Keto microbiota: A powerful contributor to host disease recovery Abstract Gut microbiota (GM) is a key contributor to host metabolism and physiology. Data generated on comparing diseased and healthy subjects have reported changes in the GM profile between both health states, suggesting certain bacterial composition could be involved in pathogenesis. Moreover, studies reported that reshaping of GM could contribute actively to disease recovery. Interestingly, ketogenic diets (KD) have emerged recently as new economic dietotherapeutic strategy to combat a myriad of diseases (refractory epilepsy, obesity, cancer, neurodegenerative diseases…). KD, understood in a broad sense, refers to whatever dietetic approximation, which causes physiological ketosis. Therefore, high fat-low carbs diets, fasting periods or caloric restriction constitute different strategies to produce an increase of main ketones bodies, acetoacetate and β-hydroxybutyrate, in blood. Involved biological mechanisms in ketotherapeutic effects are still to be unravelled. However, it has been pointed out that GM remodelling by KD, from now on “keto microbiota”, may play a crucial role in patient response to KD treatment. In fact, germ-free animals were resistant to ketotherapeutic effects; reinforcing keto microbiota may be a powerful contributor to host disease recovery. In this review, we will comment the influence of gut microbiota on host, as well as, therapeutic potential of ketogenic diets and keto microbiota to restore health status. Current progress and limitations will be argued too. In spite of few studies have defined applicability and mechanisms of KD, in the light of results, keto microbiota might be a new useful therapeutic agent.

Efficacy and safety of very low calorie ketogenic diet (VLCKD) in patients with overweight and obesity: A systematic review and meta-analysis Abstract Very low calorie ketogenic diet (VLCKD) has been proposed as a promising option to achieve a significant weight loss in a short time period. We conducted a systematic review and meta-analysis to evaluate its efficacy and safety in patients with overweight and obesity. Four databases were searched on May 2019. Studies reporting data on body weight, body mass index (BMI), waist circumference, body composition, blood pressure, HbA1c, lipids, and markers of liver and kidney function were selected. Discontinuation was also assessed. Twelve studies were included. VLCKD was associated with weight losses of −10.0 kg (I2 = 6%) and − 15.6 kg (I2 = 37%) in studies with a ketogenic phase up to and of at least four weeks, respectively. The weight lost during the ketogenic phase was stable in the subsequent follow-up up to two years (p = 0.12). Also, VLCKD was associated with reductions of BMI (−5.3 kg/m2), waist circumference (−12.6 cm), HbA1c (−0.7%), total cholesterol (−28 mg/dl), triglycerides (−30 mg/dl), AST (−7 U/l), ALT (−8 U/l), GGT (−8 U/l), systolic and diastolic blood pressure (−8 and − 7 mmHg, respectively). No changes in LDL cholesterol, HDL cholesterol, serum creatinine, serum uric acid and serum potassium were found. Serum sodium increased during VLCKD (+1.6 mEq/l). The overall prevalence of patients discontinuing VLCKD was 7.5% and this was similar to patients undergoing a low calorie diet (p = 0.83). The present review supports the use of VLCKD as an effective strategy for the management of overweight and obesity. Future guidelines should include a specific recommendation for this intervention.

The gut microbiome and heart failure: A better gut for a better heart Abstract Despite the development of new drugs and therapeutic strategies, mortality and morbidity related to heart failure (HF) remains high. It is also the leading cause of global mortality. Several concepts have been proposed to explore the underlying pathogenesis of HF, but there is still a strong need for more specific and complementary therapeutic options. In recent years, accumulating evidence has demonstrated that changes in the composition of gut microbiota, referred to as dysbiosis, might play a pivotal role in the development of several diseases, including HF. HF-associated decreased cardiac output, resulting in bowell wall oedema and intestine ischaemia, can alter gut structure, peamibility and function. These changes would favour bacterial translocation, exacerbating HF pathogenesis at least partly through activation of systemic inflammation. Although our knowledge of the precise molecular mechanisms by which gut dysbiosis influance HF is still limited, a growing body of evidence has recently demonstrated the impact of a series of gut microbiome-derived metabolites, such as trimetylamine N-oxide, short-chain fatty acids or secondary bile acids, which have been shown to play critical roles in cardiac health and disease. This review will summarize the role of gut microbiota and its metabolites in the pathogenesis of HF. Current and future preventive and therapeutic strategies to prevent HF by an adequate modulation of the microbiome and its derived metabolites are also discussed.

