Publications by authors named "Niv Zmora"

34 Publications

Personalized Postprandial Glucose Response-Targeting Diet Versus Mediterranean Diet for Glycemic Control in Prediabetes.

Diabetes Care 2021 Jul 23. Epub 2021 Jul 23.

Department of Computer Science and Applied Mathematics, Weizmann Institute of Science, Rehovot, Israel

Objective: To compare the clinical effects of a personalized postprandial-targeting (PPT) diet versus a Mediterranean (MED) diet on glycemic control and metabolic health in prediabetes.

Research Design And Methods: We randomly assigned adults with prediabetes ( = 225) to follow a MED diet or a PPT diet for a 6-month dietary intervention and additional 6-month follow-up. The PPT diet relies on a machine learning algorithm that integrates clinical and microbiome features to predict personal postprandial glucose responses. During the intervention, all participants were connected to continuous glucose monitoring (CGM) and self-reported dietary intake using a smartphone application.

Results: Among 225 participants randomized (58.7% women, mean ± SD age 50 ± 7 years, BMI 31.3 ± 5.8 kg/m, HbA, 5.9 ± 0.2% [41 ± 2.4 mmol/mol], fasting plasma glucose 114 ± 12 mg/dL [6.33 ± 0.67 mmol/L]), 200 (89%) completed the 6-month intervention. A total of 177 participants also contributed 12-month follow-up data. Both interventions reduced the daily time with glucose levels >140 mg/dL (7.8 mmol/L) and HbA levels, but reductions were significantly greater in PPT compared with MED. The mean 6-month change in "time above 140" was -0.3 ± 0.8 h/day and -1.3 ± 1.5 h/day for MED and PPT, respectively (95% CI between-group difference -1.29 to -0.66, < 0.001). The mean 6-month change in HbA was -0.08 ± 0.19% (-0.9 ± 2.1 mmol/mol) and -0.16 ± 0.24% (-1.7 ± 2.6 mmol/mol) for MED and PPT, respectively (95% CI between-group difference -0.14 to -0.02, = 0.007). The significant between-group differences were maintained at 12-month follow-up. No significant differences were noted between the groups in a CGM-measured oral glucose tolerance test.

Conclusions: In this clinical trial in prediabetes, a PPT diet improved glycemic control significantly more than a MED diet as measured by daily time of glucose levels >140 mg/dL (7.8 mmol/L) and HbA. These findings may have implications for dietary advice in clinical practice.
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http://dx.doi.org/10.2337/dc21-0162DOI Listing
July 2021

Probiotics impact the antibiotic resistance gene reservoir along the human GI tract in a person-specific and antibiotic-dependent manner.

Nat Microbiol 2021 Aug 5;6(8):1043-1054. Epub 2021 Jul 5.

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

Antimicrobial resistance poses a substantial threat to human health. The gut microbiome is considered a reservoir for potential spread of resistance genes from commensals to pathogens, termed the gut resistome. The impact of probiotics, commonly consumed by many in health or in conjunction with the administration of antibiotics, on the gut resistome is elusive. Reanalysis of gut metagenomes from healthy antibiotics-naïve humans supplemented with an 11-probiotic-strain preparation, allowing direct assessment of the gut resistome in situ along the gastrointestinal (GI) tract, demonstrated that probiotics reduce the number of antibiotic resistance genes exclusively in the gut of colonization-permissive individuals. In mice and in a separate cohort of humans, a course of antibiotics resulted in expansion of the lower GI tract resistome, which was mitigated by autologous faecal microbiome transplantation or during spontaneous recovery. In contrast, probiotics further exacerbated resistome expansion in the GI mucosa by supporting the bloom of strains carrying vancomycin resistance genes but not resistance genes encoded by the probiotic strains. Importantly, the aforementioned effects were not reflected in stool samples, highlighting the importance of direct sampling to analyse the effect of probiotics and antibiotics on the gut resistome. Analysing antibiotic resistance gene content in additional published clinical trials with probiotics further highlighted the importance of person-specific metagenomics-based profiling of the gut resistome using direct sampling. Collectively, these findings suggest opposing person-specific and antibiotic-dependent effects of probiotics on the resistome, whose contribution to the spread of antimicrobial resistance genes along the human GI tract merit further studies.
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http://dx.doi.org/10.1038/s41564-021-00920-0DOI Listing
August 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

Harnessing the gut microbiota to promote metabolic health.

