Epigenetics, Microbiota, and Breast Cancer: A Systematic Review.

Breast cancer is the most frequently diagnosed cancer in women worldwide. According to recent studies, alterations in the microbiota and epigenetic modulations are risk factors for this disease. This systematic review aims to determine the possible associations between the intestinal and mammary microbial populations, epigenetic modifications, and breast cancer. To achieve this objective, we conducted a literature search in the PubMed, Web of Science, and Science Direct databases following the PRISMA guidelines. Although no results are yet available in humans, studies in mice suggest a protective effect of maternal dietary interventions with bioactive compounds on the development of breast tumors in offspring. These dietary interventions also modified the gut microbiota, increasing the relative abundance of short-chain fatty acid-producing taxa and preventing mammary carcinogenesis. In addition, short-chain fatty acids produced by the microbiota act as epigenetic modulators. Furthermore, some authors indicate that stress alters the gut microbiota, promoting breast tumor growth through epigenetic and gene expression changes in the breast tumor microenvironment. Taken together, these findings show the ability of epigenetic modifications and alterations of the microbiota associated with environmental factors to modulate the development, aggressiveness, and progression of breast cancer.

Efficacy and Safety of Habitual Consumption of a Food Supplement Containing Miraculin in Malnourished Cancer Patients: The CLINMIR Pilot Study.

Taste disorders (TDs) are common among systemically treated cancer patients and negatively impact their nutritional status and quality of life. The novel food approved by the European Commission (EFSA), dried miracle berries (DMB), contains the natural taste-modifying protein miraculin. DMB, also available as a supplement, has emerged as a possible alternative treatment for TDs. The present study aimed to evaluate the efficacy and safety of habitual DMB consumption in malnourished cancer patients undergoing active treatment. An exploratory clinical trial was carried out in which 31 cancer patients were randomized into three arms [standard dose of DMB (150 mg DMB/tablet), high dose of DMB (300 mg DMB/tablet) or placebo (300 mg freeze-dried strawberry)] for three months. Patients consumed a DMB tablet or placebo daily before each main meal (breakfast, lunch, and dinner). Throughout the five main visits, electrochemical taste perception, nutritional status, dietary intake, quality of life and the fatty acid profile of erythrocytes were evaluated. Patients consuming a standard dose of DMB exhibited improved taste acuity over time (% change right/left side: -52.8 ± 38.5/-58.7 ± 69.2%) and salty taste perception (2.29 ± 1.25 vs. high dose: 2.17 ± 1.84 vs. placebo: 1.57 ± 1.51 points, p < 0.05). They also had higher energy intake (p = 0.075) and covered better energy expenditure (107 ± 19%). The quality of life evaluated by symptom scales improved in patients receiving the standard dose of DMB (constipation, p = 0.048). The levels of arachidonic (13.1 ± 1.8; 14.0 ± 2.8, 12.0 ± 2.0%; p = 0.004) and docosahexaenoic (4.4 ± 1.7; 4.1 ± 1.0; 3.9 ± 1.6%; p = 0.014) acids in erythrocytes increased over time after DMB intake. The standard dose of DMB increased fat-free mass vs. placebo (47.4 ± 9.3 vs. 44.1 ± 4.7 kg, p = 0.007). Importantly, habitual patients with DMB did not experience any adverse events, and metabolic parameters remained stable and within normal ranges. In conclusion, habitual consumption of a standard 150 mg dose of DMB improves electrochemical food perception, nutritional status (energy intake, fat quantity and quality, fat-free mass), and quality of life in malnourished cancer patients receiving antineoplastic treatment. Additionally, DMB consumption appears to be safe, with no changes in major biochemical parameters associated with health status. Clinical trial registered (NCT05486260).

Differential Modulation of Mouse Intestinal Organoids with Fecal Luminal Factors from Obese, Allergic, Asthmatic Children.

Asthma is a multifactorial condition that can be associated with obesity. The phenotypes of asthma in lean and obese patients are different, with proinflammatory signatures being further elevated in the latter. Both obesity and asthma are associated with alterations in intestinal barrier function and immunity, and with the composition of the intestinal microbiota and food consumption. In this study, we aimed to establish an organoid model to test the hypothesis that the intestinal content of lean and obese, allergic, asthmatic children differentially regulates epithelial intestinal gene expression. A model of mouse jejunum intestinal organoids was used. A group of healthy, normal-weight children was used as a control. The intestinal content of asthmatic obese children differentially induced the expression of inflammatory and mitochondrial response genes (Tnf-tumor necrosis factor, Cd14, Muc13-mucin 13, Tff2-Trefoil factor 2 and Tff3, Cldn1-claudin 1 and 5, Reg3g-regenerating family member 3 gamma, mt-Nd1-NADH dehydrogenase 1 and 6, and mt-Cyb-mitochondrial cytochrome b) via the RAGE-advanced glycosylation end product-specific receptor, NF-κB-nuclear factor kappa b and AKT kinase signal transduction pathways. Fecal homogenates from asthmatic normal-weight and obese children induce a differential phenotype in intestinal organoids, in which the presence of obesity plays a major role.

