From Non-Alcoholic Fatty Liver Disease to Liver Cancer: Microbiota and Inflammation as Key Players.

It is estimated that 25% of the world's population has non-alcoholic fatty liver disease. This disease can advance to a more severe form, non-alcoholic steatohepatitis (NASH), a disease with a greater probability of progression to cirrhosis and hepatocellular carcinoma (HCC). NASH could be characterized as a necro-inflammatory complication of chronic hepatic steatosis. The combination of factors that lead to NASH and its progression to HCC in the setting of inflammation is not clearly understood. The portal vein is the main route of communication between the intestine and the liver. This allows the transfer of products derived from the intestine to the liver and the hepatic response pathway of bile and antibody secretion to the intestine. The intestinal microbiota performs a fundamental role in the regulation of immune function, but it can undergo changes that alter its functionality. These changes can also contribute to cancer by disrupting the immune system and causing chronic inflammation and immune dysfunction, both of which are implicated in cancer development. In this article, we address the link between inflammation, microbiota and HCC. We also review the different in vitro models, as well as recent clinical trials addressing liver cancer and microbiota.

Effect of Probiotics on Host-Microbiota in Bacterial Infections.

Diseases caused by bacteria cause millions of deaths every year. In addition, the problem of resistance to antibiotics is so serious that it threatens the achievements of modern medicine. This is a very important global problem as some bacteria can also develop persistence. Indeed, the persistence of pathogenic bacteria has evolved as a potent survival strategy to overcome host organisms' defense mechanisms. Additionally, chronic or persistent infections may be caused by persisters which could facilitate antibiotic resistance. Probiotics are considered good bacteria. It has been described that the modulation of gut microbiota by probiotics could have a great potential to counteract the deleterious impact and/or regulate gut microbiota after bacterial infection. Probiotics might provide health benefits through the inhibition of pathogen growth or the replacement of pathogenic bacteria. Bearing in mind that current strategies to avoid bacterial persistence and prevent antibiotic resistance are not effective, other strategies need to be assessed. We have carried out a comprehensive review, which included the reported literature between 2016 and 2021, highlighting the clinical trials that reported the probiotics' potential to regulate gut microbiota after bacterial infection and focusing in particular on the context of antibiotic resistance and persister cells.

Mapping the entire functionally active endometrial microbiota.