Authors:
Niv Zmora

Nutr Rev 2020 12;78(12 Suppl 2):75-78

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

Precision medicine has become the mainstay of modern therapeutics, especially for neoplastic disease, but this paradigm does not commonly prevail in dietary planning. Compelling evidence suggests that individual features, including the structure and function of the gut microbiota, contribute to harvesting and metabolizing energy from food, and thereby modulate the host metabolic phenotype and glucose homeostasis. Here, the concept of precision to dietary planning is highlighted by demonstrating the role of the microbiota in glucose intolerance in response to noncaloric artificial sweeteners, and by linking the microbiota and other host features to postprandial increases in blood glucose. These findings highlight the heterogeneity that exists among humans, which translates into divergent metabolic responses to similar food and warrants the adoption of next-generation sequencing technologies and advanced bioinformatics to revolutionize nutrition studies, laying the groundwork for an individually focused tailor-made practice.
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http://dx.doi.org/10.1093/nutrit/nuaa076DOI Listing
December 2020

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

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

The intestinal microbiota fuelling metabolic inflammation.

Nat Rev Immunol 2020 01 6;20(1):40-54. Epub 2019 Aug 6.

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

Low-grade inflammation is the hallmark of metabolic disorders such as obesity, type 2 diabetes and nonalcoholic fatty liver disease. Emerging evidence indicates that these disorders are characterized by alterations in the intestinal microbiota composition and its metabolites, which translocate from the gut across a disrupted intestinal barrier to affect various metabolic organs, such as the liver and adipose tissue, thereby contributing to metabolic inflammation. Here, we discuss some of the recently identified mechanisms that showcase the role of the intestinal microbiota and barrier dysfunction in metabolic inflammation. We propose a concept by which the gut microbiota fuels metabolic inflammation and dysregulation.
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http://dx.doi.org/10.1038/s41577-019-0198-4DOI Listing
January 2020

Potential roles of gut microbiome and metabolites in modulating ALS in mice.

Nature 2019 08 22;572(7770):474-480. Epub 2019 Jul 22.

Department of Medical Biochemistry and Cell Biology, University of Gothenburg, Gothenburg, Sweden.

Amyotrophic lateral sclerosis (ALS) is a complex neurodegenerative disorder, in which the clinical manifestations may be influenced by genetic and unknown environmental factors. Here we show that ALS-prone Sod1 transgenic (Sod1-Tg) mice have a pre-symptomatic, vivarium-dependent dysbiosis and altered metabolite configuration, coupled with an exacerbated disease under germ-free conditions or after treatment with broad-spectrum antibiotics. We correlate eleven distinct commensal bacteria at our vivarium with the severity of ALS in mice, and by their individual supplementation into antibiotic-treated Sod1-Tg mice we demonstrate that Akkermansia muciniphila (AM) ameliorates whereas Ruminococcus torques and Parabacteroides distasonis exacerbate the symptoms of ALS. Furthermore, Sod1-Tg mice that are administered AM are found to accumulate AM-associated nicotinamide in the central nervous system, and systemic supplementation of nicotinamide improves motor symptoms and gene expression patterns in the spinal cord of Sod1-Tg mice. In humans, we identify distinct microbiome and metabolite configurations-including reduced levels of nicotinamide systemically and in the cerebrospinal fluid-in a small preliminary study that compares patients with ALS with household controls. We suggest that environmentally driven microbiome-brain interactions may modulate ALS in mice, and we call for similar investigations in the human form of the disease.
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http://dx.doi.org/10.1038/s41586-019-1443-5DOI Listing
August 2019

Lipid-Associated Macrophages Control Metabolic Homeostasis in a Trem2-Dependent Manner.

Cell 2019 07 27;178(3):686-698.e14. Epub 2019 Jun 27.