The Interplay between Microbiota and Chemotherapy-Derived Metabolites in Breast Cancer.

The most common cancer in women is breast cancer, which is also the second leading cause of death in this group. It is, however, important to note that some women will develop or will not develop breast cancer regardless of whether certain known risk factors are present. On the other hand, certain compounds are produced by bacteria in the gut, such as short-chain fatty acids, secondary bile acids, and other metabolites that may be linked to breast cancer development and mediate the chemotherapy response. Modeling the microbiota through dietary intervention and identifying metabolites directly associated with breast cancer and its complications may be useful to identify actionable targets and improve the effect of antiangiogenic therapies. Metabolomics is therefore a complementary approach to metagenomics for this purpose. As a result of the combination of both techniques, a better understanding of molecular biology and oncogenesis can be obtained. This article reviews recent literature about the influence of bacterial metabolites and chemotherapy metabolites in breast cancer patients, as well as the influence of diet.

Gut Microbiota and Breast Cancer: The Dual Role of Microbes.

Breast cancer is the most frequently diagnosed cancer and also one of the leading causes of mortality among women. The genetic and environmental factors known to date do not fully explain the risk of developing this disease. In recent years, numerous studies have highlighted the dual role of the gut microbiota in the preservation of host health and in the development of different pathologies, cancer among them. Our gut microbiota is capable of producing metabolites that protect host homeostasis but can also produce molecules with deleterious effects, which, in turn, may trigger inflammation and carcinogenesis, and even affect immunotherapy. The purpose of this review is to describe the mechanisms by which the gut microbiota may cause cancer in general, and breast cancer in particular, and to compile clinical trials that address alterations or changes in the microbiota of women with breast cancer.

Impact of Exercise on Gut Microbiota in Obesity.

Physical activity, exercise, or physical fitness are being studied as helpful nonpharmacological therapies to reduce signaling pathways related to inflammation. Studies describing changes in intestinal microbiota have stated that physical activity could increase the microbial variance and enhance the ratio of Firmicutes/Bacteroidetes, and both actions could neutralize the obesity progression and diminish body weight. The aim of this review is to provide an overview of the literature describing the relationship between physical activity profiles and gut microbiota and in obesity and some associated comorbidities. Promoting physical activity could support as a treatment to maintain the gut microbiota composition or to restore the balance toward an improvement of dysbiosis in obesity; however, these mechanisms need to be studied in more detail. The opportunity to control the microbiota by physical activity to improve health results and decrease obesity and related comorbidities is very attractive. Nevertheless, several incompletely answered questions need to be addressed before this strategy can be implemented.

New Insights Into the Role of Autophagy in Liver Surgery in the Setting of Metabolic Syndrome and Related Diseases.

Visceral obesity is an important component of metabolic syndrome, a cluster of diseases that also includes diabetes and insulin resistance. A combination of these metabolic disorders damages liver function, which manifests as non-alcoholic fatty liver disease (NAFLD). NAFLD is a common cause of abnormal liver function, and numerous studies have established the enormously deleterious role of hepatic steatosis in ischemia-reperfusion (I/R) injury that inevitably occurs in both liver resection and transplantation. Thus, steatotic livers exhibit a higher frequency of post-surgical complications after hepatectomy, and using liver grafts from donors with NAFLD is associated with an increased risk of post-surgical morbidity and mortality in the recipient. Diabetes, another MetS-related metabolic disorder, also worsens hepatic I/R injury, and similar to NAFLD, diabetes is associated with a poor prognosis after liver surgery. Due to the large increase in the prevalence of MetS, NAFLD, and diabetes, their association is frequent in the population and therefore, in patients requiring liver resection and in potential liver graft donors. This scenario requires advancement in therapies to improve postoperative results in patients suffering from metabolic diseases and undergoing liver surgery; and in this sense, the bases for designing therapeutic strategies are in-depth knowledge about the molecular signaling pathways underlying the effects of MetS-related diseases and I/R injury on liver tissue. A common denominator in all these diseases is autophagy. In fact, in the context of obesity, autophagy is profoundly diminished in hepatocytes and alters mitochondrial functions in the liver. In insulin resistance conditions, there is a suppression of autophagy in the liver, which is associated with the accumulation of lipids, being this is a risk factor for NAFLD. Also, oxidative stress occurring in hepatic I/R injury promotes autophagy. The present review aims to shed some light on the role of autophagy in livers undergoing surgery and also suffering from metabolic diseases, which may lead to the discovery of effective therapeutic targets that could be translated from laboratory to clinical practice, to improve postoperative results of liver surgeries when performed in the presence of one or more metabolic diseases.

