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Effects of personalized diets by prediction of glycemic responses on glycemic control and metabolic health in newly diagnosed T2DM: a randomized dietary intervention pilot trial.
Rein, M, Ben-Yacov, O, Godneva, A, Shilo, S, Zmora, N, Kolobkov, D, Cohen-Dolev, N, Wolf, BC, Kosower, N, Lotan-Pompan, M, et al
BMC medicine. 2022;20(1):56
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Type 2 diabetes mellitus (T2DM) affects around 10% of the global population. The primary goal in its management is to improve glycemic control. Modifying the diet can help, but many patients fail to achieve improvements with diet alone. The aim of the randomized dietary intervention pilot trial is to evaluate the effects of a personalized postprandial-targeting (PPT) diet on glycemic control and metabolic health in 23 adults with newly diagnosed T2DM, as compared to the commonly recommended Mediterranean-style (MED) diet. The PPT diet led to significant lower levels of continuous-glucose-monitoring (CGM)-based measures as compared to the MED diet. In the additional 6-months intervention, metabolic parameters were further improved and 61% of the participants exhibited diabetes remission. Improvements in clinical outcomes were also accompanied by changes in the gut microbiome. These findings may be useful for the design of larger studies in the future that may have implications for dietary advice in clinical practice.
Abstract
BACKGROUND Dietary modifications are crucial for managing newly diagnosed type 2 diabetes mellitus (T2DM) and preventing its health complications, but many patients fail to achieve clinical goals with diet alone. We sought to evaluate the clinical effects of a personalized postprandial-targeting (PPT) diet on glycemic control and metabolic health in individuals with newly diagnosed T2DM as compared to the commonly recommended Mediterranean-style (MED) diet. METHODS We enrolled 23 adults with newly diagnosed T2DM (aged 53.5 ± 8.9 years, 48% males) for a randomized crossover trial of two 2-week-long dietary interventions. Participants were blinded to their assignment to one of the two sequence groups: either PPT-MED or MED-PPT diets. The PPT diet relies on a machine learning algorithm that integrates clinical and microbiome features to predict personal postprandial glucose responses (PPGR). We further evaluated the long-term effects of PPT diet on glycemic control and metabolic health by an additional 6-month PPT intervention (n = 16). Participants were connected to continuous glucose monitoring (CGM) throughout the study and self-recorded dietary intake using a smartphone application. RESULTS In the crossover intervention, the PPT diet lead to significant lower levels of CGM-based measures as compared to the MED diet, including average PPGR (mean difference between diets, - 19.8 ± 16.3 mg/dl × h, p < 0.001), mean glucose (mean difference between diets, - 7.8 ± 5.5 mg/dl, p < 0.001), and daily time of glucose levels > 140 mg/dl (mean difference between diets, - 2.42 ± 1.7 h/day, p < 0.001). Blood fructosamine also decreased significantly more during PPT compared to MED intervention (mean change difference between diets, - 16.4 ± 37 μmol/dl, p < 0.0001). At the end of 6 months, the PPT intervention leads to significant improvements in multiple metabolic health parameters, among them HbA1c (mean ± SD, - 0.39 ± 0.48%, p < 0.001), fasting glucose (- 16.4 ± 24.2 mg/dl, p = 0.02) and triglycerides (- 49 ± 46 mg/dl, p < 0.001). Importantly, 61% of the participants exhibited diabetes remission, as measured by HbA1c < 6.5%. Finally, some clinical improvements were significantly associated with gut microbiome changes per person. CONCLUSION In this crossover trial in subjects with newly diagnosed T2DM, a PPT diet improved CGM-based glycemic measures significantly more than a Mediterranean-style MED diet. Additional 6-month PPT intervention further improved glycemic control and metabolic health parameters, supporting the clinical efficacy of this approach. TRIAL REGISTRATION ClinicalTrials.gov number, NCT01892956.
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Personalized Postprandial Glucose Response-Targeting Diet Versus Mediterranean Diet for Glycemic Control in Prediabetes.
Ben-Yacov, O, Godneva, A, Rein, M, Shilo, S, Kolobkov, D, Koren, N, Cohen Dolev, N, Travinsky Shmul, T, Wolf, BC, Kosower, N, et al
Diabetes care. 2021;(9):1980-1991
Abstract
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 (n = 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/m2, HbA1c, 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 HbA1c 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, P < 0.001). The mean 6-month change in HbA1c 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, P = 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 HbA1c. These findings may have implications for dietary advice in clinical practice.
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Harnessing SmartPhones to Personalize Nutrition in a Time of Global Pandemic.
Zmora, N, Elinav, E
Nutrients. 2021;(2)
Abstract
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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Nutrition Regulates Innate Immunity in Health and Disease.
Nobs, SP, Zmora, N, Elinav, E
Annual review of nutrition. 2020;:189-219
Abstract
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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Probiotics in the next-generation sequencing era.
Suez, J, Zmora, N, Elinav, E
Gut microbes. 2020;(1):77-93
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Abstract
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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Harnessing the gut microbiota to promote metabolic health.
Zmora, N
Nutrition reviews. 2020;(12 Suppl 2):75-78
Abstract
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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Post-Antibiotic Gut Mucosal Microbiome Reconstitution Is Impaired by Probiotics and Improved by Autologous FMT.
