosts’ gastrointestinal tract, the researchers found.

Vaishnava’s team found that Firmicutes bacteria, particularly members of the class Clostridia, reduce the expression of a protein within the cells that line the intestines. The protein, retinol dehydrogenase 7 (Rdh7) converts dietary vitamin A to its active form, retinoic acid, Vaishnava said. The Clostridia bacteria, common to both mice and men, also promote increased vitamin A storage in the liver, the team found.

Vaishnava expects the findings are generalizable to the interactions between the human microbiome and their hosts as well.

Mice genetically engineered to not have Rdh7 in their intestinal cells have less retinoic acid in the intestinal tissue, as the researchers expected. Specifically, the guts of the engineered mice had fewer immune cells that make IL-22, an important cellular signal that coordinates the antimicrobial response against gut bacteria. Other components of the immune system such as cells with immunoglobulin A and two types of T-cells were the same as in standard mice, suggesting Rdh7 is only essential for the regulating antimicrobial response, Vaishnava said.

The researchers do not know exactly how Rdh7 is suppressed, but Clostridia bacteria are known to produce short chain fatty acids that change host gene expression. As a next step in their research, the team will study how bacteria regulate Rdh7 expression, including examining various short chain fatty acids, Vaishnava said.

In addition, the team will conduct research to understand why Rdh7 suppression is critical. They are working to genetically engineer mice to always express Rdh7 in their intestinal cells. Vaishnava wants to see how this affects the mouse microbiome and if it leads to any inflammation or autoimmune disease-like conditions for the mice. They will also explore the impacts of increased vitamin A storage in the liver due to bacteria Rdh7 regulation, Vaishnava said.

Helping human health

The researchers say that understanding how bacteria regulate the immune system’s responses could be important in unlocking the keys to disorders like Crohn’s disease.

Data from clinical studies has shown that inflammation in the bowel is a result of disrupted interactions between a host and their gut microbiome, Vaishnava said.

“The role of vitamin A in inflammation is context-dependent and is very hard to tease apart,” Vaishnava said. “A change in vitamin A status and vitamin A metabolic genes coincides with inflammatory bowel diseases, but we don’t know if this promotes inflammation or not. We hope that adding our finding — that bacteria can regulate how vitamin A is being metabolized in the intestine or stored — could help clarify why the field is seeing what it is seeing.”

These findings could also provide clues about the importance of the microbiome in addressing vitamin A deficiency, a problem that is particularly prevalent in Africa and Southeast Asia.

Vitamin A deficiency affects approximately one third of children under the age of five, according to the World Health Organization (WHO). Vitamin A deficiency weakens the immune system and increases the risk of infectious diseases. The WHO has been providing at-risk children with vitamin A supplements for the past 25 years, but it hasn’t been as successful as hoped for, according to Vaishnava. This study shows bacteria are a big part of vitamin A absorption and storage and perhaps children need to have the right combination of bacteria in the gut in order for the vitamin A supplements to be most effective, she added.

“Both our diet and the bacteria in our gut are critically linked in regulating how our immune cells behave,” Vaishnava said. “Finding what those links are at a molecular level is important to figuring out how we could use either diet or bacteria, or both of them together, to have a therapeutic effect in inflammatory or infectious diseases.”

In addition to Vaishnava, other authors from Brown include Mayara Grizotte-Lake, Kellyanne Duncan, Namrata Iyer and Irina Smolenski. Authors also include Nina Isoherranen, Guo Zhong and Jay Kirkwood from the University of Washington, Seattle.

The National Institutes of Health (grants R01-DK113265 and P20-GM10903) and the Crohn’s and Colitis Foundation of America supported the research.

Story Source: https://news.brown.edu/articles/2018/12/microbiome

More information: https://doi.org/10.1016/j.immuni.2018.11.018


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Gut bacteria influence the progression of multiple myeloma

Gut bacteria influence the progression of multiple myeloma

By interacting with the immune system, some types of gut bacteria can influence the progression of multiple myeloma, a tumor that affects the bone marrow causing pain, anemia and bone fragility.