Department of Immunology, Weizmann Institute of Science, Rehovot 7610001, Israel. Electronic address:

Immune cells residing in white adipose tissue have been highlighted as important factors contributing to the pathogenesis of metabolic diseases, but the molecular regulators that drive adipose tissue immune cell remodeling during obesity remain largely unknown. Using index and transcriptional single-cell sorting, we comprehensively map all adipose tissue immune populations in both mice and humans during obesity. We describe a novel and conserved Trem2 lipid-associated macrophage (LAM) subset and identify markers, spatial localization, origin, and functional pathways associated with these cells. Genetic ablation of Trem2 in mice globally inhibits the downstream molecular LAM program, leading to adipocyte hypertrophy as well as systemic hypercholesterolemia, body fat accumulation, and glucose intolerance. These findings identify Trem2 signaling as a major pathway by which macrophages respond to loss of tissue-level lipid homeostasis, highlighting Trem2 as a key sensor of metabolic pathologies across multiple tissues and a potential therapeutic target in metabolic diseases.
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http://dx.doi.org/10.1016/j.cell.2019.05.054DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7068689PMC
July 2019

The pros, cons, and many unknowns of probiotics.

Nat Med 2019 05 6;25(5):716-729. Epub 2019 May 6.

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

Consumption of over-the-counter probiotics for promotion of health and well-being has increased worldwide in recent years. However, although probiotic use has been greatly popularized among the general public, there are conflicting clinical results for many probiotic strains and formulations. Emerging insights from microbiome research enable an assessment of gut colonization by probiotics, strain-level activity, interactions with the indigenous microbiome, safety and impacts on the host, and allow the association of probiotics with physiological effects and potentially useful medical indications. In this Perspective, we highlight key advances, challenges and limitations in striving toward an unbiased interpretation of the large amount of data regarding over-the-counter probiotics, and propose avenues to improve the quality of evidence, transparency, public awareness and regulation of their use.
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http://dx.doi.org/10.1038/s41591-019-0439-xDOI Listing
May 2019

Probiotics in the next-generation sequencing era.

Gut Microbes 2020 5;11(1):77-93. Epub 2019 Apr 5.

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

Technological developments, including massively parallel DNA sequencing, gnotobiotics, metabolomics, RNA sequencing and culturomics, have markedly propelled the field of microbiome research in recent years. These methodologies can be harnessed to improve our in-depth mechanistic understanding of basic concepts related to consumption of probiotics, including their rules of engagement with the indigenous microbiome and impacts on the human host. We have recently demonstrated that even during probiotic supplementation, resident gut bacteria in a subset of individuals resist the mucosal presence of probiotic strains, limiting their modulatory effect on the microbiome and on the host gut transcriptional landscape. Resistance is partly alleviated by antibiotics treatment, which enables probiotics to interact with the host at the gut mucosal interface, although rather than promoting reconstitution of the indigenous microbiome and of the host transcriptional profile, they inhibit these components from returning to their naïve pre-antibiotic configurations. In this commentary, we discuss our findings in the context of previous and recent works, and suggest that incorporating the state-of-the-art methods currently utilized in microbiome research into the field of probiotics may lead to improved understanding of their mechanisms of activity, as well as their efficacy and long-term safety.
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http://dx.doi.org/10.1080/19490976.2019.1586039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6973336PMC
June 2020

Transforming medicine with the microbiome.

Sci Transl Med 2019 01;11(477)

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

Advances in microbiome research are spurring the development of new therapeutics for a variety of diseases, but translational challenges remain.
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http://dx.doi.org/10.1126/scitranslmed.aaw1815DOI Listing
January 2019

You are what you eat: diet, health and the gut microbiota.

Nat Rev Gastroenterol Hepatol 2019 01;16(1):35-56

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

Since the renaissance of microbiome research in the past decade, much insight has accumulated in comprehending forces shaping the architecture and functionality of resident microorganisms in the human gut. Of the multiple host-endogenous and host-exogenous factors involved, diet emerges as a pivotal determinant of gut microbiota community structure and function. By introducing dietary signals into the nexus between the host and its microbiota, nutrition sustains homeostasis or contributes to disease susceptibility. Herein, we summarize major concepts related to the effect of dietary constituents on the gut microbiota, highlighting chief principles in the diet-microbiota crosstalk. We then discuss the health benefits and detrimental consequences that the interactions between dietary and microbial factors elicit in the host. Finally, we present the promises and challenges that arise when seeking to incorporate microbiome data in dietary planning and portray the anticipated revolution that the field of nutrition is facing upon adopting these novel concepts.
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http://dx.doi.org/10.1038/s41575-018-0061-2DOI Listing
January 2019

The epidemiology of typhoid fever in the Dhulikhel area, Nepal: A prospective cohort study.