STUDY QUESTION: Does endometrium harbour functionally active microorganisms and whether the microbial composition differs between proliferative and mid-secretory phases? SUMMARY ANSWER: Endometrium harbours functionally alive microorganisms including bacteria, viruses, archaea and fungi whose composition and metabolic functions change along the menstrual cycle. WHAT IS KNOWN ALREADY: Resident microbes in the endometrium have been detected, where microbial dysfunction has been associated with reproductive health and disease. Nevertheless, the core microorganismal composition in healthy endometrium is not determined and whether the identified bacterial DNA sequences refer to alive/functionally active microbes is not clear. Furthermore, whether there are cyclical changes in the microbial composition remains an open issue. STUDY DESIGN, SIZE, DURATION: RNA sequencing (RNAseq) data from 14 endometrial paired samples from healthy women, 7 samples from the mid-secretory phase and 7 samples from the consecutive proliferative phase were analysed for the microbial RNA sequences. PARTICIPANTS/MATERIALS, SETTING, METHODS: The raw RNAseq data were converted into FASTQ format using SRA Toolkit. The unmapped reads to human sequences were aligned to the reference database Kraken2 and visualised with Krona software. Menstrual phase taxonomic differences were performed by R package metagenomeSeq. The functional analysis of endometrial microbiota was obtained with HUMANn2 and the comparison between menstrual phases was conducted by one-way ANOVA. Human RNAseq analysis was performed using miARma-Seq and the functional enrichment analysis was carried out using gene set enrichment analysis (GSEA; HumanCyc). The integration of metabolic pathways between host and microbes was investigated. The developed method of active microbiota mapping was validated in independent sample set. MAIN RESULTS AND THE ROLE OF CHANCE: With the novel metatranscriptomic approach, we mapped the entire alive microbiota composing of >5300 microorganisms within the endometrium of healthy women. Microbes such as bacteria, fungi, viruses and archaea were identified. The validation of three independent endometrial samples from different ethnicity confirmed the findings. Significant differences in the microbial abundances in the mid-secretory vs. proliferative phases were detected with possible metabolic activity in the host-microbiota crosstalk in receptive phase endometrium, specifically in the prostanoid biosynthesis pathway and L-tryptophan metabolism. LARGE SCALE DATA: The raw RNAseq data used in the current study are available at GEO GSE86491 and at BioProject PRJNA379542. LIMITATIONS, REASONS FOR CAUTION: These pioneering results should be confirmed in a bigger sample size. WIDER IMPLICATIONS OF THE FINDINGS: Our study confirms the presence of active microbes, bacteria, fungi, viruses and archaea in the healthy human endometrium with implications in receptive phase endometrial functions, meaning that microbial dysfunction could impair the metabolic pathways important for endometrial receptivity. The results of this study contribute to the better understanding of endometrial microbiota composition in healthy women and its possible role in endometrial functions. In addition, our novel methodological pipeline for analysing alive microbes with transcriptional and metabolic activities could serve to inspire new analysis approaches in reproductive medicine. STUDY FUNDING/COMPETING INTERESTS: This work is supported by the Spanish Ministry of Economy, Industry and Competitiveness (MINECO) and European Regional Development Fund (FEDER): grants RYC-2016-21199 and ENDORE SAF2017-87526-R; FEDER/Junta de Andalucía-Consejería de Economía y Conocimiento: MENDO (B-CTS-500-UGR18) and by the University of Granada Plan Propio de Investigación 2016 - Excellence actions: Unit of Excellence on Exercise and Health (UCEES) (SOMM17/6107/UGR). A.S.-L. and N.M.M. are funded by the Spanish Ministry of Science, Innovation and Universities (PRE2018-0854409 and FPU19/01638). S.A. has received honoraria for lectures from Merck. The funder had no role in this study.

Bifidobacterium breve CNCM I-4035, Lactobacillus paracasei CNCM I-4034 and Lactobacillus rhamnosus CNCM I-4036 Modulate Macrophage Gene Expression and Ameliorate Damage Markers in the Liver of Zucker-Lepr fa/fa Rats.

Non-alcoholic fatty liver disease (NAFLD) has reached pandemic proportions worldwide. We have previously reported that the probiotic strains Bifidobacterium breve CNCM I-4035, Lactobacillus paracasei CNCM I-4034 and Lactobacillus rhamnosus CNCM I-4036 exert anti-inflammatory effects in the intestine of Zucker-Lepr fa/fa rats. In this work, we focused on their hepatic effects. M1 macrophages are related to inflammation and NAFLD pathogenesis, whereas M2 macrophages release anti-inflammatory mediators. We evaluated the effects of these 3 strains on macrophage polarization, inflammation and liver damage of Zucker-Lepr fa/fa rats. The animals received either a placebo or 1010 CFU of probiotics orally for 30 days. Nos2 and Cd86 mRNA levels were determined as markers of M1 macrophages, and Cd163 and Arg1 as M2 markers, respectively, by qRT-PCR. Liver damage was determined by lipid peroxidation, leukocyte infiltration and myeloperoxidase activity. We evaluated a panoply of circulating chemokines, the hepatic ratio P-Akt/Akt, NF-kB and P-NF-kB protein levels. All 3 probiotic strains modulated macrophage polarization in liver and circulating levels of inflammation-related mediators. L. paracasei CNCM I-4034 increased the ratio P-Akt/Akt and NF-kB protein levels. B. breve CNCM I-4035, L. paracasei CNCM I-4034 and L. rhamnosus CNCM I-4036 decreased both pro-inflammatory macrophage gene expression and leukocyte infiltration in the liver.

NAIP expression increases in a rat model of liver mass restoration.