Suez, J, Zmora, N, Zilberman-Schapira, G, Mor, U, Dori-Bachash, M, Bashiardes, S, Zur, M, Regev-Lehavi, D, Ben-Zeev Brik, R, Federici, S, et al
Cell. 2018;174(6):1406-1423.e16
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Probiotics are commonly used to reduce the risk of antibiotic associated diarrhoea (AAD). This study, in both mice and humans, investigated the effects of an 11 strain probiotic supplement and autologous faecal microbiome transplantation (aFMT) after antibiotic treatment. (Autologous meaning the person’s own, pre-antibiotic stool was transplanted.) Gut mucosa samples along the digestive tract and stool samples were investigated for microbiome composition and activity (transcriptome). The investigators found that without antibiotics the probiotics did not colonise very well, suggesting that our native microbiome offers resistance. After antibiotics, which would kill off much of our gut bacteria,the probiotics colonise the gut mucosa much better. However, the probiotics appear to then prevent the microbiome to return to its native, pre-antibiotic state. Whilst in those with the aFMT and in those who did nothing (“watchful waiting”) the microbiome returned to pre-antibiotic state fairly quickly, in the probiotic group even after 5 months the microbiome had not returned to its native composition. In vitro experiments suggest that the delay in the probiotic group is due to substances secreted by the probiotic bacteria, in particular Lactobacilli. The authors conclude that the potential benefits in terms of reducing the risk of AAD with probiotics may be offset with a delay in reconstitution of the native microbiome, and call for more research into aFMT and a more personalised approach to probiotic therapy.
Abstract
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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Personalized Gut Mucosal Colonization Resistance to Empiric Probiotics Is Associated with Unique Host and Microbiome Features.
Zmora, N, Zilberman-Schapira, G, Suez, J, Mor, U, Dori-Bachash, M, Bashiardes, S, Kotler, E, Zur, M, Regev-Lehavi, D, Brik, RB, et al
Cell. 2018;174(6):1388-1405.e21
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Evidence regarding the efficacy of probiotics in colonising the gut mucosa are sparse. The authors investigated whether probiotics colonise the gut mucosa in mice and humans, using both gut mucosa and stool samples. They found that, in both mice and humans, results from stool samples only partially correlate with colonisation of the gut mucosa as determined through gut mucosa samples. Whilst results were fairly uniform in mice, in humans a person-specific resistance to colonisation of the gut mucosa by probiotics was observed. Inter-person variation could be predicted by the composition of the pre-probiotic microbiome and host immune features.
Abstract
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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Obesity, diabetes and zinc: A workshop promoting knowledge and collaboration between the UK and Israel, november 28-30, 2016 - Israel.
Jenkins, A, Lengyel, I, Rutter, GA, Lowe, N, Shai, I, Tirosh, A, Petro, T, Khamaisi, M, Andrews, S, Zmora, N, et al
Journal of trace elements in medicine and biology : organ of the Society for Minerals and Trace Elements (GMS). 2018;:79-85
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Probiotics administration following sleeve gastrectomy surgery: a randomized double-blind trial.
Sherf-Dagan, S, Zelber-Sagi, S, Zilberman-Schapira, G, Webb, M, Buch, A, Keidar, A, Raziel, A, Sakran, N, Goitein, D, Goldenberg, N, et al
International journal of obesity (2005). 2018;(2):147-155
Abstract
BACKGROUND Probiotics are commonly used after bariatric surgery; however, uncertainty remains regarding their efficacy. Our aim was to compare the effect of probiotics vs placebo on hepatic, inflammatory and clinical outcomes following laparoscopic sleeve gastrectomy (LSG). METHODS This randomized, double-blind, placebo-controlled, trial of 6-month treatment with probiotics (Bio-25; Supherb) vs placebo and 6 months of additional follow-up was conducted among 100 morbidly obese nonalcoholic fatty liver disease (NAFLD) patients who underwent LSG surgery. The primary outcome was a reduction in liver fat content, measured by abdominal ultrasound, and secondary outcomes were improvement of fibrosis, measured by shear-wave elastography, metabolic and inflammatory parameters, anthropometrics and quality of life (QOL). Fecal samples were collected and analyzed for microbial composition. RESULTS One hundred patients (60% women, mean age of 41.9±9.8 years and body mass index of 42.3±4.7 kg m-2) were randomized, 80% attended the 6-month visit and 77% completed the 12-month follow-up. Fat content and NAFLD remission rate were similarly reduced in the probiotics and placebo groups at 6 months postsurgery (-0.9±0.5 vs -0.7±0.4 score; P=0.059 and 52.5 vs 40%; P=0.262, respectively) and at 12 months postsurgery. Fibrosis, liver-enzymes, C-reactive protein (CRP), leptin and cytokeratin-18 levels were significantly reduced and QOL significantly improved within groups (P⩽0.014 for all), but not between groups (P⩾0.173 for all) at 6 and 12 months postsurgery. Within-sample microbiota diversity (alpha-diversity) increased at 6-month postsurgery compared with baseline in both study arms (P⩽0.008) and decreased again at 12 months postsurgery compared with 6 months postsurgery (P⩽0.004) but did not reach baseline values. CONCLUSIONS Probiotics administration does not improve hepatic, inflammatory and clinical outcomes 6- and 12 months post-LSG.