Incidence of hypophosphataemia after ICU admission in mechanically ventilated patients and its relationship with risk factors for refeeding syndrome.

OBJECTIVE: To describe the incidence of hypophosphatemia in patients admitted to the ICU who have required mechanical ventilation. To analyze the presence of risk factors and its relationship with nutritional practice. DESIGN: Prospective observational study. SETTING: Polyvalent ICUs of 2 University Hospitals. PATIENTS OR PARTICIPANTS: Patients on invasive mechanical ventilation ≥72 h with normal level of phosphorus at admission. INTERVENTIONS: None. MAIN VARIABLES OF INTEREST: Electrolyte levels (phosphorus, magnesium, potassium) were determined on admission to the ICU and at 96 h. Risk categories on admission, caloric intake, insulin doses and acid-base status during the first 4 days of admission were recorded. Incidence was calculated as the number of patients who developed hypophosphataemia after admission. Univariate analysis was performed for between-group comparison and multivariate analysis of potential risk factors. RESULTS: 89 patients were included. The incidence of hypophosphataemia was 32.6%. In these patients phosphorus decreased from 3.57 ±â€¯1.02 mmol/l to 1.87 ±â€¯0.65 mmol/l (52.3%). The mean kcal/kg/24 h provided in the first 4 days was 17.4 ±â€¯4.1, with no difference between the group that developed hypophosphataemia and the group that did not. Significant risk factors were insulin doses administered and pH and PaCO2 values. CONCLUSIONS: The incidence of hypophosphataemia at 96 h from admission in mechanically ventilated patients is high and unrelated to the risk category and hypocaloric nutritional practice used. Insulin dosis and acid-base status are the main determinants of its occurrence.

Azathioprine dose tailoring based on pharmacogenetic information: Insights of clinical implementation.

Azathioprine is commonly used as an immunosuppressive antimetabolite in the treatment of acute lymphoblastic leukemia, autoimmune disorders (such as Crohn's disease and rheumatoid arthritis), and in patients receiving organ transplants. Thiopurine-S-methyltransferase (TPMT) is a cytoplasmic trans-methylase catalyzing the S-methylation of thiopurines. The active metabolites obtained from thiopurines are hydrolyzed into inactive forms by the Nudix hydrolase 15 (NUDT15). The TPMT*2 (defined by rs1800462), *3A (defined by rs1800460 and rs1142345), *3B (defined by rs1800460), *3C (defined by rs1142345), *6 (defined by rs75543815), and NUDT15 rs116855232 genetic variant have been associated, with the highest level of evidence, with the response to azathioprine, and, the approved drug label for azathioprine and main pharmacogenetic dosing guidelines recommend starting with reduced initial doses in TPMT intermediate metabolizer (IM) patients and considering an alternative treatment in TPMT poor metabolizer (PM) patients. This study aims to assess the clinical impact of azathioprine dose tailoring based on TPMT genotyping studying the azathioprine toxicity and efficacy, treatment starts, and dose adjustments during follow-up, comparing TPMT IM/PM and normal metabolizer (NM) patients. It also studied the association of NUDT15 rs116855232 with response to azathioprine in patients receiving a tailored treatment based on TPMT and characterized the TMPT and NUDT15 studied variants in our population. Results show that azathioprine dose reduction in TPMT IM patients (TPMT*1/*2, *1/*3A, or *1/*3C genotypes) is related to lower toxicity events compared to TPMT NM (TPMT *1/*1 genotype), and lower azathioprine dose adjustments during follow-up without showing differences in the efficacy. The results support the hypothesis of existing other genetic variants affecting azathioprine toxicity.

Administration of intestinal mesenchymal stromal cells reduces colitis-associated cancer in C57BL/6J mice modulating the immune response and gut dysbiosis.