Effects of Gut Metabolites and Microbiota in Healthy and Marginal Livers Submitted to Surgery.

Microbiota is defined as the collection of microorganisms within the gastrointestinal ecosystem. These microbes are strongly implicated in the stimulation of immune responses. An unbalanced microbiota, termed dysbiosis, is related to the development of several liver diseases. The bidirectional relationship between the gut, its microbiota and the liver is referred to as the gut-liver axis. The translocation of bacterial products from the intestine to the liver induces inflammation in different cell types such as Kupffer cells, and a fibrotic response in hepatic stellate cells, resulting in deleterious effects on hepatocytes. Moreover, ischemia-reperfusion injury, a consequence of liver surgery, alters the microbiota profile, affecting inflammation, the immune response and even liver regeneration. Microbiota also seems to play an important role in post-operative outcomes (i.e., liver transplantation or liver resection). Nonetheless, studies to determine changes in the gut microbial populations produced during and after surgery, and affecting liver function and regeneration are scarce. In the present review we analyze and discuss the preclinical and clinical studies reported in the literature focused on the evaluation of alterations in microbiota and its products as well as their effects on post-operative outcomes in hepatic surgery.

The Mediation Effect of Self-Report Physical Activity Patterns in the Relationship between Educational Level and Cognitive Impairment in Elderly: A Cross-Sectional Analysis of Chilean Health National Survey 2016-2017.

The aims of this cross-sectional study were (i) to determine the association of educational level attained with cognitive impairment and (ii) to investigate the mediating effect of different self-report physical activity (PA) patterns in a large sample of older Chileans. A sample of 1571 older adults from the National Chilean Survey (2016-2017) was included. The educational level attained, PA levels, mode of commuting, sedentary time, and leisure-time PA were self-reported through validated questionnaires. Cognitive impairment was determined by Mini-Mental State Examination (modified version). Association between educational level attained and cognitive impairment was examined using logistic regression models. Counterfactual mediation models were used to test the mediating effect of self-reported PA patterns. A lower educational level was consistently associated with higher odds of cognitive impairment (OR range 2.846 to 2.266, all p < 0.001), while leisure-time PA was the only PA pattern that partially mediated this association (proportion mediated 8.0%). In conclusion, leisure-time PA was the solely PA pattern that partially mediated the association between the educational level and cognitive impairment. The rest self-reported PA patterns did not modify this association.

Current Knowledge about the Effect of Nutritional Status, Supplemented Nutrition Diet, and Gut Microbiota on Hepatic Ischemia-Reperfusion and Regeneration in Liver Surgery.

Ischemia-reperfusion (I/R) injury is an unresolved problem in liver resection and transplantation. The preexisting nutritional status related to the gut microbial profile might contribute to primary non-function after surgery. Clinical studies evaluating artificial nutrition in liver resection are limited. The optimal nutritional regimen to support regeneration has not yet been exactly defined. However, overnutrition and specific diet factors are crucial for the nonalcoholic or nonalcoholic steatohepatitis liver diseases. Gut-derived microbial products and the activation of innate immunity system and inflammatory response, leading to exacerbation of I/R injury or impaired regeneration after resection. This review summarizes the role of starvation, supplemented nutrition diet, nutritional status, and alterations in microbiota on hepatic I/R and regeneration. We discuss the most updated effects of nutritional interventions, their ability to alter microbiota, some of the controversies, and the suitability of these interventions as potential therapeutic strategies in hepatic resection and transplantation, overall highlighting the relevance of considering the extended criteria liver grafts in the translational liver surgery.

Microbial Population Changes and Their Relationship with Human Health and Disease.