PLoS One 2018 27;13(9):e0204479. Epub 2018 Sep 27.

Unit of Infectious Diseases-Tropical Diseases & Travel Medicine, Internal Medicine B, Rambam Medical Center, Haifa, Israel.

Introduction: Typhoid fever (TF) continues to cause considerable morbidity and mortality in Nepal, but only limited epidemiologic data is available about TF outside Kathmandu.

Methods: As part of an interventional trial, we performed a prospective cohort study of bacteremic TF patients in Dhulikhel Hospital between October 2012 and October 2014. Demographic, epidemiological, clinical, and microbiologic data were recorded.

Results: 116 bacteremic typhoid patients were included in the study. Most were young, healthy, adults (mean age 27.9±12 years), 41.4% of whom were female. More than 70% of patients were employed in non-manual services or were university students. Salmonella Typhi accounted for 64/115 (55.7%) of all isolates, while Salmonella Paratyphi accounted for 51/115 (44.3%), of which 42 were Paratyphi A and 9 Paratyphi B. A significant proportion of TF cases occurred also during the dry season (48/116, 41.6%). The clinical presentation of Salmonella Typhi and Paratyphi infections was similar, except for a greater proportion of arthralgia in patients with Salmonella Typhi. Most Salmonella Typhi and Paratyphi isolates were resistant to nalidixic acid and susceptible to older antibiotics. One Salmonella Paratyphi isolate was resistant to ceftriaxone.

Conclusions: TF remains common in the Dhulikhel area, even among those with a high level of education. Public health measures aimed at reducing the incidence of TF in the Dhulikhel area are warranted. The relative burden of TF caused by Salmonella Paratyphi is rising; a vaccine with activity against Salmonella Paratyphi is needed. Since Salmonella Paratyphi B was more prevalent in this cohort than in large cohorts of patients from Kathmandu, it is likely that there are significant regional variations in the epidemiology of TF outside Kathmandu.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0204479PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6160059PMC
March 2019

Post-Antibiotic Gut Mucosal Microbiome Reconstitution Is Impaired by Probiotics and Improved by Autologous FMT.

Cell 2018 09;174(6):1406-1423.e16

Immunology Department, Weizmann Institute of Science, 7610001 Rehovot, Israel. Electronic address:

Probiotics are widely prescribed for prevention of antibiotics-associated dysbiosis and related adverse effects. However, probiotic impact on post-antibiotic reconstitution of the gut mucosal host-microbiome niche remains elusive. We invasively examined the effects of multi-strain probiotics or autologous fecal microbiome transplantation (aFMT) on post-antibiotic reconstitution of the murine and human mucosal microbiome niche. Contrary to homeostasis, antibiotic perturbation enhanced probiotics colonization in the human mucosa but only mildly improved colonization in mice. Compared to spontaneous post-antibiotic recovery, probiotics induced a markedly delayed and persistently incomplete indigenous stool/mucosal microbiome reconstitution and host transcriptome recovery toward homeostatic configuration, while aFMT induced a rapid and near-complete recovery within days of administration. In vitro, Lactobacillus-secreted soluble factors contributed to probiotics-induced microbiome inhibition. Collectively, potential post-antibiotic probiotic benefits may be offset by a compromised gut mucosal recovery, highlighting a need of developing aFMT or personalized probiotic approaches achieving mucosal protection without compromising microbiome recolonization in the antibiotics-perturbed host.
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http://dx.doi.org/10.1016/j.cell.2018.08.047DOI Listing
September 2018

Personalized Gut Mucosal Colonization Resistance to Empiric Probiotics Is Associated with Unique Host and Microbiome Features.

Cell 2018 09;174(6):1388-1405.e21

Immunology Department, Weizmann Institute of Science, Rehovot, 7610001, Israel. Electronic address:

Empiric probiotics are commonly consumed by healthy individuals as means of life quality improvement and disease prevention. However, evidence of probiotic gut mucosal colonization efficacy remains sparse and controversial. We metagenomically characterized the murine and human mucosal-associated gastrointestinal microbiome and found it to only partially correlate with stool microbiome. A sequential invasive multi-omics measurement at baseline and during consumption of an 11-strain probiotic combination or placebo demonstrated that probiotics remain viable upon gastrointestinal passage. In colonized, but not germ-free mice, probiotics encountered a marked mucosal colonization resistance. In contrast, humans featured person-, region- and strain-specific mucosal colonization patterns, hallmarked by predictive baseline host and microbiome features, but indistinguishable by probiotics presence in stool. Consequently, probiotics induced a transient, individualized impact on mucosal community structure and gut transcriptome. Collectively, empiric probiotics supplementation may be limited in universally and persistently impacting the gut mucosa, meriting development of new personalized probiotic approaches.
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http://dx.doi.org/10.1016/j.cell.2018.08.041DOI Listing
September 2018

Induction of Nitric-Oxide Metabolism in Enterocytes Alleviates Colitis and Inflammation-Associated Colon Cancer.