The discovery, limited so far to the animal model of the disease, is published today in Nature Communications by the team of Matteo Bellone, head of Cellular immunology Unit at IRCCS Ospedale San Raffaele. The study, supported by AIRC – The Italian Association for Cancer Research – is among the first to trace a direct link between intestinal microbiota and a tumor located in a different organ, thus demonstrating the capability of these bacteria to interact with the whole organism. Moreover, researchers identified a biological marker that could predict the aggressiveness of multiple myeloma in asymptomatic patients and suggest the efficacy of some anti-inflammatory drugs, already approved for other conditions, in slowing down the disease progression.

Multiple myeloma is a severe tumor affecting plasma cells, the immune cells responsible for antibody production. In patients with multiple myeloma, these cells accumulate inside the bone marrow, interfering with its normal blood regeneration activity and weakening the bones. The disease is preceded by a painless and asymptomatic phase, in which some plasma cells have already acquired tumor characteristics and release a specific protein that can be detected in both the blood and the urine of patients, even in the absence of other pathological manifestations.

To understand the process underlying the disease progression from its asymptomatic phase to the symptomatic one, researchers focused on the animal model of the disease and on the role played by commensal bacteria. They discovered that a specific type of bacteria, also present in humans and called Prevotella heparinolytica, promotes the multiplication of inflammatory lymphocytes Th17 and that these lymphocytes are directly involved in tumor progression inside the bone marrow.

According to the study, Th17 cells migrate from the gut to the bone marrow, where they foster plasma cells proliferation, facilitating the transition from the asymptomatic phase of multiple myeloma to the actual disease through the release of a cytokine – an inflammatory molecule – called IL-17. «Given the key role IL-17 plays in multiple myeloma progression, this molecule could become a predictive tool: the amount of IL-17 in the bone marrow of asymptomatic patients could be the first biomarker able to identify patients at high risk of developing multiple myeloma», explains Arianna Brevi, first author of the research together with Arianna Calcinotto.

To test their hypothesis on the role of Th17 lymphocytes and IL-17 cytokine, researchers performed two experiments: at first, they blocked IL-17 and other inflammatory molecules

involved in tumor progression using anti-inflammatory drugs already approved for other conditions; secondly, they modified mice commensal microbiota, through the administration of antibiotics and the transplantation of bacteria species of known anti-inflammatory activity. In both cases, they managed to slow down the onset of multiple myeloma.

“The evidence collected suggests a way to identify patients at greater risk of developing multiple myeloma and to act in advance, thus containing the disease in its asymptomatic stage or, at least, slowing down its more severe manifestation”, says Matteo Bellone. “Although the experimental results obtained so far have to be further confirmed in clinical settings, they provide new hopes for patients and clinicians.”

Story Source: http://research.hsr.it/en/news/gut-bacteria-influence-the-progression-of-multiple-myeloma.html

More information: Microbiota-driven interleukin-17-prodcuing cells and eosinophils synergize to accelerate multiple myeloma progression, Nature Communications doi.org/10.1038/s41467-018-07305-8


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Synthetic microbiome? Genetic engineering allows different species of bacteria to communicate

Synthetic microbiome? Genetic engineering allows different species of bacteria to communicate

What if the bacteria that live in your gut could monitor your health, report disease, and produce beneficial molecules? Researchers have gotten one step closer to creating such a ‘synthetic microbiome’ by engineering different species of bacteria so they can talk to each other. Given that there are over 1,000 different strains of intestinal interlopers in the human gut, such coordination is crucial for the development of systems that can sense and improve human digestive health.

More than 1,000 species of bacteria have been identified in the human gut, and understanding this incredibly diverse “microbiome” that can greatly impact health and disease is a hot topic in scientific research. Because bacteria are routinely genetically engineered in science labs, there is great excitement about the possibility of tweaking the genes of our intestinal interlopers so that they can do more than just help digest our food (e.g., record information about the state of the gut in real-time, report the presence of disease, etc.). However, little is known about how all those different strains communicate with each other, and whether it is even possible to create the kinds of signaling pathways that would allow information to be passed between them.

