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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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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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A double-blind, placebo-controlled study to assess the effect of a probiotic mixture on symptoms and inflammatory markers in women with diarrhea-predominant IBS.
Hod, K, Sperber, AD, Ron, Y, Boaz, M, Dickman, R, Berliner, S, Halpern, Z, Maharshak, N, Dekel, R
Neurogastroenterology and motility. 2017;(7)
Abstract
BACKGROUND Micro-inflammation is considered an element in the pathogenesis of irritable bowel syndrome (IBS). High-sensitivity C reactive protein (hs-CRP) was previously shown to be higher in IBS compared to healthy controls, albeit within the normal range. Since probiotics may suppress micro-inflammation in the gut, we tested if they reduce symptoms and inflammatory markers (hs-CRP and fecal calprotectin (FC) in diarrhea-predominant IBS (IBS-D). The aim of this study was to assess the clinical and laboratory effects of BIO-25, a multispecies probiotic, in women with IBS-D. METHODS A double-blind, placebo-controlled study. Following a 2-week run-in, eligible women were assigned at random to a probiotic capsule or an indistinguishable placebo, twice daily for 8 weeks. IBS symptoms and stool consistency were rated daily by Visual Analogue Scales (VAS) and the Bristol Stool Scale (BSS). High-sensitivity C reactive protein was tested at baseline, 4 and 8 weeks. FC was tested at baseline and 8 weeks. KEY RESULTS One hundred and seventy-two IBS-D patients were recruited and 107 eligible patients were allocated to the intervention (n=54) or placebo (n=53) group. All symptoms improved in both groups with no significant difference between them in symptom improvement, hs-CRP or FC levels. CONCLUSIONS & INFERENCES An 8-week treatment with BIO-25 improved symptoms in women with IBS-D, but was not superior to placebo. This rigorously designed and executed study supports the findings of other studies that did not demonstrate superiority of probiotics over placebo in IBS. High quality clinical studies are necessary to examine the efficacy of other specific probiotics in IBS-D patients since data are still conflicting.
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Personalized Nutrition by Prediction of Glycemic Responses.
Zeevi, D, Korem, T, Zmora, N, Israeli, D, Rothschild, D, Weinberger, A, Ben-Yacov, O, Lador, D, Avnit-Sagi, T, Lotan-Pompan, M, et al
Cell. 2015;(5):1079-1094
Abstract
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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Effect of resistance training on non-alcoholic fatty-liver disease a randomized-clinical trial.
Zelber-Sagi, S, Buch, A, Yeshua, H, Vaisman, N, Webb, M, Harari, G, Kis, O, Fliss-Isakov, N, Izkhakov, E, Halpern, Z, et al
World journal of gastroenterology. 2014;(15):4382-92
Abstract
AIM: To evaluate the effect of resistance training (RT) on non alcoholic liver disease (NAFLD) patients. METHODS A randomized clinical trial enrolling NAFLD patients without secondary liver disease (e.g., without hepatitis B virus, hepatitis C virus or excessive alcohol consumption). Patients were randomly allocated either to RT, three times weekly, for 3 mo or a control arm consisting of home stretching. The RT included leg press, chest press, seated rowing, latissimus pull down etc. with 8-12 repetitions, 3 sets for each exercise, for a total duration of 40 min. Hepatic ultrasound, fasting blood tests, anthropometrics and body composition by dual energy X-ray absorptiometry were assessed. At baseline and follow-up, patients filled out a detailed semi-quantitative food frequency questionnaire reporting their habitual nutritional intake. Steatosis was quantified by the hepatorenal-ultrasound index (HRI) representing the ratio between the brightness level of the liver and the right kidney. The HRI has been previously demonstrated to be highly reproducible and was validated against liver biopsy and proton magnetic resonance spectroscopy. RESULTS Eighty two patients with primary NAFLD were randomized to receive 3 mo of either RT or stretching. After dropout or exclusion from analysis because of protocol violation (weight change > 3 kg), thirty three patients in the RT arm and 31 in the stretching arm completed the study per protocol. All baseline characteristics were similar for the two treatment groups with respect to demographics, anthropometrics and body composition, blood tests and liver steatosis on imaging. HRI score was reduced significantly in the RT arm as compared to the stretching arm (-0.25 ± 0.37 vs -0.05 ± 0.28, P = 0.017). The RT arm had a significantly higher reduction in total, trunk and android fat with increase in lean body mass. There was no correlation between the reduction in HRI in the RT arm and weight change during the study, but it was positively correlated with the change in trunk fat (r = 0.37, P = 0.048). The RT arm had a significant reduction in serum ferritin and total cholesterol. There was no significant difference between arms in dietary changes and these did not correlate with HRI change. CONCLUSION Three months RT improves hepatic fat content accompanied by favorable changes in body composition and ferritin. RT may serve as a complement to treatment of NAFLD.
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Ensure preparation and capsule endoscopy: a two-center prospective study.