The neuronal apoptosis inhibitory protein (NAIP) is a constituent of the NLRC4 inflammasome, which plays a key role in innate immunity, and an antiapoptotic protein. Recently, we reported the previously undescribed role of NAIP in cell division. The liver is one of the body's most actively regenerative organs. Given the novel mitotic role of NAIP, we examined its expression in hepatic mass restoration. The major liver lobe of Wistar rats was removed, and samples from both newly formed liver tissue, assessed by positive Ki67 immunostaining, and the remnant, intact liver lobes from hepatectomized rats were taken 3 and 7 days after surgery. Naip5 and Naip6 mRNA levels were significantly higher in regenerating hepatic tissue than in intact liver lobe tissue, and this increase was also observed at the protein level. Naip5 and Naip6 mRNA in situ hybridization showed that this increase occurred in the hepatic parenchyma. The histology of the regenerated liver tissue was normal, with the exception of a noticeable deficiency of hepatic lobule central veins. The results of this study suggest the involvement of NAIP in liver mass restoration following partial hepatectomy.

Optimization of Efficient Neuron Models With Realistic Firing Dynamics. The Case of the Cerebellar Granule Cell.

Biologically relevant large-scale computational models currently represent one of the main methods in neuroscience for studying information processing primitives of brain areas. However, biologically realistic neuron models tend to be computationally heavy and thus prevent these models from being part of brain-area models including thousands or even millions of neurons. The cerebellar input layer represents a canonical example of large scale networks. In particular, the cerebellar granule cells, the most numerous cells in the whole mammalian brain, have been proposed as playing a pivotal role in the creation of somato-sensorial information representations. Enhanced burst frequency (spiking resonance) in the granule cells has been proposed as facilitating the input signal transmission at the theta-frequency band (4-12 Hz), but the functional role of this cell feature in the operation of the granular layer remains largely unclear. This study aims to develop a methodological pipeline for creating neuron models that maintain biological realism and computational efficiency whilst capturing essential aspects of single-neuron processing. Therefore, we selected a light computational neuron model template (the adaptive-exponential integrate-and-fire model), whose parameters were progressively refined using an automatic parameter tuning with evolutionary algorithms (EAs). The resulting point-neuron models are suitable for reproducing the main firing properties of a realistic granule cell from electrophysiological measurements, including the spiking resonance at the theta-frequency band, repetitive firing according to a specified intensity-frequency (I-F) curve and delayed firing under current-pulse stimulation. Interestingly, the proposed model also reproduced some other emergent properties (namely, silent at rest, rheobase and negligible adaptation under depolarizing currents) even though these properties were not set in the EA as a target in the fitness function (FF), proving that these features are compatible even in computationally simple models. The proposed methodology represents a valuable tool for adjusting AdEx models according to a FF defined in the spiking regime and based on biological data. These models are appropriate for future research of the functional implication of bursting resonance at the theta band in large-scale granular layer network models.

New Opportunities for Endometrial Health by Modifying Uterine Microbial Composition: Present or Future?

Current knowledge suggests that the uterus harbours its own microbiota, where the microbes could influence the uterine functions in health and disease; however, the core uterine microbial composition and the host-microbial relationships remain to be fully elucidated. Different studies are indicating, based on next-generation sequencing techniques, that microbial dysbiosis could be associated with several gynaecological disorders, such as endometriosis, chronic endometritis, dysfunctional menstrual bleeding, endometrial cancer, and infertility. Treatments using antibiotics and probiotics and/or prebiotics for endometrial microbial dysbiosis are being applied. Nevertheless there is no unified protocol for assessing the endometrial dysbiosis and no optimal treatment protocol for the established dysbiosis. With this review we outline the microbes (mostly bacteria) identified in the endometrial microbiome studies, the current treatments offered for bacterial dysbiosis in the clinical setting, and the future possibilities such as pro- and prebiotics and microbial transplants for modifying uterine microbial composition.

An integrative methodology based on protein-protein interaction networks for identification and functional annotation of disease-relevant genes applied to channelopathies.