Cell Rep 2018 05;23(7):1962-1976

Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel. Electronic address:

Nitric oxide (NO) plays an established role in numerous physiological and pathological processes, but the specific cellular sources of NO in disease pathogenesis remain unclear, preventing the implementation of NO-related therapy. Argininosuccinate lyase (ASL) is the only enzyme able to produce arginine, the substrate for NO generation by nitric oxide synthase (NOS) isoforms. Here, we generated cell-specific conditional ASL knockout mice in combination with genetic and chemical colitis models. We demonstrate that NO derived from enterocytes alleviates colitis by decreasing macrophage infiltration and tissue damage, whereas immune cell-derived NO is associated with macrophage activation, resulting in increased severity of inflammation. We find that induction of endogenous NO production by enterocytes with supplements that upregulate ASL expression and complement its substrates results in improved epithelial integrity and alleviation of colitis and of inflammation-associated colon cancer.
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http://dx.doi.org/10.1016/j.celrep.2018.04.053DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5976577PMC
May 2018

Open label comparative trial of mono versus dual antibiotic therapy for Typhoid Fever in adults.

PLoS Negl Trop Dis 2018 04 23;12(4):e0006380. Epub 2018 Apr 23.

Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.

Background: Emerging resistance to antibiotics renders therapy of Typhoid Fever (TF) increasingly challenging. The current single-drug regimens exhibit prolonged fever clearance time (FCT), imposing a great burden on both patients and health systems, and potentially contributing to the development of antibiotic resistance and the chronic carriage of the pathogens. The aim of our study was to assess the efficacy of combining third-generation cephalosporin therapy with azithromycin on the outcomes of TF in patients living in an endemic region.

Methods: An open-label, comparative trial was conducted at Dhulikhel Hospital, Nepal, between October 2012 and October 2014. Only culture-confirmed TF cases were eligible. Patients were alternately allocated to one of four study arms: hospitalized patients received either intravenous ceftriaxone or a combination of ceftriaxone and oral azithromycin, while outpatients received either oral azithromycin or a combination of oral azithromycin and cefexime. The primary outcome evaluated was FCT and the secondary outcomes included duration of bacteremia.

Results: 105 blood culture-confirmed patients, of whom 51 were treated as outpatients, were eligible for the study. Of the 88 patients who met the inclusion criteria for FCT analysis 41 patients received a single-agent regimen, while 47 patients received a combined regimen. Results showed that FCT was significantly shorter for the latter (95 versus 88 hours, respectively, p = 0·004), and this effect was exhibited in both the hospitalized and the outpatient sub-groups. Repeat blood cultures, drawn on day 3, were positive for 8/47 (17%) patients after monotherapy, versus 2/51 (4%) after combination therapy (p = 0·045). No severe complications or fatalities occurred in any of the groups.

Conclusions: Combined therapy of third-generation cephalosporins and azithromycin for TF may surpass monotherapy in terms of FCT and time to elimination of bacteremia.

Trial Registration: Trial registration number: NCT02224040.
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http://dx.doi.org/10.1371/journal.pntd.0006380DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5912710PMC
April 2018

Environment dominates over host genetics in shaping human gut microbiota.

Nature 2018 03 28;555(7695):210-215. Epub 2018 Feb 28.

Department of Computer Science and Applied Mathematics, Weizmann Institute of Science, Rehovot 7610001, Israel.

