Benefits of Mediterranean diet in cancer treatment shown in PRIMM study

Benefits of Mediterranean diet in cancer treatment shown in PRIMM study

Benefits of Mediterranean diet in cancer treatment shown in PRIMM study

Recent findings from the multicenter cohort study (PRIMM study) have been published in JAMA Oncology, showing that a Mediterranean diet is associated with improved efficacy of immunotherapy for patients with metastatic melanoma, a serious form of skin cancer. The findings provide encouraging news for cancer patients worldwide.

This publication is part of a large multi-national effort to collect samples and analyse data in a standardised manner, and is already the third data layer published on this cohort. The resulting multi-omic signatures have the potential to reveal novel diagnostic and therapeutic opportunities across the diet-microbiome-immunity axis in cancer.

The latest study investigated the potential to improve the efficacy and tolerability of immune checkpoint blockade (ICB) treatment through nutrition and its association with the immune system and gut microbiome. Therefore, the study addresses two existing gaps in research (1) the large variability in the response to ICB and related adverse events, and (2) the role of improved diversity in the microbiome which is associated with a healthy diet.

Within the cohort study of patients with advanced melanoma in the UK and the Netherlands treated with ICB and followed for 12 months, researchers assessed the dietary intake of 91 patients through questionnaires before and after treatment. CT scans were used to measure the effect of immunotherapy, and progression-free survival established after one year.

Excitingly, this investigation showed that a Mediterranean-style diet was positively associated with patients’ response to ICB.

The Mediterranean diet – enriched in whole grains, fish, nuts, fruit, legumes and vegetables – is a widely recommended model of healthy eating and has shown positive effects in multiple previous studies investigating other indications.

Seerave has supported the outstanding research teams including the Netherlands’ University Medical Center Groningen’s Laura Bolte, Johannes Björk, Geke Hospers and Rinse Weersma, alongside their King’s College London colleagues Karla Lee, Veronique Bataille and Tim Spector, to achieve this next milestone publication in JAMA Oncology.

While we are just scratching the surface on the role of nutrition and the microbiome in cancer care, more and more evidence is surfacing, pointing to them as powerful parameters in patients’ treatment and health.

We are excited to continue working with world-leading organisations to ultimately help prevent and defeat cancer and other immune-related diseases by enabling personalized modulation of the nutrition-microbiome-immune system axis.

This published peer-reviewed report adds to a previous study (Lee et al. Nature Medicine, 2022) from the same patient cohort, establishing that the gut microbiome is implicated in the response to cancer immunotherapy as well.

The complete JAMA Oncology report (“Association of a Mediterranean Diet With Outcomes for Patients Treated With Immune Checkpoint Blockade for Advanced Melanoma”) can be accessed online: [here] Furthermore, you can also listen to the podcast on this publication: [here]


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More effective cancer immunotherapy thanks to the gut microbiome

More effective cancer immunotherapy thanks to the gut microbiome

For more than four years, Seerave Foundation has been supporting the outstanding research teams at King’s College London (UK), UMCG (NL) and University of Trento (I) to find out whether there is a link between the presence and function of the gut microbiome and the outcome of cancer immunotherapy. We are thrilled to see this milestone work being published in Nature Medicine!

Congrats to all the authors and especially Karla Lee, Andrew Thomas, Laura Bolte, Johannes Björk, Laurence Zitvogel, Veronique Bataille, Geke Hospers, Tim Spector, Rinse Weersma and Nicola Segata from the Seerave network!

In summary, the team found that the gut microbiome has a relevant, but cohort-dependent, association with the response to ICIs. A panel of species, including Bifidobacterium pseudocatenulatumRoseburia spp. and Akkermansia muciniphila, associated with responders was identified, but no single species could be regarded as a fully consistent biomarker across studies. Overall, the role of the human gut microbiome in ICI response appears more complex than previously thought, extending beyond differing microbial species simply present or absent in responders and non-responders.