BACKGROUND: Patients with inflammatory bowel disease (IBD) have a higher risk of developing colitis-associated colorectal cancer (CAC) with poor prognosis. IBD etiology remains undefined but involves environmental factors, genetic predisposition, microbiota imbalance (dysbiosis) and mucosal immune defects. Mesenchymal stromal cell (MSC) injections have shown good efficacy in reducing intestinal inflammation in animal and human studies. However, their effect on tumor growth in CAC and their capacity to restore gut dysbiosis are not clear. METHODS: The outcome of systemic administrations of in vitro expanded human intestinal MSCs (iMSCs) on tumor growth in vivo was evaluated using the AOM/DSS model of CAC in C57BL/6J mice. Innate and adaptive immune responses in blood, mesenteric lymph nodes (MLNs) and colonic tissue were analyzed by flow cytometry. Intestinal microbiota composition was evaluated by 16S rRNA amplicon sequencing. RESULTS: iMSCs significantly inhibited colitis and intestinal tumor development, reducing IL-6 and COX-2 expression, and IL-6/STAT3 and PI3K/Akt signaling. iMSCs decreased colonic immune cell infiltration, and partly restored intestinal monocyte homing and differentiation. iMSC administration increased the numbers of Tregs and IFN-γ+CD8+ T cells in the MLNs while decreasing the IL-4+Th2 response. It also ameliorated intestinal dysbiosis in CAC mice, increasing diversity and Bacillota/Bacteroidota ratio, as well as Akkermansia abundance, while reducing Alistipes and Turicibacter, genera associated with inflammation. CONCLUSION: Administration of iMSCs protects against CAC, ameliorating colitis and partially reverting intestinal dysbiosis, supporting the use of MSCs for the treatment of IBD.

Gut Microbiota Composition Can Predict Colonization by Multidrug-Resistant Bacteria in SARS-CoV-2 Patients in Intensive Care Unit: A Pilot Study.

The SARS-CoV-2 infection has increased the number of patients entering Intensive Care Unit (ICU) facilities and antibiotic treatments. Concurrently, the multi-drug resistant bacteria (MDRB) colonization index has risen. Considering that most of these bacteria are derived from gut microbiota, the study of its composition is essential. Additionally, SARS-CoV-2 infection may promote gut dysbiosis, suggesting an effect on microbiota composition. This pilot study aims to determine bacteria biomarkers to predict MDRB colonization risk in SARS-CoV-2 patients in ICUs. Seventeen adult patients with an ICU stay >48 h and who tested positive for SARS-CoV-2 infection were enrolled in this study. Patients were assigned to two groups according to routine MDRB colonization surveillance: non-colonized and colonized. Stool samples were collected when entering ICUs, and microbiota composition was determined through Next Generation Sequencing techniques. Gut microbiota from colonized patients presented significantly lower bacterial diversity compared with non-colonized patients (p < 0.05). Microbiota in colonized subjects showed higher abundance of Anaerococcus, Dialister and Peptoniphilus, while higher levels of Enterococcus, Ochrobactrum and Staphylococcus were found in non-colonized ones. Moreover, LEfSe analysis suggests an initial detection of Dialister propionicifaciens as a biomarker of MDRB colonization risk. This pilot study shows that gut microbiota profile can become a predictor biomarker for MDRB colonization in SARS-CoV-2 patients.

The melatonergic agonist agomelatine ameliorates high fat diet-induced obesity in mice through the modulation of the gut microbiome.

BACKGROUND AND PURPOSE: Melatonin has shown beneficial effects on obesity, both in humans and experimental models, via regulating the altered circadian rhythm and thus ameliorating the gut dysbiosis associated with this metabolic condition. However, its clinical use is limited, mostly due to its short half-life. Agomelatine is an agonist of the melatonin receptors that could be used to manage obesity and offer a better profile than melatonin. EXPERIMENTAL APPROACH: Male C57BL/6 mice were fed a high fat diet and orally treated for five weeks with agomelatine, or melatonin or metformin, used as control drugs. Metabolic profile, inflammatory status, vascular dysfunction and intestinal microbiota composition were assessed. KEY RESULTS: Agomelatine lessened body weight gain, enhanced glucose and lipid metabolisms, and improved insulin resistance. It also reduced the obesity-associated inflammatory status and endothelial dysfunction, probably linked to its effect on gut dysbiosis, consisting of the restoration of bacterial populations with key functions, such as short chain fatty acid production. CONCLUSIONS AND IMPLICATIONS: Agomelatine can be considered as a novel therapeutic tool for the management of human obesity and its associated comorbidities.

Allium-Derived Compound Propyl Propane Thiosulfonate (PTSO) Attenuates Metabolic Alterations in Mice Fed a High-Fat Diet through Its Anti-Inflammatory and Prebiotic Properties.