Human gut microbiome composition is shaped by multiple factors but the relative contribution of host genetics remains elusive. Here we examine genotype and microbiome data from 1,046 healthy individuals with several distinct ancestral origins who share a relatively common environment, and demonstrate that the gut microbiome is not significantly associated with genetic ancestry, and that host genetics have a minor role in determining microbiome composition. We show that, by contrast, there are significant similarities in the compositions of the microbiomes of genetically unrelated individuals who share a household, and that over 20% of the inter-person microbiome variability is associated with factors related to diet, drugs and anthropometric measurements. We further demonstrate that microbiome data significantly improve the prediction accuracy for many human traits, such as glucose and obesity measures, compared to models that use only host genetic and environmental data. These results suggest that microbiome alterations aimed at improving clinical outcomes may be carried out across diverse genetic backgrounds.
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http://dx.doi.org/10.1038/nature25973DOI Listing
March 2018

Perspective: Improving Nutritional Guidelines for Sustainable Health Policies: Current Status and Perspectives.

Adv Nutr 2017 Jul 14;8(4):532-545. Epub 2017 Jul 14.

Giovanni Lorenzini Medical Science Foundation, Milan, Italy;

A large body of evidence supports the notion that incorrect or insufficient nutrition contributes to disease development. A pivotal goal is thus to understand what exactly is appropriate and what is inappropriate in food ingestion and the consequent nutritional status and health. The effective application of these concepts requires the translation of scientific information into practical approaches that have a tangible and measurable impact at both individual and population levels. The agenda for the future is expected to support available methodology in nutrition research to personalize guideline recommendations, properly grading the quality of the available evidence, promoting adherence to the well-established evidence hierarchy in nutrition, and enhancing strategies for appropriate vetting and transparent reporting that will solidify the recommendations for health promotion. The final goal is to build a constructive coalition among scientists, policy makers, and communication professionals for sustainable health and nutritional policies. Currently, a strong rationale and available data support a personalized dietary approach according to personal variables, including sex and age, circulating metabolic biomarkers, food quality and intake frequency, lifestyle variables such as physical activity, and environmental variables including one's microbiome profile. There is a strong and urgent need to develop a successful commitment among all the stakeholders to define novel and sustainable approaches toward the management of the health value of nutrition at individual and population levels. Moving forward requires adherence to well-established principles of evidence evaluation as well as identification of effective tools to obtain better quality evidence. Much remains to be done in the near future.
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http://dx.doi.org/10.3945/an.116.014738DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5502870PMC
July 2017

Bread Affects Clinical Parameters and Induces Gut Microbiome-Associated Personal Glycemic Responses.

Cell Metab 2017 Jun;25(6):1243-1253.e5

Department of Computer Science and Applied Mathematics, Weizmann Institute of Science, Rehovot 7610001, Israel; Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 7610001, Israel. Electronic address:

Bread is consumed daily by billions of people, yet evidence regarding its clinical effects is contradicting. Here, we performed a randomized crossover trial of two 1-week-long dietary interventions comprising consumption of either traditionally made sourdough-leavened whole-grain bread or industrially made white bread. We found no significant differential effects of bread type on multiple clinical parameters. The gut microbiota composition remained person specific throughout this trial and was generally resilient to the intervention. We demonstrate statistically significant interpersonal variability in the glycemic response to different bread types, suggesting that the lack of phenotypic difference between the bread types stems from a person-specific effect. We further show that the type of bread that induces the lower glycemic response in each person can be predicted based solely on microbiome data prior to the intervention. Together, we present marked personalization in both bread metabolism and the gut microbiome, suggesting that understanding dietary effects requires integration of person-specific factors.
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http://dx.doi.org/10.1016/j.cmet.2017.05.002DOI Listing
June 2017

The Role of the Immune System in Metabolic Health and Disease.

Cell Metab 2017 03;25(3):506-521

Immunology Department, Weizmann Institute of Science, Rehovot 7610001, Israel. Electronic address:

In addition to the immune system's traditional roles of conferring anti-infectious and anti-neoplastic protection, it has been recently implicated in the regulation of systemic metabolic homeostasis. This cross-talk between the immune and the metabolic systems is pivotal in promoting "metabolic health" throughout the life of an organism and plays fundamental roles in its adaptation to ever-changing environmental makeups and nutritional availability. Perturbations in this intricate immune-metabolic cross-talk contribute to the tendency to develop altered metabolic states that may culminate in metabolic disorders such as malnutrition, obesity, type 2 diabetes mellitus (T2DM), and other features of the metabolic syndrome. Regulators of immune-metabolic interactions include host genetics, nutritional status, and the intestinal microbiome. In this Perspective, we highlight current understanding of immune-metabolism interactions, illustrate differences among individuals and between populations in this respect, and point toward future avenues of research possibly enabling immune harnessing as means of personalized treatment for common metabolic disorders.
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http://dx.doi.org/10.1016/j.cmet.2017.02.006DOI Listing
March 2017

Microbiota Diurnal Rhythmicity Programs Host Transcriptome Oscillations.