We hope that this open access publication will drive more research into finding the mechanistic answers needed to drive personalised microbiome-targeted interventions forward. Dedicated papers regarding the association of different diet patterns with response in the same cohorts will be published separately in the coming months (as well as papers including proteomic, glycomic and metabolomic analysis).

Stay tuned!

Source: https://www.nature.com/articles/s41591-022-01695-5.pdf


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Happy #WorldMicrobiomeDay 2021! 🎉

Happy #WorldMicrobiomeDay 2021! 🎉

On World Microbiome Day we celebrate all things microbial, all around the world.

Today we would like to raise special attention to one of our initiatives: The collaboration between MyFoodRepo @EPFL and Microsetta @UCSD. Together they aim to roll out a US-wide citizen science project aiming to collect as much information as possible on everyday food items we consume. This information will help to train an algorithm that enables researchers in the future to better track nutrition and give more profound insights. Therefore…

We ask all of you to contribute to the microbe revolution: the “FoodRepo Scan” app is a new way #CitizenScientists can help advance the understanding between diet & microbes! Download the app on iOS or Android and start adding barcodes and images of food items you have at home or encounter in any store. The data will then become publicly available on FoodRepo. This will create a hugely valuable dataset, available to anyone in the world, with which research into nutrition and health will be accelerated. For example, it will serve as a nutritional library for the MyFoodRepo platform, a new AI-assisted tool that allows tracking of high dimensional nutritional data during clinical studies. Become part of tomorrow’s science today!

The collaboration between Microsetta and the Digital Epidemiology team at EPFL is made possible thanks to the support from the Seerave Foundation for nutrition and microbiome research @Seerave Foundation; please see http://www.seerave.org/projects for more details.


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Long-term dietary patterns are associated with pro- inflammatory and anti-inflammatory features of the gut microbiome

Long-term dietary patterns are associated with pro- inflammatory and anti-inflammatory features of the gut microbiome

Researchers found that specific foods and nutrients correlated with species known to have mucosal protection and anti-inflammatory effects, according to data published in Gut.

“We identified dietary patterns that consistently correlate with groups of bacteria with shared functional roles in both health and disease,” Laura A. Bolte, BSc, from the department of gastroenterology and hepatology, University of Groningen and University Medical Centre Groningen, Groningen, the Netherlands, and colleagues wrote. “Moreover, specific foods and nutrients were associated with species known to infer mucosal protection and anti-inflammatory effects. We propose microbial mechanisms through which the diet affects inflammatory responses in the gut as a rationale for future intervention studies.”

Bolte and colleagues analyzed the relationship between 173 dietary factors and the microbiome of 1,425 patients from different cohorts including Crohn’s disease, ulcerative colitis, irritable bowel syndrome and the general population. They profiled gut microbial composition and function with shotgun metagenomic sequencing assessed dietary intake via food frequency questionnaires.

“We performed unsupervised clustering to identify dietary patterns and microbial clusters,” Bolte and colleagues wrote. “Associations between diet and microbial features were explored per cohort, followed by a meta-analysis and heterogeneity estimation.”

The researchers identified 38 links between dietary patterns and microbial clusters. In their meta-analysis of healthy individuals and patients with IBS, Crohn’s disease and UC, investigators found 61 individual foods and nutrients correlated with 61 species and 249 metabolic pathways.

“Processed foods and animal-derived foods were consistently associated with higher abundances of Firmicutes, Ruminococcus species of the Blautia genus and endotoxin synthesis pathways,” Bolte and colleagues wrote. “The opposite was found for plant foods and fish, which were positively associated with short-chain fatty acid-producing commensals and pathways of nutrient metabolism.”

DOI: doi:10.1136/gutjnl-2020-322670.

