Publications by authors named "Eran Elinav"

169 Publications

Toward a better understanding of intermittent fasting effects: Ramadan fasting as a model.

Am J Clin Nutr 2021 Mar 12. Epub 2021 Mar 12.

Department of Immunology, Weizmann Institute of Science, Rehovot, Israel.

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http://dx.doi.org/10.1093/ajcn/nqab017DOI Listing
March 2021

Remembering past infections: training exercise for gut microbes.

Cell Res 2021 Apr;31(4):375-376

Immunology Department, Weizmann Institute of Science, Rehovot, Israel.

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http://dx.doi.org/10.1038/s41422-021-00481-1DOI Listing
April 2021

Breakthroughs and Bottlenecks in Microbiome Research.

Trends Mol Med 2021 Apr 6;27(4):298-301. Epub 2021 Feb 6.

Immunology Department, Weizmann Institute of Science, Rehovot, 7610001, Israel; Cancer-Microbiome Division Deutsches Krebsforschungszentrum (DKFZ), Neuenheimer Feld 280, 69120 Heidelberg, Germany. Electronic address:

Over the past 15 years, the research community has witnessed unprecedented progress in microbiome research. We review this increasing knowledge and first attempts of its clinical application, and also limitations and challenges faced by the research community, in mechanistically understanding host-microbiome interactions and integrating these insights into clinical practice.
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http://dx.doi.org/10.1016/j.molmed.2021.01.003DOI Listing
April 2021

Harnessing SmartPhones to Personalize Nutrition in a Time of Global Pandemic.

Nutrients 2021 Jan 28;13(2). Epub 2021 Jan 28.

Immunology Department, Weizmann Institute of Science, Rehovot 7610001, Israel.

The soar in COVID-19 cases around the globe has forced many to adapt to social distancing and self-isolation. In order to reduce contact with healthcare facilities and other patients, the CDC has advocated the use of telemedicine, i.e., electronic information and telecommunication technology. While these changes may disrupt normal behaviors and routines and induce anxiety, resulting in decreased vigilance to healthy diet and physical activity and reluctance to seek medical attention, they may just as well be circumvented using modern technology. Indeed, as the beginning of the pandemic a plethora of alternatives to conventional physical interactions were introduced. In this Perspective, we portray the role of SmartPhone applications (apps) in monitoring healthy nutrition, from their basic functionality as food diaries required for simple decision-making and nutritional interventions, through more advanced purposes, such as multi-dimensional data-mining and development of machine learning algorithms. Finally, we will delineate the emerging field of personalized nutrition and introduce pioneering technologies and concepts yet to be incorporated in SmartPhone-based dietary surveillance.
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http://dx.doi.org/10.3390/nu13020422DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7911023PMC
January 2021

The hygiene hypothesis, the COVID pandemic, and consequences for the human microbiome.

Proc Natl Acad Sci U S A 2021 02;118(6)

Humans and the Microbiome Program, Canadian Institute for Advanced Research, Toronto, ON M5G 1M1, Canada;

The COVID-19 pandemic has the potential to affect the human microbiome in infected and uninfected individuals, having a substantial impact on human health over the long term. This pandemic intersects with a decades-long decline in microbial diversity and ancestral microbes due to hygiene, antibiotics, and urban living (the hygiene hypothesis). High-risk groups succumbing to COVID-19 include those with preexisting conditions, such as diabetes and obesity, which are also associated with microbiome abnormalities. Current pandemic control measures and practices will have broad, uneven, and potentially long-term effects for the human microbiome across the planet, given the implementation of physical separation, extensive hygiene, travel barriers, and other measures that influence overall microbial loss and inability for reinoculation. Although much remains uncertain or unknown about the virus and its consequences, implementing pandemic control practices could significantly affect the microbiome. In this Perspective, we explore many facets of COVID-19-induced societal changes and their possible effects on the microbiome, and discuss current and future challenges regarding the interplay between this pandemic and the microbiome. Recent recognition of the microbiome's influence on human health makes it critical to consider both how the microbiome, shaped by biosocial processes, affects susceptibility to the coronavirus and, conversely, how COVID-19 disease and prevention measures may affect the microbiome. This knowledge may prove key in prevention and treatment, and long-term biological and social outcomes of this pandemic.
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http://dx.doi.org/10.1073/pnas.2010217118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8017729PMC
February 2021

The gut microbiome: a key player in the complexity of amyotrophic lateral sclerosis (ALS).

BMC Med 2021 Jan 20;19(1):13. Epub 2021 Jan 20.

Sheffield Institute for Translational Neuroscience, University of Sheffield, Sheffield, UK.