BACKGROUND: Biologically data-driven networks have become powerful analytical tools that handle massive, heterogeneous datasets generated from biomedical fields. Protein-protein interaction networks can identify the most relevant structures directly tied to biological functions. Functional enrichments can then be performed based on these structural aspects of gene relationships for the study of channelopathies. Channelopathies refer to a complex group of disorders resulting from dysfunctional ion channels with distinct polygenic manifestations. This study presents a semi-automatic workflow using protein-protein interaction networks that can identify the most relevant genes and their biological processes and pathways in channelopathies to better understand their etiopathogenesis. In addition, the clinical manifestations that are strongly associated with these genes are also identified as the most characteristic in this complex group of diseases. RESULTS: In particular, a set of nine representative disease-related genes was detected, these being the most significant genes in relation to their roles in channelopathies. In this way we attested the implication of some voltage-gated sodium (SCN1A, SCN2A, SCN4A, SCN4B, SCN5A, SCN9A) and potassium (KCNQ2, KCNH2) channels in cardiovascular diseases, epilepsies, febrile seizures, headache disorders, neuromuscular, neurodegenerative diseases or neurobehavioral manifestations. We also revealed the role of Ankyrin-G (ANK3) in the neurodegenerative and neurobehavioral disorders as well as the implication of these genes in other systems, such as the immunological or endocrine systems. CONCLUSIONS: This research provides a systems biology approach to extract information from interaction networks of gene expression. We show how large-scale computational integration of heterogeneous datasets, PPI network analyses, functional databases and published literature may support the detection and assessment of possible potential therapeutic targets in the disease. Applying our workflow makes it feasible to spot the most relevant genes and unknown relationships in channelopathies and shows its potential as a first-step approach to identify both genes and functional interactions in clinical-knowledge scenarios of target diseases. METHODS: An initial gene pool is previously defined by searching general databases under a specific semantic framework. From the resulting interaction network, a subset of genes are identified as the most relevant through the workflow that includes centrality measures and other filtering and enrichment databases.

Association of breast and gut microbiota dysbiosis and the risk of breast cancer: a case-control clinical study.

BACKGROUND: Breast cancer ranks first in women, and is the second cause of death in this gender. In addition to genetics, the environment contributes to the development of the disease, although the factors involved are not well known. Among the latter is the influence of microorganisms and, therefore, attention is recently being paid to the mammary microbiota. We hypothesize that the risk of breast cancer could be associated with the composition and functionality of the mammary/gut microbiota, and that exposure to environmental contaminants (endocrine disruptors, EDCs) might contribute to alter these microbiota. METHODS: We describe a case-control clinical study that will be performed in women between 25 and 70 years of age. Cases will be women diagnosed and surgically intervened of breast cancer (stages I and II). Women with antecedents of cancer or advanced tumor stage (metastasis), or who have received antibiotic treatment within a period of 3 months prior to recruitment, or any neoadjuvant therapy, will be excluded. Controls will be women surgically intervened of breast augmentation or reduction. Women with oncological, gynecological or endocrine history, and those who have received antibiotic treatment within a period of 3 months prior to recruitment will also be excluded. Blood, urine, breast tissue and stool samples will be collected. Data regarding anthropometric, sociodemographic, reproductive history, tumor features and dietary habits will be gathered. Metabolomic studies will be carried out in stool and breast tissue samples. Metagenomic studies will also be performed in stool and breast tissue samples to ascertain the viral, fungal, bacterial and archaea populations of the microbiota. Quantitation of estrogens, estrogen metabolites and EDCs in samples of serum, urine and breast tissue will also be performed. DISCUSSION: This is the first time that the contribution of bacteria, archaea, viruses and fungi together with their alteration by environmental contaminants to the risk of breast cancer will be evaluated in the same study. Results obtained could contribute to elucidate risk factors, improve the prognosis, as well as to propose novel intervention studies in this disease. TRIAL REGISTRATION: ClinicalTrials.gov NCT03885648 , 03/25/2019. Retrospectively registered.

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.

Passive Commuting and Higher Sedentary Time Is Associated with Vitamin D Deficiency in Adult and Older Women: Results from Chilean National Health Survey 2016⁻2017.