Story Source:  https://www.healio.com/news/gastroenterology/20210405/diet-patterns-linked-with-gut-proinflammatory-antiinflammatory-features


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Ketogenic diet and ketone bodies enhance the anticancer effects of PD-1 blockade

Ketogenic diet and ketone bodies enhance the anticancer effects of PD-1 blockade

Limited experimental evidence bridges nutrition and cancer immunosurveillance. Here, the team at IGR Paris shows that ketogenic diet (KD) or its principal ketone body, 3-hydroxybutyrate (3HB), most specifically in an intermittent scheduling, induced T cell-dependent tumour growth retardation of aggressive tumour models.

In conditions in which anti-PD-1, alone or in combination with anti-CTLA-4, failed to reduce tumour growth in mice receiving a standard diet, KD or oral supplementation of 3HB reestablished therapeutic responses. Supplementation of KD with sucrose (which breaks ketogenesis, abolishing 3HB production) or with a pharmacological antagonist of the 3HB receptor GPR109A abolished the anti-tumour effects. Mechanistically, 3HB prevented the ICB-linked up-regulation of PD-L1 on myeloid cells while favouring the expansion of CXCR3+ T cells. KD induced compositional changes of the gut microbiota with distinct species such as Eisenbergiella massiliensis commonly emerging in mice and humans subjected to carbohydrate low diet interventions and highly correlating with serum concentrations of 3HB. Altogether, these results demonstrate that KD induces a 3HB-mediated antineoplastic effect that relies on T-cell mediated cancer immunosurveillance.

Source: http://www.ncbi.nlm.nih.gov/pubmed/33320838

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Landmark nutritional study PREDICT shows dietary inflammation after meals varies dramatically among healthy adults

Landmark nutritional study PREDICT shows dietary inflammation after meals varies dramatically among healthy adults

Researchers led by the Department of Twin Research announced today the first published results from PREDICT, the largest ongoing nutritional study of its kind.

The team found a wide range of metabolic responses after eating in apparently healthy adults, and that inflammation triggered by the food we eat varies up to ten-fold.

Poor metabolic responses to food, where the body takes longer and works harder to clear the blood of fat and sugar, are linked with increased risk of conditions such as low-grade inflammatory diseases including heart disease, type 2 diabetes and obesity.

The results suggests improved health could be achieved by eating foods that are personalised to reduce inflammation after meals.

Senior researcher on the study Professor Tim Spector said:   “When it comes to weight, we’ve traditionally put a huge emphasis on factors we have no control over, like genetics. The fact is, while genetics plays a role, there are many more important factors that impact an individual’s response to food and maintenance of a healthy metabolism. This study shows that achieving a healthy weight requires a scientific approach to eating that takes into account an individual’s unique biology.

Led by Professor Tim Spector and his team at King’s College London and spin-out  health science company ZOE, the PREDICT study consisted of 1,103 participants, including 660 identical and non-identical twins from TwinsUK.

The study measured a wide range of markers from blood glucose, fat and insulin levels to exercise, sleep and gut bacteria (microbiome) over two weeks. It is the most detailed study to date to look at all the different factors that affect our responses to food together.

Despite wide variation in metabolic responses between participants, results from identical meals eaten on different days showed that individual responses to the same foods were remarkably consistent for each person.

The team also found that the optimal time to eat for nutritional health also depends on the individual rather than fixed “perfect” mealtimes. The researchers found that some people clearly metabolised food better at breakfast while others saw no difference.

Dr Sarah Berry, Senior Lecturer of Nutrition Sciences at King’s College London, led on the inflammation part of the study. She said:  “We found that the increase in fat and glucose in our blood after eating a meal initiates an inflammatory response which differs hugely between individuals. Dietary and lifestyle strategies to reduce prolonged elevations in blood fat and glucose may therefore be a useful target to reduce low-grade inflammation, and protect people from low-grade inflammatory conditions such as type 2 diabetes and cardiovascular disease.

Story Source: https://twinsuk.ac.uk/landmark-nutritional-study-predict-shows-dietary-inflammation-after-meals-varies-dramatically-among-healthy-adults/

DOI: https://doi.org/10.1038/s41591-020-0934-0


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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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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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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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