Background: Much progress has been made in mapping genetic abnormalities linked to amyotrophic lateral sclerosis (ALS), but the majority of cases still present with no known underlying cause. Furthermore, even in families with a shared genetic abnormality there is significant phenotypic variability, suggesting that non-genetic elements may modify pathogenesis. Identification of such disease-modifiers is important as they might represent new therapeutic targets. A growing body of research has begun to shed light on the role played by the gut microbiome in health and disease with a number of studies linking abnormalities to ALS.

Main Body: The microbiome refers to the genes belonging to the myriad different microorganisms that live within and upon us, collectively known as the microbiota. Most of these microbes are found in the intestines, where they play important roles in digestion and the generation of key metabolites including neurotransmitters. The gut microbiota is an important aspect of the environment in which our bodies operate and inter-individual differences may be key to explaining the different disease outcomes seen in ALS. Work has begun to investigate animal models of the disease, and the gut microbiomes of people living with ALS, revealing changes in the microbial communities of these groups. The current body of knowledge will be summarised in this review. Advances in microbiome sequencing methods will be highlighted, as their improved resolution now enables researchers to further explore differences at a functional level. Proposed mechanisms connecting the gut microbiome to neurodegeneration will also be considered, including direct effects via metabolites released into the host circulation and indirect effects on bioavailability of nutrients and even medications.

Conclusion: Profiling of the gut microbiome has the potential to add an environmental component to rapidly advancing studies of ALS genetics and move research a step further towards personalised medicine for this disease. Moreover, should compelling evidence of upstream neurotoxicity or neuroprotection initiated by gut microbiota emerge, modification of the microbiome will represent a potential new avenue for disease modifying therapies. For an intractable condition with few current therapeutic options, further research into the ALS microbiome is of crucial importance.
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http://dx.doi.org/10.1186/s12916-020-01885-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7816375PMC
January 2021

Maturation of the neonatal oral mucosa involves unique epithelium-microbiota interactions.

Cell Host Microbe 2021 02 6;29(2):197-209.e5. Epub 2021 Jan 6.

Institute of Dental Sciences, Faculty of Dental Medicine, Hebrew University, Jerusalem, Israel. Electronic address:

Postnatal host-microbiota interplay governs mucosal homeostasis and is considered to have life-long health consequences. The intestine monolayer epithelium is critically involved in such early-life processes; nevertheless, the role of the oral multilayer epithelium remains ill defined. We demonstrate that unlike the intestine, the neonate oral cavity is immensely colonized by the microbiota that decline to adult levels during weaning. Neutrophils are present in the oral epithelium prenatally, and exposure to the microbiota postnatally further recruits them to the preamble neonatal epithelium by γδT17 cells. These neutrophils virtually disappear during weaning as the epithelium seals. The neonate and adult epithelium display distinct turnover kinetics and transcriptomic signatures, with neonate epithelium reminiscent of the signature found in germ-free mice. Microbial reduction during weaning is mediated by the upregulation of saliva production and induction of salivary antimicrobial components by the microbiota. Collectively, unique postnatal interactions between the multilayer epithelium and microbiota shape oral homeostasis.
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http://dx.doi.org/10.1016/j.chom.2020.12.006DOI Listing
February 2021

The NLRP6 inflammasome.

Immunology 2021 Mar 27;162(3):281-289. Epub 2020 Dec 27.

Immunology Department, Weizmann Institute of Science, Rehovot, Israel.

The NOD-like receptor family pyrin domain containing 6 (NLRP6), a member of the NOD-like receptor (NLR) family, acts as a cytosolic innate immune sensor that recognizes microbe-associated molecular patterns. In some circumstances upon activation, NLRP6 recruits the adaptor apoptosis-associated speck-like protein (ASC) and the inflammatory caspase-1 or caspase-11 to form an inflammasome, which mediates the maturation and secretion of the pro-inflammatory cytokines IL-18 and IL-1β. In other contexts, NLRP6 can exert its function in an inflammasome-independent manner. Tight regulation of the NLRP6 inflammasome is critical in maintaining tissue homeostasis, while improper inflammasome activation may contribute to the development of multiple diseases. In intestinal epithelial cells, the NLRP6 inflammasome is suggested to play a role in regulating gut microbiome composition, goblet cell function and related susceptibility to gastrointestinal inflammatory, infectious and neoplastic diseases. Additionally, NLRP6 may regulate extra-intestinal diseases. In this review, we summarize current knowledge on the NLRP6 inflammasome and its activation and regulation patterns, as well as its effector functions contributing to disease modulation. We discuss current challenges in NLRP6 research and future prospects in harnessing its function into potential human interventions.
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http://dx.doi.org/10.1111/imm.13293DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7884648PMC
March 2021

Our Microbiome: On the Challenges, Promises, and Hype.

Results Probl Cell Differ 2020 ;69:539-557

Immunology Department, Weizmann Institute of Science, Rehovot, Israel.