Cell 2016 Dec;167(6):1495-1510.e12

Department of Immunology, Weizmann Institute of Science, Rehovot 7610001, Israel. Electronic address:

The intestinal microbiota undergoes diurnal compositional and functional oscillations that affect metabolic homeostasis, but the mechanisms by which the rhythmic microbiota influences host circadian activity remain elusive. Using integrated multi-omics and imaging approaches, we demonstrate that the gut microbiota features oscillating biogeographical localization and metabolome patterns that determine the rhythmic exposure of the intestinal epithelium to different bacterial species and their metabolites over the course of a day. This diurnal microbial behavior drives, in turn, the global programming of the host circadian transcriptional, epigenetic, and metabolite oscillations. Surprisingly, disruption of homeostatic microbiome rhythmicity not only abrogates normal chromatin and transcriptional oscillations of the host, but also incites genome-wide de novo oscillations in both intestine and liver, thereby impacting diurnal fluctuations of host physiology and disease susceptibility. As such, the rhythmic biogeography and metabolome of the intestinal microbiota regulates the temporal organization and functional outcome of host transcriptional and epigenetic programs.
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http://dx.doi.org/10.1016/j.cell.2016.11.003DOI Listing
December 2016

The microbiome and innate immunity.

Nature 2016 07;535(7610):65-74

Department of Immunology, Weizmann Institute of Science, Rehovot 76100, Israel.

The intestinal microbiome is a signalling hub that integrates environmental inputs, such as diet, with genetic and immune signals to affect the host's metabolism, immunity and response to infection. The haematopoietic and non-haematopoietic cells of the innate immune system are located strategically at the host-microbiome interface. These cells have the ability to sense microorganisms or their metabolic products and to translate the signals into host physiological responses and the regulation of microbial ecology. Aberrations in the communication between the innate immune system and the gut microbiota might contribute to complex diseases.
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http://dx.doi.org/10.1038/nature18847DOI Listing
July 2016

The gut microbiome in human immunodeficiency virus infection.

BMC Med 2016 06 3;14(1):83. Epub 2016 Jun 3.

Department of Immunology, Weizmann Institute of Science, 234 Herzl Street, Rehovot, 76100, Israel.

HIV/AIDS causes severe dysfunction of the immune system through CD4+ T cell depletion, leading to dysregulation of both the adaptive and innate immune arms. A primary target for viral infection is the gastrointestinal tract, which is a reservoir of CD4+ T cells. In addition to being a major immune hub, the human gastrointestinal tract harbors trillions of commensal microorganisms, the microbiota, which have recently been shown to play critical roles in health. Alterations in the composition and function of microbiota have been implicated in a variety of 'multi-factorial' disorders, including infectious, autoimmune, metabolic, and neoplastic disorders. It is widely accepted that, in addition to its direct role in altering the gastrointestinal CD4+ T cell compartment, HIV infection is characterized by gut microbiota compositional and functional changes. Herein, we review such alterations and discuss their potential local and systemic effects on the HIV-positive host, as well as potential roles of novel microbiota-targeting treatments in modulating HIV progression and associated adverse systemic manifestations.
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http://dx.doi.org/10.1186/s12916-016-0625-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4891875PMC
June 2016

Taking it Personally: Personalized Utilization of the Human Microbiome in Health and Disease.

Cell Host Microbe 2016 Jan;19(1):12-20

Department of Immunology, Weizmann Institute of Science, Rehovot 7610001, Israel. Electronic address:

The genomic revolution enabled the clinical inclusion of an immense body of person-specific information to an extent that is revolutionizing medicine and science. The gut microbiome, our "second genome," dynamically integrates signals from the host and its environment, impacting health and risk of disease. Herein, we summarize how individualized characterization of the microbiome composition and function may assist in personalized diagnostic assessment, risk stratification, disease prevention, treatment decision-making, and patients' follow up. We further discuss the limitations, pitfalls, and challenges that the microbiome field faces in integrating patient-specific microbial data into the clinical realm. Finally, we highlight how recent insights into personalized modulation of the microbiome, by nutritional and pre-, pro-, and post-biotic intervention, may lead to development of individualized approaches that may enable us to harness the microbiome as a central precision medicine target.
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http://dx.doi.org/10.1016/j.chom.2015.12.016DOI Listing
January 2016

Personalized Nutrition by Prediction of Glycemic Responses.