BACKGROUND: Propyl propane thiosulfonate (PTSO) is an organosulfur compound from Allium spp. that has shown interesting antimicrobial properties and immunomodulatory effects in different experimental models. In this sense, our aim was to evaluate its effect on an experimental model of obesity, focusing on inflammatory and metabolic markers and the gut microbiota. METHODS AND RESULTS: Mice were fed a high-fat diet and orally treated with different doses of PTSO (0.1, 0.5 and 1 mg/kg/day) for 5 weeks. PTSO lessened the weight gain and improved the plasma markers associated with glucose and lipid metabolisms. PTSO also attenuated obesity-associated systemic inflammation, reducing the immune cell infiltration and, thus, the expression of pro-inflammatory cytokines in adipose and hepatic tissues (Il-1ẞ, Il-6, Tnf-α, Mcp-1, Jnk-1, Jnk-2, Leptin, Leptin R, Adiponectin, Ampk, Ppar-α, Ppar-γ, Glut-4 and Tlr-4) and improving the expression of different key elements for gut barrier integrity (Muc-2, Muc-3, Occludin, Zo-1 and Tff-3). Additionally, these effects were connected to a regulation of the gut microbiome, which was altered by the high-fat diet. CONCLUSION: Allium-derived PTSO can be considered a potential new tool for the treatment of metabolic syndrome.

Intestinal mesenchymal cells regulate immune responses and promote epithelial regeneration in vitro and in dextran sulfate sodium-induced experimental colitis in mice.

AIM: Disruption of the intestinal mucosal tolerance, that is, the immunological unresponsiveness to innocuous food antigens and the commensal microbiota, in the colon is associated with several chronic diseases including inflammatory bowel disease (IBD). Understanding the mechanisms responsible for intestinal mucosal tolerance has potential translational value for its therapy and management. Human intestinal mesenchymal cells (iMCs) play important roles in colonic mucosal tolerance, but further studies on their tissue regenerative and immunomodulatory capacities are necessary in order to fully understand their function in health and disease. METHODS: In this study, we have isolated and analysed the capacity of human iMCs to promote wound healing and modulate immune responses in vitro and in vivo, using the dextran sulfate sodium (DSS)-induced colitis model. RESULTS: Cultured iMCs were CD45- CD73+ CD90+ CD105+ and accelerated the wound closure in a normal colon mucosa (NCM) 356 human epithelial cell wound healing assay. Furthermore, iMCs blocked the LPS-mediated induction of TNF-α in THP-1 macrophages and inhibited the proliferation of peripheral blood mononuclear cells, partly through the induction of indoleamine-2,3-dioxygenase. In DSS colitic mice, iMCs administration reduced the disease activity index and ameliorated intestinal tissue damage and permeability. Furthermore, iMCs reduced intestinal inflammation, evidenced by a decreased mRNA expression of pro-inflammatory cytokines, reduced IL-1ß secretion by intestinal explants and inhibited colonic iNOS protein expression. CONCLUSIONS: Our data show that human iMCs isolated from the noninflamed intestine possess tissue-regenerative and immunomodulatory capacities that could potentially be harnessed/restored in order to reduce IBD severity.

Intestinal anti-inflammatory effects of probiotics in DNBS-colitis via modulation of gut microbiota and microRNAs.

PURPOSE: Probiotics have been shown to exert beneficial effects in IBD although their exact mechanisms are not completely understood. The aim of the present study was to assess the intestinal anti-inflammatory activity of different probiotics (Lactobacillus fermentum CECT5716, Lactobacillus salivarius CECT5713, Escherichia coli Nissle 1917, Saccharomyces boulardii CNCMI-745 in the dinitrobenzene sulfonic acid (DNBS) model of mouse colitis and correlate it with the modifications of the gut microbiota and the immune response, focusing on miRNA expression. METHODS: The probiotics were daily administered orally for 25 days. On day 19 colitis was induced by rectal installation of DNBS. At the end of the treatment, mice were sacrificed and the colonic damage was assessed biochemically by analysing the expression of different markers involved in the immune response, including miRNAs; and the colonic microbiota by pyrosequencing. Probiotics properties were also evaluated in vitro in different immune cell types (CMT-93 intestinal epithelial cells and bone marrow-derived macrophages), where the expression of different mRNAs and miRNAs was examined. RESULTS: All the probiotics displayed intestinal anti-inflammatory effects but slightly different, especially regarding miRNAs expression. Likewise, the probiotics ameliorated the colitis-associated dysbiosis, although showing differences in the main bacterial groups affected. CONCLUSION: Among the probiotics assayed, Lactobacillus fermentum CECT5716 and Escherichia coli Nissle 1917 appear to present the best intestinal anti-inflammatory effects, being the latter one of the few probiotics with reputed efficacy in human IBD. Therefore, Lactobacillus fermentum CECT5716 could be considered as a complementary nutritional strategy for IBD treatment.