The microbiome field is increasingly raising interest among scientists, clinicians, biopharmaceutical entities, and the general public. Technological advances from the past two decades have enabled the rapid expansion of our ability to characterize the human microbiome in depth, highlighting its previously underappreciated role in contributing to multifactorial diseases including those with unknown etiology. Consequently, there is growing evidence that the microbiome could be utilized in medical diagnosis and patient stratification. Moreover, multiple gut microbes and their metabolic products may be bioactive, thereby serving as future potential microbiome-targeting or -associated therapeutics. Such therapies could include new generation probiotics, prebiotics, fecal microbiota transplantations, postbiotics, and dietary modulators. However, microbiome research has also been associated with significant limitations, technical and conceptual challenges, and, at times, "over-hyped" expectations that microbiome research will produce quick solutions to chronic and mechanistically complex human disorders. Herein, we summarize these challenges and also discuss some of the realistic promises associated with microbiome research and its applicability into clinical application.
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http://dx.doi.org/10.1007/978-3-030-51849-3_20DOI Listing
January 2021

Acute liver failure is regulated by MYC- and microbiome-dependent programs.

Nat Med 2020 12 26;26(12):1899-1911. Epub 2020 Oct 26.

Immunology Department, Weizmann Institute of Science, Rehovot, Israel.

Acute liver failure (ALF) is a fulminant complication of multiple etiologies, characterized by rapid hepatic destruction, multi-organ failure and mortality. ALF treatment is mainly limited to supportive care and liver transplantation. Here we utilize the acetaminophen (APAP) and thioacetamide (TAA) ALF models in characterizing 56,527 single-cell transcriptomes to define the mouse ALF cellular atlas. We demonstrate that unique, previously uncharacterized stellate cell, endothelial cell, Kupffer cell, monocyte and neutrophil subsets, and their intricate intercellular crosstalk, drive ALF. We unravel a common MYC-dependent transcriptional program orchestrating stellate, endothelial and Kupffer cell activation during ALF, which is regulated by the gut microbiome through Toll-like receptor (TLR) signaling. Pharmacological inhibition of MYC, upstream TLR signaling checkpoints or microbiome depletion suppress this cell-specific, MYC-dependent program, thereby attenuating ALF. In humans, we demonstrate upregulated hepatic MYC expression in ALF transplant recipients compared to healthy donors. Collectively we demonstrate that detailed cellular/genetic decoding may enable pathway-specific ALF therapeutic intervention.
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http://dx.doi.org/10.1038/s41591-020-1102-2DOI Listing
December 2020

Rationale and design of a randomised controlled trial testing the effect of personalised diet in individuals with pre-diabetes or type 2 diabetes mellitus treated with metformin.

BMJ Open 2020 10 10;10(10):e037859. Epub 2020 Oct 10.

Healthy Ageing Theme, Garvan Institute of Medical Research, Sydney, New South Wales, Australia

Introduction: Metformin and diets aimed at promoting healthy body weight are the first line in treating type 2 diabetes mellitus (T2DM). Clinical practice, backed by clinical trials, suggests that many individuals do not reach glycaemic targets using this approach alone. The primary aim of the Personalised Medicine in Pre-diabetes-Towards Preventing Diabetes in Individuals at Risk (PREDICT) Study is to test the efficacy of personalised diet as adjuvant to metformin in improving glycaemic control in individuals with dysglycaemia.

Methods And Analysis: PREDICT is a two-arm, parallel group, single-masked randomised controlled trial in adults with pre-diabetes or early-stage T2DM (with glycated haemoglobin (HbA1c) up to 8.0% (64 mmol/mol)), not treated with glucose-lowering medication. PREDICT is conducted at the Clinical Research Facility at the Garvan Institute of Medical Research (Sydney). Enrolment of participants commenced in December 2018 and expected to complete in December 2021. Participants are commenced on metformin (Extended Release, titrated to a target dose of 1500 mg/day) and randomised with equal allocation to either (1) the Personalised Nutrition Project algorithm-based diet or (2) low-fat high-dietary fibre diet, designed to provide caloric restriction (75%) in individuals with body mass index >25 kg/m. Treatment duration is 6 months and participants visit the Clinical Research Facility five times over approximately 7 months. The primary outcome measure is HbA1c. The secondary outcomes are (1) time of interstitial glucose <7.8 mmol/L and (2) glycaemic variability (continuous glucose monitoring), (3) body weight, (4) fat mass and (5) abdominal visceral fat volume (dual-energy X-ray absorptiometry), serum (6) low-density lipoprotein cholesterol (7) high-density lipoprotein cholesterol and (8) triglycerides concentrations, (9) blood pressure, and (10) liver fat (Fibroscan).

Ethics And Dissemination: The study has been approved by the St Vincent's Hospital Human Research Ethics Committee (File 17/080, Sydney, Australia) and the Weizmann Institutional Review Board (File 528-3, Rehovot, Israel). The findings will be published in peer-reviewed open access medical journals.