Cell 2015 Nov;163(5):1079-1094

Department of Computer Science and Applied Mathematics, Weizmann Institute of Science, Rehovot 7610001, Israel; Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 7610001, Israel. Electronic address:

Elevated postprandial blood glucose levels constitute a global epidemic and a major risk factor for prediabetes and type II diabetes, but existing dietary methods for controlling them have limited efficacy. Here, we continuously monitored week-long glucose levels in an 800-person cohort, measured responses to 46,898 meals, and found high variability in the response to identical meals, suggesting that universal dietary recommendations may have limited utility. We devised a machine-learning algorithm that integrates blood parameters, dietary habits, anthropometrics, physical activity, and gut microbiota measured in this cohort and showed that it accurately predicts personalized postprandial glycemic response to real-life meals. We validated these predictions in an independent 100-person cohort. Finally, a blinded randomized controlled dietary intervention based on this algorithm resulted in significantly lower postprandial responses and consistent alterations to gut microbiota configuration. Together, our results suggest that personalized diets may successfully modify elevated postprandial blood glucose and its metabolic consequences. VIDEO ABSTRACT.
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http://dx.doi.org/10.1016/j.cell.2015.11.001DOI Listing
November 2015

Transkingdom control of microbiota diurnal oscillations promotes metabolic homeostasis.

Cell 2014 Oct 16;159(3):514-29. Epub 2014 Oct 16.

Department of Immunology, Weizmann Institute of Science, Rehovot 76100, Israel. Electronic address:

All domains of life feature diverse molecular clock machineries that synchronize physiological processes to diurnal environmental fluctuations. However, no mechanisms are known to cross-regulate prokaryotic and eukaryotic circadian rhythms in multikingdom ecosystems. Here, we show that the intestinal microbiota, in both mice and humans, exhibits diurnal oscillations that are influenced by feeding rhythms, leading to time-specific compositional and functional profiles over the course of a day. Ablation of host molecular clock components or induction of jet lag leads to aberrant microbiota diurnal fluctuations and dysbiosis, driven by impaired feeding rhythmicity. Consequently, jet-lag-induced dysbiosis in both mice and humans promotes glucose intolerance and obesity that are transferrable to germ-free mice upon fecal transplantation. Together, these findings provide evidence of coordinated metaorganism diurnal rhythmicity and offer a microbiome-dependent mechanism for common metabolic disturbances in humans with aberrant circadian rhythms, such as those documented in shift workers and frequent flyers.
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http://dx.doi.org/10.1016/j.cell.2014.09.048DOI Listing
October 2014

Artificial sweeteners induce glucose intolerance by altering the gut microbiota.

Nature 2014 Oct 17;514(7521):181-6. Epub 2014 Sep 17.

Department of Immunology, Weizmann Institute of Science, Rehovot 76100, Israel.

Non-caloric artificial sweeteners (NAS) are among the most widely used food additives worldwide, regularly consumed by lean and obese individuals alike. NAS consumption is considered safe and beneficial owing to their low caloric content, yet supporting scientific data remain sparse and controversial. Here we demonstrate that consumption of commonly used NAS formulations drives the development of glucose intolerance through induction of compositional and functional alterations to the intestinal microbiota. These NAS-mediated deleterious metabolic effects are abrogated by antibiotic treatment, and are fully transferrable to germ-free mice upon faecal transplantation of microbiota configurations from NAS-consuming mice, or of microbiota anaerobically incubated in the presence of NAS. We identify NAS-altered microbial metabolic pathways that are linked to host susceptibility to metabolic disease, and demonstrate similar NAS-induced dysbiosis and glucose intolerance in healthy human subjects. Collectively, our results link NAS consumption, dysbiosis and metabolic abnormalities, thereby calling for a reassessment of massive NAS usage.
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http://dx.doi.org/10.1038/nature13793DOI Listing
October 2014
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