Dietary Interventions to Modulate the Gut Microbiome-How Far Away Are We From Precision Medicine

The importance of the gut microbiome in human health and disease is fully acknowledged. A perturbation in the equilibrium among the different microbial populations living in the gut (dysbiosis) has been associated with the development of several types of diseases. Modulation of the gut microbiome through dietary intervention is an emerging therapeutic and preventive strategy for many conditions. Nevertheless, interpersonal differences in response to therapeutic treatments or dietary regimens are often observed during clinical trials, and recent research has suggested that subject-specific features of the gut microbiota may be responsible. In this review, we summarize recent findings in personalized nutrition, highlighting how individualized characterization of the microbiome may assist in designing ad hoc tailored dietary intervention for disease treatment and prevention. Moreover, we discuss the limitations and challenges encountered in integrating patient-specific microbial data into clinical practice

Transthyretin binding heterogeneity and antiamyloidogenic activity of natural polyphenols and their metabolites

Transthyretin (TTR) is an amyloidogenic protein, the amyloidogenic potential of which is enhanced by a number of specific point mutations. The ability to inhibit TTR fibrillogenesis is known for several classes of compounds, including natural polyphenols, which protect the native state of TTR by specifically interacting with its thyroxine binding sites. Comparative analyses of the interaction and of the ability to protect the TTR native state for polyphenols, both stilbenoids and flavonoids, and some of their main metabolites have been carried out. A main finding of this investigation was the highly preferential binding of resveratrol and thyroxine, both characterized by negative binding cooperativity, to distinct sites in TTR, consistent with the data of x-ray analysis of TTR in complex with both ligands. Although revealing the ability of the two thyroxine binding sites of TTR to discriminate between different ligands, this feature has allowed us to evaluate the interactions of polyphenols with both resveratrol and thyroxine preferential binding sites, by using resveratrol and radiolabeled T4 as probes. Among flavonoids, genistein and apigenin were able to effectively displace resveratrol from its preferential binding site, whereas genistein also showed the ability to interact, albeit weakly, with the preferential thyroxine binding site. Several glucuronidated polyphenol metabolites did not exhibit significant competition for resveratrol and thyroxine preferential binding sites and lacked the ability to stabilize TTR. However, resveratrol-3-O-sulfate was able to significantly protect the protein native state. A rationale for the in vitro properties found for polyphenol metabolites was provided by x-ray analysis of their complexes with TTR

Effects of a Lactobacillus paracasei B21060 based synbiotic on steatosis, insulin signaling and toll-like receptor expression in rats fed a high-fat diet.

Insulin resistance (IR) has been identified as crucial pathophysiological factor in the development and progression of non-alcoholic fatty liver disease (NAFLD). Although mounting evidence suggests that perturbation of gut microflora exacerbates the severity of chronic liver diseases, therapeutic approaches using synbiotic has remained overlooked. Here, we show that a synbiotic composed by Lactobacillus paracasei B21060 plus arabinogalactan and fructo-oligosaccharides lessens NAFLD progression in a rat model of high fat feeding. IR and steatosis were induced by administration of high fat diet (HFD) for 6 weeks. Steatosis and hepatic inflammation, Toll-like receptor (TLR) pattern, glucose tolerance, insulin signaling and gut permeability were studied. Liver inflammatory markers were down-regulated in rats receiving the synbiotic, along with an increased expression of nuclear peroxisome proliferator-activated receptors and expression of downstream target genes. The synbiotic improved many aspects of IR, such as fasting response, hormonal homeostasis and glycemic control. Indeed it prevented the impairment of hepatic insulin signaling, reducing the phosphorylation of insulin receptor substrate-1 in Ser 307 and down-regulating suppressor of cytokine signaling 3. Gene expression analysis revealed that in the liver the synbiotic reduced cytokines synthesis and restored the HFD-dysregulated TLR 2, 4 and 9 mRNAs toward a physiological level of expression. The synbiotic preserved gut barrier integrity and reduced the relative amount of Gram-negative Enterobacteriales and Escherichia coli in colonic mucosa. Overall, our data indicate that the L. paracasei B21060 based synbiotic is effective in reducing the severity of liver injury and IR associated with high fat intake, suggesting its possible therapeutic/preventive clinical utilization

Evaluation of the cost-effectiveness of rifaximin-α for the management of patients with hepatic encephalopathy in the United Kingdom

Objective: Rifaximin-α 550 mg twice daily plus lactulose has demonstrated efficacy in reducing recurrence of episodes of overt HE (OHE) and the risk of HE-related hospitalisations compared with lactulose alone. This analysis estimated the cost effectiveness of rifaximin-α 550 mg twice daily plus lactulose versus lactulose alone in UK cirrhotic patients with OHE. Method: A Markov model was built to estimate the incremental cost effectiveness ratio (ICER). The perspective was that of the UK National Health Service (NHS). Clinical data were sourced from a randomised controlled trial (RCT) and an open-label maintenance (OLM) study in cirrhotic patients in remission from recurrent episodes of OHE. Health-related utility was estimated indirectly from disease-specific quality of life RCT data. Resource use data describing the impact of rifaximin-α on hospital admissions and length of stay for cirrhotic patients with OHE were from four single-centre UK audits. Costs (2012) were derived from published sources; costs and benefits were discounted at 3.5%. The base-case time horizon was five years. Results: The average cost per patient was £22,971 in the rifaximin-α plus lactulose arm and £23,545 in the lactulose arm, a saving of £573. The corresponding values for benefit were 2.35 QALYs and 1.83 QALYs per person, a difference of 0.52 QALYs. This translated into a dominant base-case ICER. Key parameters that impacted the ICER included number of hospital admissions and length of stay. Conclusion: Rifaximin-α 550 mg twice daily in patients with recurrent episodes of overt HE was estimated to generate cost savings and improved clinical outcomes compared to standard care over five years