The Beneficial Effects of Lippia Citriodora Extract on Diet-Induced Obesity in Mice Are Associated with Modulation in the Gut Microbiota Composition.

SCOPE: Obesity is characterized by a dysfunction in the adipose tissue and an inflammatory subclinical state leading to insulin resistance and increased risk of cardiovascular diseases. It is also associated with intestinal dysbiosis that contributes to inflammation development. Lippia citriodora (LCE) contains high levels of polyphenolpropanoids and has shown promising results in obesity. The aim of this study is to investigate a well-characterized extract of LCE in a model of metabolic syndrome in mice, focusing on its effects on metabolic tissues, endothelial dysfunction, and microbiome. METHODS: Mice are fed a high fat diet (HFD) for six weeks and treated daily with LCE (1, 10, and 25 mg kg-1 ). Glucose and lipid metabolism is investigated. The inflammatory state in the metabolic tissues and the intestinal microbiota composition are characterized, as well as the endothelium-dependent vasodilator response to acetylcholine. RESULTS: LCE reduces fat accumulation and improves plasma glycemic and lipid profiles, as well as the inflammatory process and vascular dysfunction. Moreover, LCE lessens intestinal dysbiosis, as it reduces the Firmicutes/Bacteroidetes ratio and increases Akkermansia abundance in comparison with untreated HFD mice. CONCLUSION: The antiobesity therapeutic properties of LCE are most probably mediated by the synergic effects of its bioactive compounds.

The Importance of the Microbiome in Critically Ill Patients: Role of Nutrition.

Critically ill patients have an alteration in the microbiome in which it becomes a disease-promoting pathobiome. It is characterized by lower bacterial diversity, loss of commensal phyla, like Firmicutes and Bacteroidetes, and a domination of pathogens belonging to the Proteobacteria phylum. Although these alterations are multicausal, many of the treatments administered to these patients, like antibiotics, play a significant role. Critically ill patients also have a hyperpermeable gut barrier and dysregulation of the inflammatory response that favor the development of the pathobiome, translocation of pathogens, and facilitate the emergence of sepsis. In order to restore the homeostasis of the microbiome, several nutritional strategies have been evaluated with the aim to improve the management of critically ill patients. Importantly, enteral nutrition has proven to be more efficient in promoting the homeostasis of the gut microbiome compared to parenteral nutrition. Several nutritional therapies, including prebiotics, probiotics, synbiotics, and fecal microbiota transplantation, are currently being used, showing variable results, possibly due to the unevenness of clinical trial conditions and the fact that the beneficial effects of probiotics are specific to particular species or even strains. Thus, it is of great importance to better understand the mechanisms by which nutrition and supplement therapies can heal the microbiome in critically ill patients in order to finally implement them in clinical practice with optimal safety and efficacy.

Plantago ovata husks-supplemented diet ameliorates metabolic alterations in obese Zucker rats through activation of AMP-activated protein kinase. Comparative study with other dietary fibers.