Now, researchers from the Wyss Institute at Harvard University, Harvard Medical School (HMS), and Brigham and Women’s Hospital have successfully engineered a genetic signal-transmission system in which a molecular signal sent by Salmonella Typhimurium bacteria in response to an environmental cue can be received and recorded by E. coli in the gut of a mouse, bringing scientists a step closer to developing a “synthetic microbiome” composed of bacteria that are programmed to perform specific functions. The study is reported in ACS Synthetic Biology.

“In order to improve human health through engineered gut bacteria, we need to start figuring out how to make the bacteria communicate,” said Suhyun Kim, a graduate student in the lab of Pamela Silver at the Wyss Institute and HMS, who is the first author of the paper. “We want to make sure that, as engineered probiotics develop, we have a means to coordinate and control them in harmony.”

The team harnessed an ability that naturally occurs in some strains of bacteria called “quorum sensing,” in which the bacteria send and receive signal molecules that indicate the overall density of the bacterial colony and regulate the expression of many genes involved in group activities. A particular type of quorum sensing known as acyl-homoserine lactone (acyl-HSL) sensing has not yet been observed in the mammalian gut, so the team decided to see if they could repurpose its signaling system to create a bacterial information transfer system using genetic engineering.

The researchers introduced two new genetic circuits into different colonies of a strain of E. coli bacteria: a “signaler” circuit, and a “responder” circuit. The signaler circuit contains a single copy of a gene called luxI that is turned on by the molecule anhydrotetracycline (ATC) and produces a quorum-sensing signaling molecule. The responder circuit is structured such that when the signaling molecule binds to it, a gene called cro is activated to produce the protein Cro, which then turns on a “memory element” within the responder circuit. The memory element expresses two additional genes: LacZ and another copy of cro. The expression of LacZ causes the bacterium to turn blue if plated on a special agar, thus producing visual confirmation that the signal molecule has been received. The extra copy of cro forms a positive feedback loop that keeps the memory element on, ensuring that the bacterium continues to express LacZ over an extended period of time.

The researchers confirmed that this system works in vitro in both E. coli and S. Typhimurium bacteria, observing that the responder bacteria turned blue when ATC was added to the signaler bacteria. To see if it would work in vivo, they administered both signaler and responder E. coli bacteria to mice, and then gave the mice ATC in their drinking water for two days. When fecal samples from the mice were analyzed, over half of the mice displayed clear signs of 3OC6HSL signal transmission that persisted after two days on ATC.

“It was exciting and promising that our system, with single copy-based circuits, can create functional communication in the mouse gut,” explained Kim. “Traditional genetic engineering introduces multiple copies of a gene of interest into the bacterial genome via plasmids, which places a high metabolic burden on the engineered bacteria and causes them to be easily outcompeted by other bacteria in the host.”

Finally, the team repeated the in vivo experiment, but gave the mice signaler S. Typhimurium bacteria and E. coli responder bacteria, to see if the signal could be transmitted across different species of bacteria within the mouse’s gut. All mice displayed signs of signal transmission, confirming that the engineered circuits allowed communication between different species of bacteria in the complex environment of the mammalian gut.

The researchers hope to continue this line of inquiry by engineering more species of bacteria so that they can communicate, and by searching for and developing other signaling molecules that can be used to transmit information between them.

“Ultimately, we aim to create a synthetic microbiome with completely or mostly engineered bacteria species in our gut, each of which has a specialized function (e.g., detecting and curing disease, creating beneficial molecules, improving digestion, etc.) but also communicates with the others to ensure that they are all balanced for optimal human health,” said corresponding author Silver, Ph.D., a Founding Core Faculty member of the Wyss Institute who is also the Elliot T. and Onie H. Adams Professor of Biochemistry and Systems Biology at HMS.

“The microbiome is the next frontier in medicine as well as wellness. Devising new technologies to engineer intestinal microbes for the better while appreciating that they function as part of a complex community, as was done here, represents a major step forward in this direction,” said Wyss Founding Director Donald Ingber, M.D., Ph.D., who is also the Judah Folkman Professor of Vascular Biology at HMS and the Vascular Biology Program at Boston Children’s Hospital, as well as Professor of Bioengineering at SEAS.