Trial Registration Number: NCT03558867; Pre-results.
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http://dx.doi.org/10.1136/bmjopen-2020-037859DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7552859PMC
October 2020

The Gut Microbiome and Individual-Specific Responses to Diet.

mSystems 2020 Sep 29;5(5). Epub 2020 Sep 29.

Department of Immunology, Weizmann Institute of Science, Rehovot, Israel

Nutritional content and timing are increasingly appreciated to constitute important human variables collectively impacting all aspects of human physiology and disease. However, person-specific mechanisms driving nutritional impacts on the human host remain incompletely understood, while current dietary recommendations remain empirical and nonpersonalized. Precision nutrition aims to harness individualized bodies of data, including the human gut microbiome, in predicting person-specific physiological responses (such as glycemic responses) to food. With these advances notwithstanding, many unknowns remain, including the long-term efficacy of such interventions in delaying or reversing human metabolic disease, mechanisms driving these dietary effects, and the extent of the contribution of the gut microbiome to these processes. We summarize these conceptual advances, while highlighting challenges and means of addressing them in the next decade of study of precision medicine, toward generation of insights that may help to evolve precision nutrition as an effective future tool in a variety of "multifactorial" human disorders.
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http://dx.doi.org/10.1128/mSystems.00665-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7527138PMC
September 2020

Longitudinal Multi-omics Reveals Subset-Specific Mechanisms Underlying Irritable Bowel Syndrome.

Cell 2020 09 10;182(6):1460-1473.e17. Epub 2020 Sep 10.

Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN 55905, USA; Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN 55905, USA. Electronic address:

The gut microbiome has been implicated in multiple human chronic gastrointestinal (GI) disorders. Determining its mechanistic role in disease has been difficult due to apparent disconnects between animal and human studies and lack of an integrated multi-omics view of disease-specific physiological changes. We integrated longitudinal multi-omics data from the gut microbiome, metabolome, host epigenome, and transcriptome in the context of irritable bowel syndrome (IBS) host physiology. We identified IBS subtype-specific and symptom-related variation in microbial composition and function. A subset of identified changes in microbial metabolites correspond to host physiological mechanisms that are relevant to IBS. By integrating multiple data layers, we identified purine metabolism as a novel host-microbial metabolic pathway in IBS with translational potential. Our study highlights the importance of longitudinal sampling and integrating complementary multi-omics data to identify functional mechanisms that can serve as therapeutic targets in a comprehensive treatment strategy for chronic GI diseases. VIDEO ABSTRACT.
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http://dx.doi.org/10.1016/j.cell.2020.08.007DOI Listing
September 2020

Phages and their potential to modulate the microbiome and immunity.

Cell Mol Immunol 2021 Apr 8;18(4):889-904. Epub 2020 Sep 8.

Immunology Department, Weizmann Institute of Science, Rehovot, 7610001, Israel.

Bacteriophages (hence termed phages) are viruses that target bacteria and have long been considered as potential future treatments against antibiotic-resistant bacterial infection. However, the molecular nature of phage interactions with bacteria and the human host has remained elusive for decades, limiting their therapeutic application. While many phages and their functional repertoires remain unknown, the advent of next-generation sequencing has increasingly enabled researchers to decode new lytic and lysogenic mechanisms by which they attack and destroy bacteria. Furthermore, the last decade has witnessed a renewed interest in the utilization of phages as therapeutic vectors and as a means of targeting pathogenic or commensal bacteria or inducing immunomodulation. Importantly, the narrow host range, immense antibacterial repertoire, and ease of manipulating phages may potentially allow for their use as targeted modulators of pathogenic, commensal and pathobiont members of the microbiome, thereby impacting mammalian physiology and immunity along mucosal surfaces in health and in microbiome-associated diseases. In this review, we aim to highlight recent advances in phage biology and how a mechanistic understanding of phage-bacteria-host interactions may facilitate the development of novel phage-based therapeutics. We provide an overview of the challenges of the therapeutic use of phages and how these could be addressed for future use of phages as specific modulators of the human microbiome in a variety of infectious and noncommunicable human diseases.
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http://dx.doi.org/10.1038/s41423-020-00532-4DOI Listing
April 2021

Diet Diurnally Regulates Small Intestinal Microbiome-Epithelial-Immune Homeostasis and Enteritis.

Cell 2020 09 3;182(6):1441-1459.e21. Epub 2020 Sep 3.