BACKGROUND & AIMS: Our aim was to compare the effects of intake of diets supplemented with different dietary fibers, namely cellulose, methylcellulose or Plantago ovata husks, (insoluble, soluble non-fermentable, and soluble fermentable fiber, respectively), on the abnormalities clustered in the metabolic syndrome. METHODS: Adult obese Zucker rats were distributed in four groups which were fed respectively a standard, a cellulose-supplemented, a methylcellulose-supplemented or a P. ovata husks-supplemented diet, for ten weeks. RESULTS: Increased body weight, hyperlipidemia, hyperinsulinemia and hyperleptinemia, increased TNF-alpha and reduced adiponectin secretion by adipose tissue found in obese Zucker rats were significantly improved in obese rats fed the P. ovata husks-supplemented diet, together with a lower hepatic lipid content which parallels activation of the signaling pathway of AMP-protein kinase in the liver. The methylcellulose-supplemented diet reduced body weight, hyperlipidemia, circulating free fatty acids concentration and ameliorated adipose tissue secretion of adiponectin and TNF-alpha. Feeding with the cellulose-supplemented diet only reduced free fatty acids circulating levels. CONCLUSIONS: The soluble dietary fibers essayed are more beneficial than insoluble fiber in the treatment of metabolic syndrome, being the soluble and fermentable the more efficient to improve metabolic alterations. Fermentation products of P. ovata husks must play an important role in such effects.

Long-term resveratrol administration reduces metabolic disturbances and lowers blood pressure in obese Zucker rats.

Resveratrol is a natural polyphenolic stilbene derivative found in several human diet components that possess important and wide-ranging effects in biological systems including anticancer, anti-inflammatory, antioxidant, cardio-protective, and anti-ageing actions and beneficial properties against metabolic diseases. This study addresses the effects of long-term administration of resveratrol on several functional alterations arising from the metabolic syndrome experimental model of obese Zucker rats, and the possible mechanisms involved. The high plasma concentrations of triglycerides, total cholesterol, free fatty acids, insulin and leptin found in obese Zucker rats were reduced in obese rats that received resveratrol. Furthermore, the elevated hepatic lipid content was significantly lower in obese rats treated with resveratrol, an effect which was related to the increased phosphorylation of 5'-AMP-activated protein kinase (AMPK) and acetyl-CoA carboxylase (ACC) in the liver of these animals. Resveratrol treatment also improved the inflammatory status peculiar to this model, as it increased the concentration of adiponectin and lowered tumor necrosis factor-alpha production in the visceral adipose tissue (VAT) of obese Zucker rats. Moreover, chronic intake of resveratrol enhanced VAT eNOS expression among obese Zucker rats. These effects parallel the activation of AMPK and inhibition by phosphorylation of ACC in this tissue. The raised systolic blood pressure and reduced aortic eNOS expression found in obese Zucker rats were significantly improved in the resveratrol-treated obese rats. In conclusion, resveratrol improved dyslipidemia, hyperinsulinemia, hyperleptinemia and hypertension in obese Zucker rats, and produced anti-inflammatory effects in VAT, effects that seem to be mediated by AMPK activation.

Quercetin ameliorates metabolic syndrome and improves the inflammatory status in obese Zucker rats.

The aim of this study was to analyze the effects of chronic administration of high doses of quercetin on metabolic syndrome abnormalities, including obesity, dyslipidemia, hypertension, and insulin resistance. For this purpose, obese Zucker rats and their lean littermates were used. The rats received a daily dose of quercetin (2 or 10 mg/kg of body weight) or vehicle for 10 weeks. Body weight and systolic blood pressure (SBP) were recorded weekly. At the end of the treatment, plasma concentrations of triglycerides, total cholesterol, free-fatty acids (FFAs), glucose, insulin, adiponectin, and nitrate plus nitrite (NOx) were determined. Tumor necrosis factor-alpha (TNF-alpha) production, inducible nitric oxide synthase (iNOS), and endothelial nitric oxide synthase (eNOS) protein expression were analyzed in visceral adipose tissue (VAT). The raised SBP and high plasma concentrations of triglycerides, total cholesterol, FFA, and insulin found in obese Zucker rats were reduced in obese rats that received either of the doses of quercetin assayed. The higher dose also improved the inflammatory status peculiar to this model, as it increased the plasma concentration of adiponectin, reduced NOx levels in plasma, and lowered VAT TNF-alpha production in obese Zucker rats. Furthermore, chronic intake of the higher dose of quercetin enhanced VAT eNOS expression among obese Zucker rats, whereas it downregulated VAT iNOS expression. In conclusion, both doses of quercetin improved dyslipidemia, hypertension, and hyperinsulinemia in obese Zucker rats, but only the high dose produced antiinflammatory effects in VAT together with a reduction in body weight gain.