Impact of COVID-19 pandemic on cardiometabolic patients without SARS CoV-2 infection in Latin America

A cross-sectional survey including 38 questions about demography, clinical condition, changes in health habits, and medical treatments for cardiometabolic patients in outpatient follow-up was conducted. From June 15 to July 15, 2020, a total of 13 Latin-American countries participated in enrolling patients. These countries were divided into 3 geographic regions: Region 1 including North, Central, and Caribbean Regions (NCCR), Region 2 including the Andean Region (AR), and Region 3 including the Southern Cone Region (SCR). 4.216 patients were analyzed, resulting in a coefficient of 33.82%, 32.23%, and 33.94% for NCCR, AR, and SCR, respectively. Significant differences were found between the AR, SCR, and NCCR regions. The analysis of habitual medication usage showed that discontinued use of medication was more present in AR, reaching almost 30% (p < 0.001). The main finding of this study was the negative impact that restrictive measures have on adherence to medications and physical activity: Rs = 0.84 (p = 0.0003) and Rs = 0.61 (p = 0.0032), respectively. AR was the most vulnerable region. Restrictive quarantine measures imposed by the different countries showed a positive correlation with medication discontinuation and a negative correlation with physical activity levels in patients analyzed. These findings characterize the impact of the consequences left by this pandemic. Undoubtedly, restrictive measures have been and will continue to have reverberating negative effects in most Latin-American countries.Fil: Camiletti, Jorge. Hospital Italiano de La Plata; ArgentinaFil: Renna, Nicolas Federico. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; Argentina. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas. Cátedra de Fisiología Patológica; Argentina. Hospital Español de Mendoza; ArgentinaFil: López Santi, Ricardo. Hospital Italiano de La Plata; ArgentinaFil: Erriest, Juan. Hospital Italiano de La Plata; ArgentinaFil: García-Bello, Eliomar. Centro de Diagnóstico Medicina Avanzada y Telemedicina; República DominicanaFil: Araujo, John. Centro Cardiovascular Somer Incare; ColombiaFil: Varleta-Olivares, Paola. Hospital Dipreca; ChileFil: Gómez-Díaz, Eduardo. Hospital Metropolitano del Norte; VenezuelaFil: Ramírez, Gisselle. Medicina Cardiovascular Asociada; República DominicanaFil: Berni Betancourt, Ana. Sociedad interamericana de Cardiología; México. Consejo Interamericano de Electrocardiográfica y Arritmias; México. Hospital Ángeles Pedregal; MéxicoFil: Escalada Lesme, Gustavo. Centro Médico Nacional-Hospital Nacional Itaguá; ParaguayFil: Campos Alcántara, Lourdes V.. Consultorio de Lourdes Victoria Campos Alcántara; PerúFil: Moya Loor, Leonardo. Hospital Santa Margarita; EcuadorFil: Rey Benavente, Claudio. Hospital Arroyabe Pichanal; ArgentinaFil: Almonte, Claudia. Medicina Cardiovascular Asociada; República DominicanaFil: Cortez Sandoval, Maicol. Hospital Nacional Edgardo Rebagliti Martins; PerúFil: Alvarado Cuadros, María. Department of Cardiology, Institution; EcuadorFil: Rosario, Monica I.. Centro de Diagnóstico Medicina Avanzada y Telemedicina; República DominicanaFil: Gupta, Shyla. Queen’s University; CanadáFil: Ibarrola, Martin. Cardiovascular Center BV; ArgentinaFil: Baranchuk, Adrián. Kingston Health Sciences Centre; Canad

Butyrate Regulates Liver Mitochondrial Function, Efficiency, and Dynamics in Insulin-Resistant Obese Mice

Fatty liver, oxidative stress, and mitochondrial dysfunction are key pathophysiological features of insulin resistance and obesity. Butyrate, produced by fermentation in the large intestine by gut microbiota, and its synthetic derivative, the N-(1-carbamoyl-2-phenyl-ethyl) butyramide, FBA, have been demonstrated to be protective against insulin resistance and fatty liver. Here, hepatic mitochondria were identified as the main target of the beneficial effect of both butyrate-based compounds in reverting insulin resistance and fat accumulation in diet-induced obese mice. In particular, butyrate and FBA improved respiratory capacity and fatty acid oxidation, activated the AMPK-acetyl-CoA carboxylase pathway, and promoted inefficient metabolism, as shown by the increase in proton leak. Both treatments consistently increased utilization of substrates, especially fatty acids, leading to the reduction of intracellular lipid accumulation and oxidative stress. Finally, the shift of the mitochondrial dynamic toward fusion by butyrate and FBA resulted in the improvement not only of mitochondrial cell energy metabolism but also of glucose homeostasis. In conclusion, butyrate and its more palatable synthetic derivative, FBA, modulating mitochondrial function, efficiency, and dynamics, can be considered a new therapeutic strategy to counteract obesity and insulin resistance