Immunology Department, Weizmann Institute of Science, Rehovot 7610001, Israel; Division of Cancer-Microbiome Research, DKFZ, Heidelberg 69120, Germany. Electronic address:

Throughout a 24-h period, the small intestine (SI) is exposed to diurnally varying food- and microbiome-derived antigenic burdens but maintains a strict immune homeostasis, which when perturbed in genetically susceptible individuals, may lead to Crohn disease. Herein, we demonstrate that dietary content and rhythmicity regulate the diurnally shifting SI epithelial cell (SIEC) transcriptional landscape through modulation of the SI microbiome. We exemplify this concept with SIEC major histocompatibility complex (MHC) class II, which is diurnally modulated by distinct mucosal-adherent SI commensals, while supporting downstream diurnal activity of intra-epithelial IL-10 lymphocytes regulating the SI barrier function. Disruption of this diurnally regulated diet-microbiome-MHC class II-IL-10-epithelial barrier axis by circadian clock disarrangement, alterations in feeding time or content, or epithelial-specific MHC class II depletion leads to an extensive microbial product influx, driving Crohn-like enteritis. Collectively, we highlight nutritional features that modulate SI microbiome, immunity, and barrier function and identify dietary, epithelial, and immune checkpoints along this axis to be potentially exploitable in future Crohn disease interventions.
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http://dx.doi.org/10.1016/j.cell.2020.08.027DOI Listing
September 2020

The microbiome and cytosolic innate immune receptors.

Immunol Rev 2020 09 13;297(1):207-224. Epub 2020 Jul 13.

Immunology Department, Weizmann Institute of Science, Rehovot, Israel.

The discovery of innate immune sensors (pattern recognition receptors, PRRs) has profoundly transformed the notion of innate immunity, in providing a mechanistic basis for host immune interactions with a wealth of environmental signals, leading to a variety of immune-mediated outcomes including instruction and activation of the adaptive immune arm. As part of this growing understanding of host-environmental cross talk, an intimate connection has been unveiled between innate immune sensors and signals perceived from the commensal microbiota, which may be regarded as a hub integrating a variety of environmental cues. Among cytosolic PRRs impacting on host homeostasis by interacting with the commensal microbiota are nucleotide-binding domain, leucine-rich repeat-containing protein receptors (NLRs), together with a number of cytosolic DNA sensors and the family of absent in melanoma (AIM)-like receptors (ALRs). NLR sensors have been a particular focus of research, and some NLRs have emerged as key orchestrators of inflammatory responses and host homeostasis. Some NLRs achieve this through the formation of cytoplasmic multiprotein complexes termed inflammasomes. More recently discovered PRRs include retinoic acid-inducible gene-I (RIG-I)-like receptors (RLRs), cyclic GMP-AMP synthase (cGAS), and STING. In the present review, they summarize recent advancements in knowledge on structure and function of cytosolic PRRs and their roles in host-microbiota cross talk and immune surveillance. In addition, we discuss their relevance for human health and disease and future therapeutic applications involving modulation of their activation and signaling.
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http://dx.doi.org/10.1111/imr.12901DOI Listing
September 2020

High-Throughput Screen Identifies Host and Microbiota Regulators of Intestinal Barrier Function.

Gastroenterology 2020 11 9;159(5):1807-1823. Epub 2020 Jul 9.

Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel; Immunology Department, Weizmann Institute of Science, Rehovot, Israel. Electronic address:

Background & Aims: The intestinal barrier protects intestinal cells from microbes and antigens in the lumen-breaches can alter the composition of the intestinal microbiota, the enteric immune system, and metabolism. We performed a screen to identify molecules that disrupt and support the intestinal epithelial barrier and tested their effects in mice.

Methods: We performed an imaging-based, quantitative, high-throughput screen (using CaCo-2 and T84 cells incubated with lipopolysaccharide; tumor necrosis factor; histamine; receptor antagonists; and libraries of secreted proteins, microbial metabolites, and drugs) to identify molecules that altered epithelial tight junction (TJ) and focal adhesion morphology. We then tested the effects of TJ stabilizers on these changes. Molecules we found to disrupt or stabilize TJs were administered mice with dextran sodium sulfate-induced colitis or Citrobacter rodentium-induced intestinal inflammation. Colon tissues were collected and analyzed by histology, fluorescence microscopy, and RNA sequencing.

Results: The screen identified numerous compounds that disrupted or stabilized (after disruption) TJs and monolayers of epithelial cells. We associated distinct morphologic alterations with changes in barrier function, and identified a variety of cytokines, metabolites, and drugs (including inhibitors of actomyosin contractility) that prevent disruption of TJs and restore TJ integrity. One of these disruptors (putrescine) disrupted TJ integrity in ex vivo mouse colon tissues; administration to mice exacerbated colon inflammation, increased gut permeability, reduced colon transepithelial electrical resistance, increased pattern recognition receptor ligands in mesenteric lymph nodes, and decreased colon length and survival times. Putrescine also increased intestine levels and fecal shedding of viable C rodentium, increased bacterial attachment to the colonic epithelium, and increased levels of inflammatory cytokines in colon tissues. Colonic epithelial cells from mice given putrescine increased expression of genes that regulate metal binding, oxidative stress, and cytoskeletal organization and contractility. Co-administration of taurine with putrescine blocked disruption of TJs and the exacerbated inflammation.