Dietary lipids, gut microbiota and lipid metabolism Abstract The gut microbiota is a central regulator of host metabolism. The composition and function of the gut microbiota is dynamic and affected by diet properties such as the amount and composition of lipids. Hence, dietary lipids may influence host physiology through interaction with the gut microbiota. Lipids affect the gut microbiota both as substrates for bacterial metabolic processes, and by inhibiting bacterial growth by toxic influence. The gut microbiota has been shown to affect lipid metabolism and lipid levels in blood and tissues, both in mice and humans. Furthermore, diseases linked to dyslipidemia, such as non-alcoholic liver disease and atherosclerosis, are associated with changes in gut microbiota profile. The influence of the gut microbiota on host lipid metabolism may be mediated through metabolites produced by the gut microbiota such as short-chain fatty acids, secondary bile acids and trimethylamine and by pro-inflammatory bacterially derived factors such as lipopolysaccharide. Here we will review the association between gut microbiota, dietary lipids and lipid metabolism

The gut microbiota to the brain axis in the metabolic control Abstract The regulation of glycemia is under a tight neuronal detection of glucose levels performed by the gut-brain axis and an efficient efferent neuronal message sent to the peripheral organs, as the pancreas to induce insulin and inhibit glucagon secretions. The neuronal detection of glucose levels is performed by the autonomic nervous system including the enteric nervous system and the vagus nerve innervating the gastro-intestinal tractus, from the mouth to the anus. A dysregulation of this detection leads to the one of the most important current health issue around the world i.e. diabetes mellitus. Furthemore, the consequences of diabetes mellitus on neuronal homeostasis and activities participate to the aggravation of the disease establishing a viscious circle. Prokaryotic cells as bacteria, reside in our gut. The strong relationship between prokaryotic cells and our eukaryotic cells has been established long ago, and prokaryotic and eukaryotic cells in our body have evolved synbiotically. For the last decades, studies demonstrated the critical role of the gut microbiota on the metabolic control and how its shift can induce diseases such as diabetes. Despite an important increase of knowledge, few is known about 1) how the gut microbiota influences the neuronal detection of glucose and 2) how the diabetes mellitus-induced gut microbiota shift observed participates to the alterations of autonomic nervous system and the gut-brain axis activity.

Gut microbiota-derived succinate: Friend or foe in human metabolic diseases? Abstract There is now a wealth of evidence showing that communication between microbiota and the host is critical to sustain the vital functions of the healthy host, and disruptions of this homeostatic coexistence are known to be associated with a range of diseases including obesity and type 2 diabetes. Microbiota-derived metabolites act both as nutrients and as messenger molecules and can signal to distant organs in the body to shape host pathophysiology. In this review, we provide a new perspective on succinate as a gut microbiota-derived metabolite with a key role governing intestinal homeostasis and energy metabolism. Thus, succinate is not merely a major intermediary of the TCA traditionally considered as an extracellular danger signal in the host, but also a by-product of some bacteria and a primary cross-feeding metabolite between gut resident microbes. In addition to maintain a healthy microbiome, specific functions of microbiota-derived succinate in peripheral tissues regulating host nutrient metabolism should not be rule out. Indeed, recent research point to some probiotic interventions directed to modulate succinate levels in the intestinal lumen, as a new microbiota-based therapies to treat obesity and related co-morbidities. While further research is essential, a large body of evidence point to succinate as a new strategic mediator in the microbiota-host cross-talk, which might provide the basis for new therapeutically approaches in a near future.

Vasopressin and Copeptin in health and disease Abstract Arginine Vasopressin (AVP) and copeptin derive from the same precursor molecule. Due to the equimolar secretion, copeptin responds as rapidly as AVP to osmotic, hemodynamic and unspecific stress-related stimuli and both peptides show a very strong correlation. The physiological functions of AVP are homeostasis of fluid balance, vascular tonus and regulation of the endocrine stress response. In contrast, the exact function of copeptin remains unknown. Since copeptin, in contrast to AVP, can easily be measured with a sandwich immunoassay, its main function so far that it indirectly indicates the amount of AVP in the circulation. Copeptin has emerged as a useful measure in different diseases. On one hand, through its characteristics as a marker of stress, it provides a unique measure of the individual stress burden. As such, it is a prognostic marker in different acute diseases such as ischemic stroke or myocardial infarction. On the other side, it has emerged as a promising marker in the diagnosis of AVP-dependent fluid disorders. Copeptin reliably differentiates various entities of the polyuria polydipsia syndrome; baseline levels >20 pmol/L without prior fluid deprivation identify patients with nephrogenic diabetes insipidus, whereas levels measured upon osmotic stimulation with hypertonic saline or upon non-osmotic stimulation with arginine differentiate primary polydipsia from central diabetes insipidus. In patients with hyponatremia, low levels of copeptin together with low urine osmolality identify patients with primary polydipsia, but copeptin levels overlap in all other causes of hyponatremia, limiting its diagnostic use in hyponatremia. Copeptin has also been put forward as predictive marker for autosomal dominant polycystic kidney disease and for diabetes mellitus, but more studies are needed to confirm these findings.