Niv, E, Ovadia, B, Ron, Y, Santo, E, Mahajna, E, Halpern, Z, Fireman, Z
World journal of gastroenterology. 2013;(8):1264-70
Abstract
AIM: To compare small bowel (SB) cleanliness and capsule endoscopy (CE) image quality following Ensure(®), polyethylene glycol (PEG) and standard preparations. METHODS A preparation protocol for CE that is both efficacious and acceptable to patients remains elusive. Considering the physiological function of the SB as a site for the digestion and absorption of food and not as a stool reservoir, preparation consisting of a liquid, fiber-free formula ingested one day before a CE study might have an advantage over other kinds of preparations. We conducted a prospective, blind-to-preparation, two-center study that compared four types of preparations. The participants' demographic and clinical data were collected. Gastric and SB transit times were calculated. The presence of bile in the duodenum was scored by a single, blinded-to-preparation gastroenterologist expert in CE, as was cleanliness within the proximal, middle and distal part of the SB. A four-point scale was used (grade 1 = no bile or residue, grade 4 ≥ 90% of lumen full of bile or residual material). RESULTS The 198 consecutive patients who were referred to CE studies due to routine medical reasons were divided into four groups. They all observed a 12-h overnight fast before undergoing CE. Throughout the 24 h preceding the fast, control group 1 (n = 45 patients) ate light unrestricted meals, control group 2 (n = 81) also ate light meals but free of fruits and vegetables, the PEG group (n = 50) ate unrestricted light meals and ingested the PEG preparation, and the Ensure group (n = 22) ingested only the Ensure formula. Preparation with Ensure improved the visualization of duodenal mucosa (a score of 1.76) by decreasing the bile content compared to preparation with PEG (a score of 2.9) (P = 0.053). Overall, as expected, there was less residue and stool in the proximal part of the SB than in the middle and distal parts in all groups. The total score of cleanliness throughout the length of the SB showed some benefit for Ensure (a score of 1.8) over control group 2 (a score of 2) (P = 0.06). The cleanliness grading of the proximal and distal parts of the SB was similar in all four groups (P = 0.6 for both). The cleanliness in the middle part of the SB in the PEG (a score of 1.8) and Ensure groups (a score of 1.7) was equally better than that of control group 2 (a score of 2.1) (P = 0.057 and P = 0.07, respectively). All 50 PEG patients had diarrhea as an anticipated side effect, compared with only one patient in the Ensure group. CONCLUSION Preparation with Ensure, a liquid, fiber-free formula has advantages over standard and PEG preparations, with significantly fewer side effects than PEG.
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Failure of Synbiotic 2000 to prevent postoperative recurrence of Crohn's disease.
Chermesh, I, Tamir, A, Reshef, R, Chowers, Y, Suissa, A, Katz, D, Gelber, M, Halpern, Z, Bengmark, S, Eliakim, R
Digestive diseases and sciences. 2007;(2):385-9
Abstract
Complications of Crohn's disease (CD) lead to surgery in about 70-90% of patients. The majority of patients suffer from relapse of the disease. Colonic bacteria are essential to the development of CD. Therefore, a rationale exists in trying to prevent relapse by manipulation of gut microflora. This is feasible by treatment with probiotics or antibiotics. Synbiotic 2000 is a cocktail containing 4 probiotic species and 4 prebiotics. It is rational to pursue that it could be effective in preventing postoperative disease. We sought to check weather treatment with Synbiotic 2000 could prevent postoperative recurrence in patients with CD. This was a prospective multicenter, randomized study. Patients were randomized to active treatment or placebo in a 2:1 ratio. Follow-up consisted of endoscopic, clinical, and laboratory parameters. Thirty patients were enrolled. No differences were found between the 2 treatment groups regarding gender, age at diagnosis, age at surgery, weight, smoking status, type of disease, length of the resected segment, or medical treatment prior to surgery. No difference in either endoscopic or clinical relapse rate was found between patients treated with once daily dose of Synbiotic 2000 or placebo. In our small study, Synbiotic 2000 had no effect on postoperative recurrence of patients with CD. Larger studies in patients with the inflammatory type of CD undergoing surgery, using higher doses of probiotics cocktail might prove effective.
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A double-blind randomized placebo-controlled trial of orlistat for the treatment of nonalcoholic fatty liver disease.
Zelber-Sagi, S, Kessler, A, Brazowsky, E, Webb, M, Lurie, Y, Santo, M, Leshno, M, Blendis, L, Halpern, Z, Oren, R
Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association. 2006;(5):639-44
Abstract
BACKGROUND & AIMS Few controlled studies have addressed the issue of effective medical treatment for nonalcoholic fatty liver disease (NAFLD). We herein assessed the effect of orlistat in patients with NAFLD. METHODS We performed a randomized, double-blind, placebo-controlled study on 52 patients with NAFLD diagnosed by ultrasound (US) and confirmed by liver biopsy (40 patients). The patients were randomized to receive either orlistat (120 mg 3 times daily for 6 months) or placebo. All patients participated in an identical behavioral weight loss program. All patients underwent monthly evaluation by abdominal US; liver enzyme levels, lipid profiles, insulin levels, and anthropometric parameters were monitored, and all patients underwent nutritional follow-up evaluation. Twenty-two patients underwent a second liver biopsy examination at the end of the study. RESULTS Fifty-two patients were recruited and 44 (mean age, 47.7 y; mean body mass index, 33) completed the study. Serum glucose and insulin levels (P<.03) were significantly higher in the orlistat group, which also presented a higher degree of fibrosis. Body mass index was reduced significantly in each group, with a nonsignificant difference between the groups. Serum alanine transaminase (ALT) levels decreased significantly in both groups, with an almost 2-fold reduction in the orlistat group (48% vs 26.4%). There was a statistically significant reversal of fatty liver by US only in the orlistat group (P<.05). CONCLUSIONS Orlistat improves serum ALT levels and steatosis on US in NAFLD patients, beyond its effect on weight reduction.