Conclusions: We identified molecules that disrupt and stabilize intestinal epithelial TJs and barrier function and affect development of colon inflammation in mice. These agents might be developed for treatment of barrier intestinal impairment-associated and inflammatory disorders in patients, or avoided to prevent inflammation.
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http://dx.doi.org/10.1053/j.gastro.2020.07.003DOI Listing
November 2020

Inflammasome activation and regulation: toward a better understanding of complex mechanisms.

Cell Discov 2020 9;6:36. Epub 2020 Jun 9.

Immunology Department, Weizmann Institute of Science, Rehovot, 7610001 Israel.

Inflammasomes are cytoplasmic multiprotein complexes comprising a sensor protein, inflammatory caspases, and in some but not all cases an adapter protein connecting the two. They can be activated by a repertoire of endogenous and exogenous stimuli, leading to enzymatic activation of canonical caspase-1, noncanonical caspase-11 (or the equivalent caspase-4 and caspase-5 in humans) or caspase-8, resulting in secretion of IL-1β and IL-18, as well as apoptotic and pyroptotic cell death. Appropriate inflammasome activation is vital for the host to cope with foreign pathogens or tissue damage, while aberrant inflammasome activation can cause uncontrolled tissue responses that may contribute to various diseases, including autoinflammatory disorders, cardiometabolic diseases, cancer and neurodegenerative diseases. Therefore, it is imperative to maintain a fine balance between inflammasome activation and inhibition, which requires a fine-tuned regulation of inflammasome assembly and effector function. Recently, a growing body of studies have been focusing on delineating the structural and molecular mechanisms underlying the regulation of inflammasome signaling. In the present review, we summarize the most recent advances and remaining challenges in understanding the ordered inflammasome assembly and activation upon sensing of diverse stimuli, as well as the tight regulations of these processes. Furthermore, we review recent progress and challenges in translating inflammasome research into therapeutic tools, aimed at modifying inflammasome-regulated human diseases.
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http://dx.doi.org/10.1038/s41421-020-0167-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7280307PMC
June 2020

Nutrition Regulates Innate Immunity in Health and Disease.

Annu Rev Nutr 2020 09 10;40:189-219. Epub 2020 Jun 10.

Department of Immunology, Weizmann Institute of Science, Rehovot 7610001, Israel; email:

Nutrient content and nutrient timing are considered key regulators of human health and a variety of diseases and involve complex interactions with the mucosal immune system. In particular, the innate immune system is emerging as an important signaling hub that modulates the response to nutritional signals, in part via signaling through the gut microbiota. In this review we elucidate emerging evidence that interactions between innate immunity and diet affect human metabolic health and disease, including cardiometabolic disorders, allergic diseases, autoimmune disorders, infections, and cancers. Furthermore, we discuss the potential modulatory effects of the gut microbiota on interactions between the immune system and nutrition in health and disease, namely how it relays nutritional signals to the innate immune system under specific physiological contexts. Finally, we identify key open questions and challenges to comprehensively understanding the intersection between nutrition and innate immunity and how potential nutritional, immune, and microbial therapeutics may be developed into promising future avenues of precision treatment.
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http://dx.doi.org/10.1146/annurev-nutr-120919-094440DOI Listing
September 2020

Amyotrophic lateral sclerosis and intestinal microbiota-toward establishing cause and effect.

Gut Microbes 2020 11 5;11(6):1833-1841. Epub 2020 Jun 5.

Immunology Department, Weizmann Institute of Science , Rehovot, Israel.

The intestinal microbiota may be involved, through metabolic gut-brain interactions, in a variety of neurological conditions. In this addendum, we summarize the findings of our recent study investigating the potentially modulatory influence of the microbiome in a transgenic ALS mouse model, and the possible application to human disease. We found that transgenic mice show evidence of dysbiosis, even at the pre-symptomatic stage, and have a more severe disease course under germ-free conditions or after receiving broad-spectrum antibiotics. We demonstrated that ameliorated the disease in mice and that this may be due to the production of nicotinamide. We then conducted a preliminary study in human ALS and identified functionally similar alterations within the metagenome. Furthermore, we found that patients with ALS had lower systemic and CSF levels of nicotinamide, suggesting that the changes observed in the mouse model may be relevant to human disease.
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http://dx.doi.org/10.1080/19490976.2020.1767464DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7524331PMC
November 2020

Niche rather than origin dysregulates mucosal Langerhans cells development in aged mice.

Mucosal Immunol 2020 09 26;13(5):767-776. Epub 2020 May 26.

The Institute of Dental Sciences, Faculty of Dental Medicine, Hebrew University, Jerusalem, Israel.