Specific microbial profiles and changes in intestinal microbiota have been widely demonstrated to be associated with the pathogenesis of a number of extra-intestinal (obesity and metabolic syndrome) and intestinal (inflammatory bowel disease) diseases as well as other metabolic disorders, such as non-alcoholic fatty liver disease and type 2 diabetes. Thus, maintaining a healthy gut ecosystem could aid in avoiding the early onset and development of these diseases. Furthermore, it is mandatory to evaluate the alterations in the microbiota associated with pathophysiological conditions and how to counteract them to restore intestinal homeostasis. This review highlights and critically discusses recent literature focused on identifying changes in and developing gut microbiota-targeted interventions (probiotics, prebiotics, diet, and fecal microbiota transplantation, among others) for the above-mentioned pathologies. We also discuss future directions and promising approaches to counteract unhealthy alterations in the gut microbiota. Altogether, we conclude that research in this field is currently in its infancy, which may be due to the large number of factors that can elicit such alterations, the variety of related pathologies, and the heterogeneity of the population involved. Further research on the effects of probiotics, prebiotics, or fecal transplantations on the composition of the human gut microbiome is necessary.

The Role of Adipokines in Surgical Procedures Requiring Both Liver Regeneration and Vascular Occlusion.

Liver regeneration is a perfectly calibrated mechanism crucial to increase mass recovery of small size grafts from living donor liver transplantation, as well as in other surgical procedures including hepatic resections and liver transplantation from cadaveric donors. Regeneration involves multiple events and pathways in which several adipokines contribute to their orchestration and drive hepatocytes to proliferate. In addition, ischemia-reperfusion injury is a critical factor in hepatic resection and liver transplantation associated with liver failure or graft dysfunction post-surgery. This review aims to summarize the existing knowledge in the role of adipokines in surgical procedures requiring both liver regeneration and vascular occlusion, which increases ischemia-reperfusion injury and regenerative failure. We expose and discuss results in small-for-size liver transplantation and hepatic resections from animal studies focused on the modulation of the main adipokines associated with liver diseases and/or regeneration published in the last five years and analyze future perspectives and their applicability as potential targets to decrease ischemia-reperfusion injury and improve regeneration highlighting marginal states such as steatosis. In our view, adipokines means a promising approach to translate to the bedside to improve the recovery of patients subjected to partial hepatectomy and to increase the availability of organs for transplantation.

PAX4 preserves endoplasmic reticulum integrity preventing beta cell degeneration in a mouse model of type 1 diabetes mellitus.

AIMS/HYPOTHESIS: A strategy to enhance pancreatic islet functional beta cell mass (BCM) while restraining inflammation, through the manipulation of molecular and cellular targets, would provide a means to counteract the deteriorating glycaemic control associated with diabetes mellitus. The aims of the current study were to investigate the therapeutic potential of such a target, the islet-enriched and diabetes-linked transcription factor paired box 4 (PAX4), to restrain experimental autoimmune diabetes (EAD) in the RIP-B7.1 mouse model background and to characterise putative cellular mechanisms associated with preserved BCM. METHODS: Two groups of RIP-B7.1 mice were genetically engineered to: (1) conditionally express either PAX4 (BPTL) or its diabetes-linked mutant variant R129W (mutBPTL) using doxycycline (DOX); and (2) constitutively express luciferase in beta cells through the use of RIP. Mice were treated or not with DOX, and EAD was induced by immunisation with a murine preproinsulin II cDNA expression plasmid. The development of hyperglycaemia was monitored for up to 4 weeks following immunisation and alterations in the BCM were assessed weekly by non-invasive in vivo bioluminescence intensity (BLI). In parallel, BCM, islet cell proliferation and apoptosis were evaluated by immunocytochemistry. Alterations in PAX4- and PAX4R129W-mediated islet gene expression were investigated by microarray profiling. PAX4 preservation of endoplasmic reticulum (ER) homeostasis was assessed using thapsigargin, electron microscopy and intracellular calcium measurements. RESULTS: PAX4 overexpression blunted EAD, whereas the diabetes-linked mutant variant PAX4R129W did not convey protection. PAX4-expressing islets exhibited reduced insulitis and decreased beta cell apoptosis, correlating with diminished DNA damage and increased islet cell proliferation. Microarray profiling revealed that PAX4 but not PAX4R129W targeted expression of genes implicated in cell cycle and ER homeostasis. Consistent with the latter, islets overexpressing PAX4 were protected against thapsigargin-mediated ER-stress-related apoptosis. Luminal swelling associated with ER stress induced by thapsigargin was rescued in PAX4-overexpressing beta cells, correlating with preserved cytosolic calcium oscillations in response to glucose. In contrast, RNA interference mediated repression of PAX4-sensitised MIN6 cells to thapsigargin cell death. CONCLUSIONS/INTERPRETATION: The coordinated regulation of distinct cellular pathways particularly related to ER homeostasis by PAX4 not achieved by the mutant variant PAX4R129W alleviates beta cell degeneration and protects against diabetes mellitus. The raw data for the RNA microarray described herein are accessible in the Gene Expression Omnibus database under accession number GSE62846.