Risk of vertebral fractures in hypoparathyroidism Abstract Parathyroid hormone (PTH) exerts both anabolic and catabolic actions on bone,depending on the duration and periodicity of exposure. Hypoparathyroidism is defined by inadequate production of PTH in the presence oflow serum calcium. In hypoparathyroidism it has been reported an increase in corticaland trabecular bone mass, but it is still unknown if these quantitative variations maybe accompanied by qualitative ones and increased bone strength. Despite the extensive data available on the effects of hypoparathyroidism on bone, itseffect on the hard end point in this area which is the risk of fractures still remainsunresolved and highly debated. As a matter of fact no previous review has focused onthis relevant clinical topic. This review will deal with the various aspects of bone metabolism (turn-over,density, quality) in hypoparathyroidism, focusing on the few data available on therisk of fracture and in particular of morphometric vertebral fractures, the emerging way to assess actual skeletal fragility particularly in secondary forms of osteoporosis.

Genetics, adaptation to environmental changes and archaic admixture in the pathogenesis of diabetes mellitus in Indigenous Australians Abstract Indigenous Australians are particularly affected by type 2 diabetes mellitus (T2D) due to both their genetic susceptibility and a range of environmental and lifestyle risk factors. Recent genetic studies link predisposition to some diseases, including T2D, to alleles acquired from archaic hominins, such as Neanderthals and Denisovans, which persist in the genomes of modern humans today. Indo-Pacific human populations, including Indigenous Australians, remain extremely underrepresented in genomic research with a paucity of data examining the impact of Denisovan or Neanderthal lineages on human phenotypes in Oceania. The few genetic studies undertaken emphasize the uniqueness and antiquity of Indigenous Australian genomes, with possibly the largest proportion of Denisovan ancestry of any population in the world. In this review, we focus on the potential contributions of ancient genes/pathways to modern human phenotypes, while also highlighting the evolutionary roles of genetic adaptation to dietary and environmental changes associated with an adopted Western lifestyle. We discuss the role of genetic and epigenetic factors in the pathogenesis of T2D in understudied Indigenous Australians, including the potential impact of archaic gene lineages on this disease. Finally, we propose that greater understanding of the underlying genetic predisposition may contribute to the clinical efficacy of diabetes management in Indigenous Australians. We suggest that improved identification of T2D risk variants in Oceania is needed. Such studies promise to clarify how genetic and phenotypic differences vary between populations and, crucially, provide novel targets for personalised medical therapies in currently marginalized groups.

Clinical applications of (epi)genetics in gastroenteropancreatic neuroendocrine neoplasms: Moving towards liquid biopsies Abstract High-throughput analysis, including next-generation sequencing and microarrays, have strongly improved our understanding of cancer biology. However, genomic data on rare cancer types, such as neuroendocrine neoplasms, has been lagging behind. Neuroendocrine neoplasms (NENs) develop from endocrine cells spread throughout the body and are highly heterogeneous in biological behavior. In this challenging disease, there is an urgent need for new therapies and new diagnostic, prognostic, follow-up and predictive biomarkers to aid patient management. The last decade, molecular data on neuroendocrine neoplasms of the gastrointestinal tract and pancreas, termed gastroenteropancreatic NENs (GEP-NENs), has strongly expanded. The aim of this review is to give an overview of the recent advances on (epi)genetic level and highlight their clinical applications to address the current needs in GEP-NENs. We illustrate how molecular alterations can be and are being used as therapeutic targets, how mutations in DAXX/ATRX and copy number variations could be used as prognostic biomarkers, how far we are in identifying predictive biomarkers and how genetics can contribute to GEP-NEN classification. Finally, we discuss recent studies on liquid biopsies in the field of GEP-NENs and illustrate how liquid biopsies can play a role in patient management. In conclusion, molecular studies have suggested multiple potential biomarkers, but further validation is ongoing.