Unlike epidermal Langerhans cells (LCs) that originate from embryonic precursors and are self-renewed locally, mucosal LCs arise and are replaced by circulating bone marrow (BM) precursors throughout life. While the unique lifecycle of epidermal LCs is associated with an age-dependent decrease in their numbers, whether and how aging has an impact on mucosal LCs remains unclear. Focusing on gingival LCs we found that mucosal LCs are reduced with age but exhibit altered morphology with that observed in aged epidermal LCs. The reduction of gingival but not epidermal LCs in aged mice was microbiota-dependent; nevertheless, the impact of the microbiota on gingival LCs was indirect. We next compared the ability of young and aged BM precursors to differentiate to mucosal LCs. Mixed BM chimeras, as well as differentiation cultures, demonstrated that aged BM has intact if not superior capacity to differentiate into LCs than young BM. This was in line with the higher percentages of mucosal LC precursors, pre-DCs, and monocytes, detected in aged BM. These findings suggest that while aging is associated with reduced LC numbers, the niche rather than the origin controls this process in mucosal barriers.
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http://dx.doi.org/10.1038/s41385-020-0301-yDOI Listing
September 2020

Interaction between microbiota and immunity in health and disease.

Cell Res 2020 06 20;30(6):492-506. Epub 2020 May 20.

Immunology Department, Weizmann Institute of Science, 234 Herzl Street, 7610001, Rehovot, Israel.

The interplay between the commensal microbiota and the mammalian immune system development and function includes multifold interactions in homeostasis and disease. The microbiome plays critical roles in the training and development of major components of the host's innate and adaptive immune system, while the immune system orchestrates the maintenance of key features of host-microbe symbiosis. In a genetically susceptible host, imbalances in microbiota-immunity interactions under defined environmental contexts are believed to contribute to the pathogenesis of a multitude of immune-mediated disorders. Here, we review features of microbiome-immunity crosstalk and their roles in health and disease, while providing examples of molecular mechanisms orchestrating these interactions in the intestine and extra-intestinal organs. We highlight aspects of the current knowledge, challenges and limitations in achieving causal understanding of host immune-microbiome interactions, as well as their impact on immune-mediated diseases, and discuss how these insights may translate towards future development of microbiome-targeted therapeutic interventions.
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http://dx.doi.org/10.1038/s41422-020-0332-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7264227PMC
June 2020

Moving from probiotics to precision probiotics.

Nat Microbiol 2020 07;5(7):878-880

Immunology Department, Weizmann Institute of Science, Rehovot, Israel.

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http://dx.doi.org/10.1038/s41564-020-0721-1DOI Listing
July 2020

Circadian Influences of Diet on the Microbiome and Immunity.

Trends Immunol 2020 06 28;41(6):512-530. Epub 2020 Apr 28.

Immunology Department, Weizmann Institute of Science, Rehovot, 7610001, Israel; Cancer Microbiome Division, Deutsches Krebsforschungszentrum (DKFZ), Neuenheimer Feld 280, 69120 Heidelberg, Germany. Electronic address:

Host circadian rhythmicity and the timing of feeding are increasingly recognized to cross-regulate and entrain each other, and may play crucial roles in regulating multiple physiological functions including host immunity and metabolic health. Of relevance, these circadian diet-immune interactions may be modulated by the gut microbiota. We review current knowledge linking the circadian clock and dietary timing to host immune-microbiota interactions, exemplifying how this axis may impact on host immunity in health and in a variety of immune-mediated diseases. We also discuss current challenges in reaching mechanistic insights regarding the functions of the diurnally shifting diet-microbiome-host immune axis. We highlight the possible implications of circadian reprogramming by dietary timing patterns as a future intervention to modulate a variety of immune-related diseases.
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http://dx.doi.org/10.1016/j.it.2020.04.005DOI Listing
June 2020

Immune-Microbiota Interplay and Colonization Resistance in Infection.

Mol Cell 2020 05 23;78(4):597-613. Epub 2020 Mar 23.

Immunology Department, Weizmann Institute of Science, Rehovot 7610001, Israel; Cancer-Microbiome Division Deutsches Krebsforschungszentrum (DKFZ), Neuenheimer Feld 280, 69120 Heidelberg, Germany. Electronic address:

Commensal microbial communities inhabit biological niches in the mammalian host, where they impact the host's physiology through induction of "colonization resistance" against infections by a multitude of molecular mechanisms. These colonization-regulating activities involve microbe-microbe and microbe-host interactions, which induce, through utilization of complex bacterial networks, competition over nutrients, inhibition by antimicrobial peptides, stimulation of the host immune system, and promotion of mucus and intestinal epithelial barrier integrity. Distinct virulent pathogens overcome this colonization resistance and host immunity as part of a hostile takeover of the host niche, leading to clinically overt infection. The following review provides a mechanistic overview of the role of commensal microbes in modulating colonization resistance and pathogenic infections and means by which infectious agents may overcome such inhibition. Last, we outline evidence, unknowns, and challenges in developing strategies to harness this knowledge to treat infections by microbiota transfer, phage therapy, or supplementation by rationally defined bacterial consortia.
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http://dx.doi.org/10.1016/j.molcel.2020.03.001DOI Listing
May 2020

The microbiota programs DNA methylation to control intestinal homeostasis and inflammation.