Story Source: ScienceDaily

Journal Reference:

  1. Suhyun Kim, S. Jordan Kerns, Marika Ziesack, Lynn Bry, Georg K. Gerber, Jeffrey C. Way, Pamela A. Silver. Quorum Sensing Can Be Repurposed To Promote Information Transfer between Bacteria in the Mammalian GutACS Synthetic Biology, 2018; DOI: 10.1021/acssynbio.8b00271

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Fiber-fermenting bacteria improve health of type 2 diabetes patients

Fiber-fermenting bacteria improve health of type 2 diabetes patients

The fight against type 2 diabetes may soon improve thanks to a pioneering high-fiber diet study led by a Rutgers University-New Brunswick professor.

Promotion of a select group of gut bacteria by a diet high in diverse fibers led to better blood glucose control, greater weight loss and better lipid levels in people with type 2 diabetes, according to research published today in Science.

The study, underway for six years, provides evidence that eating more of the right dietary fibers may rebalance the gut microbiota, or the ecosystem of bacteria in the gastrointestinal tract that help digest food and are important for overall human health.

“Our study lays the foundation and opens the possibility that fibers targeting this group of gut bacteria could eventually become a major part of your diet and your treatment,” said Liping Zhao, the study’s lead author and a professor in the Department of Biochemistry and Microbiology, School of Environmental and Biological Sciences at Rutgers University-New Brunswick.

Type 2 diabetes, one of the most common debilitating diseases, develops when the pancreas makes too little insulin — a hormone that helps glucose enter cells for use as energy — or the body doesn’t use insulin well.

In the gut, many bacteria break down carbohydrates, such as dietary fibers, and produce short-chain fatty acids that nourish our gut lining cells, reduce inflammation and help control appetite. A shortage of short-chain fatty acids has been associated with type 2 diabetes and other diseases. Many clinical studies also show that increasing dietary fiber intake could alleviate type 2 diabetes, but the effectiveness can vary due to the lack of understanding of the mechanisms, according to Zhao, who works in New Jersey Institute for Food, Nutrition, and Health at Rutgers-New Brunswick.

In research based in China, Zhao and scientists from Shanghai Jiao Tong University and Yan Lam, a research assistant professor in Zhao’s lab at Rutgers, randomized patients with type 2 diabetes into two groups. The control group received standard patient education and dietary recommendations. The treatment group was given a large amount of many types of dietary fibers while ingesting a similar diet for energy and major nutrients. Both groups took the drug acarbose to help control blood glucose.

The high-fiber diet included whole grains, traditional Chinese medicinal foods rich in dietary fibers and prebiotics, which promote growth of short-chain fatty acid-producing gut bacteria. After 12 weeks, patients on the high-fiber diet had greater reduction in a three-month average of blood glucose levels. Their fasting blood glucose levels also dropped faster and they lost more weight.

Surprisingly, of the 141 strains of short-chain fatty acid-producing gut bacteria identified by next-generation sequencing, only 15 are promoted by consuming more fibers and thus are likely to be the key drivers of better health. Bolstered by the high-fiber diet, they became the dominant strains in the gut after they boosted levels of the short-chain fatty acids butyrate and acetate. These acids created a mildly acidic gut environment that reduced populations of detrimental bacteria and led to increased insulin production and better blood glucose control.

The study supports establishing a healthy gut microbiota as a new nutritional approach for preventing and managing type 2 diabetes.

Story Source: ScienceDaily

Journal Reference:

  1. Liping Zhao, Feng Zhang, Xiaoying Ding, Guojun Wu, Yan Y. Lam, Xuejiao Wang, Huaqing Fu, Xinhe Xue, Chunhua Lu, Jilin Ma, Lihua Yu, Chengmei Xu, Zhongying Ren, Ying Xu, Songmei Xu, Hongli Shen, Xiuli Zhu, Yu Shi, Qingyun Shen, Weiping Dong, Rui Liu, Yunxia Ling, Yue Zeng, Xingpeng Wang, Qianpeng Zhang, Jing Wang, Linghua Wang, Yanqiu Wu, Benhua Zeng, Hong Wei, Menghui Zhang, Yongde Peng, Chenhong Zhang. Gut bacteria selectively promoted by dietary fibers alleviate type 2 diabetes. Science, 2018; 359 (6380): 1151 DOI: 10.1126/science.aao5774

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