Nat Microbiol 2020 04 3;5(4):610-619. Epub 2020 Feb 3.

Department of Developmental Biology and Cancer Research, Institute for Medical Research Israel-Canada, Hebrew University Medical School, Jerusalem, Israel.

Although much research has been done on the diversity of the gut microbiome, little is known about how it influences intestinal homeostasis under normal and pathogenic conditions. Epigenetic mechanisms have recently been suggested to operate at the interface between the microbiota and the intestinal epithelium. We performed whole-genome bisulfite sequencing on conventionally raised and germ-free mice, and discovered that exposure to commensal microbiota induced localized DNA methylation changes at regulatory elements, which are TET2/3-dependent. This culminated in the activation of a set of 'early sentinel' response genes to maintain intestinal homeostasis. Furthermore, we demonstrated that exposure to the microbiota in dextran sodium sulfate-induced acute inflammation results in profound DNA methylation and chromatin accessibility changes at regulatory elements, leading to alterations in gene expression programs enriched in colitis- and colon-cancer-associated functions. Finally, by employing genetic interventions, we show that microbiota-induced epigenetic programming is necessary for proper intestinal homeostasis in vivo.
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http://dx.doi.org/10.1038/s41564-019-0659-3DOI Listing
April 2020

Harnessing the microbiota for therapeutic purposes.

Am J Transplant 2020 06 30;20(6):1482-1488. Epub 2019 Dec 30.

Immunology Department, Weizmann Institute of Science, Rehovot, Israel.

The myriads of microorganisms colonizing the human host (microbiome) affect virtually every aspect of its physiology in health and disease. The past decade witnessed unprecedented advances in microbiome research. The field rapidly transitioned from descriptive studies to deep mechanistic insights into host-microbiome interactions. This offers the opportunity for microbiome-targeted therapeutic manipulation. Currently, several strategies of microbiome-targeted interventions are intensively explored. Best evidence from human randomized clinical trials is available for fecal microbiota transplantation (FMT). However, patient eligibility as well as long-term efficacy and safety are not sufficiently defined. Therefore, there is currently no officially approved indication for FMT. Probiotics (live microorganisms) have long been discussed as a means to aid human health but have yielded varying results. Emerging techniques utilizing microbiota-targeted diets, small microbial molecules, recombinant bacteriophages, and precise control of strain abundance recently yielded promising results but require further investigation. The rapid technological progress of "omics" tools spurs advances in personalized medicine. Understanding and integration of interindividual microbiome variability holds potential to promote personalized preventive and therapeutic approaches. Emerging evidence points towards the microbiome as an important player having an impact on transplantation outcomes. Microbiome-targeted interventions have potential to aid against the many challenges faced by transplant recipients.
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http://dx.doi.org/10.1111/ajt.15753DOI Listing
June 2020

Personalized Nutrition: Are We There Yet?

J Pediatr Gastroenterol Nutr 2019 12;69(6):633-638

Immunology Department, Weizmann Institute of Science, Rehovot, Israel.

The human genome has been proposed to contribute to interpersonal variability in the way we respond to nutritional intake. However, personalized diets solely based on gene-nutrient interactions have not lived up to their expectations to date. Advances in microbiome research have indicated that a science-based generation of a personalized diet based on a combination of clinical and microbial features may constitute a promising new approach enabling accurate prediction of dietary responses. In addition, scientific advances in our understanding of defined dietary components and their effects on human physiology led to the incorporation and testing of defined diets as preventive and treatment approaches for diseases, such as epilepsy, ulcerative colitis, Crohn disease, and type 1 diabetes mellitus. Additionally, exciting new studies show that tailored diet regiments have the potential to modulate pharmaceutical treatment efficacy in cancer treatment. Overall, the true therapeutic potential of nutritional interventions is coming to light but is also facing substantial challenges in understanding mechanisms of activity, optimization of dietary interventions for specific human subpopulations, and elucidation of adverse effects potentially stemming from some dietary components in a number of individuals.
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http://dx.doi.org/10.1097/MPG.0000000000002491DOI Listing
December 2019

Embrace the fat when getting old.

Aging (Albany NY) 2019 10 23;11(20):8730-8732. Epub 2019 Oct 23.

Immunology Department, Weizmann Institute of Science, Rehovot, Israel.

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http://dx.doi.org/10.18632/aging.102341DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6834405PMC
October 2019