The aim was to investigate the associations between different physical activity (PA) patterns and sedentary time (ST) with vitamin D deficiency (<12 ng/mL) in a large sample of Chilean women. In this cross-sectional study, the final sample included 1245 adult and 686 older women. The PA levels, mode of commuting, ST, and leisure-time PA were self-reported. Vitamin D deficiency was defined as <12 ng/mL and insufficiency as <20 ng/mL. A higher ST was associated with vitamin D deficiency (odds ratio (OR): 2.4, 95%: 1.6⁻4.3) in adults, and passive commuting was associated with vitamin D deficiency in older (OR: 1.7, 95%: 1.1⁻2.7). Additionally, we found a joint association in the high ST/passive commuting group in adults (OR: 2.8, 95%: 1.6⁻4.9) and older (OR: 2.8, 95%: 1.5⁻5.2) with vitamin D deficiency, in respect to low ST/active commuting. The PA levels and leisure-time PA were not associated with vitamin D deficiency. In conclusion, mode of commuting and ST seems important variables related to vitamin D deficiency. Promoting a healthy lifestyle appears important also for vitamin D levels in adult and older women. Further studies are needed to establish causality of this association and the effect of vitamin D deficiency in different diseases in this population.

Effects of Sweeteners on the Gut Microbiota: A Review of Experimental Studies and Clinical Trials.

The consumption of sugar-free foods is growing because of their low-calorie content and the health concerns about products with high sugar content. Sweeteners that are frequently several hundred thousand times sweeter than sucrose are being consumed as sugar substitutes. Although nonnutritive sweeteners (NNSs) are considered safe and well tolerated, their effects on glucose intolerance, the activation of sweet taste receptors, and alterations to the composition of the intestinal microbiota are controversial. This review critically discusses the evidence supporting the effects of NNSs, both synthetic sweeteners (acesulfame K, aspartame, cyclamate, saccharin, neotame, advantame, and sucralose) and natural sweeteners (NSs; thaumatin, steviol glucosides, monellin, neohesperidin dihydrochalcone, and glycyrrhizin) and nutritive sweeteners (polyols or sugar alcohols) on the composition of microbiota in the human gut. So far, only saccharin and sucralose (NNSs) and stevia (NS) change the composition of the gut microbiota. By definition, a prebiotic is a nondigestible food ingredient, but some polyols can be absorbed, at least partially, in the small intestine by passive diffusion: however, a number of them, such as isomaltose, maltitol, lactitol, and xylitol, can reach the large bowel and increase the numbers of bifidobacteria in humans. Further research on the effects of sweeteners on the composition of the human gut microbiome is necessary.

Gene expression profiling in the intestinal mucosa of obese rats administered probiotic bacteria.

We investigated whether the administration of Lactobacillus paracasei CNCM I-4034, Bifidobacterium breve CNCM I-4035 and Lactobacillus rhamnosus CNCM I-4036 modulate the expression of genes in the intestinal mucosa of obese Zucker rats. Forty-eight Zucker-Leprfa/fa and 16 Zucker lean Lepr+/fa rats were used. Eight Zucker lean Lepr+/fa and 8 Zucker-Leprfa/fa rats were euthanized as a reference. The remaining 40 Zucker-Leprfa/fa rats were then assigned to receive 1010 colony forming units (CFU) of one of the three probiotic strains, a mixture of L. paracasei CNCM I-4034 and B. breve CNCM I-4035, or a placebo by oral administration for 30 days. An additional group of 8 Zucker lean Lepr+/fa rats received the placebo for 30 days. Over 27,000 rat genes were studied using a DNA array. Four animals per group were used. Total RNA was extracted from intestinal mucosa and cDNA was synthesized, fragmented and labeled. Labeled cDNA was hybridized using GeneChip kits, and the latter were scanned. Intensity values of each probe were processed and normalized to obtain an individual value for each set of probes.

Adamdec1, Ednrb and Ptgs1/Cox1, inflammation genes upregulated in the intestinal mucosa of obese rats, are downregulated by three probiotic strains.

We have previously reported that administration of Lactobacillus paracasei CNCM I-4034, Bifidobacterium breve CNCM I-4035 and Lactobacillus rhamnosus CNCM I-4036 to obese Zucker-Lepr fa/fa rats attenuates liver steatosis and exerts anti-inflammatory effects. The goal of the present work was to investigate the modulation of gene expression in intestinal mucosa samples of obese Zucker-Lepr fa/fa rats fed the probiotic strains using a DNA microarray and postgenomic techniques. We also measured secretory IgA content in the gut and lipopolysaccharide (LPS)-binding protein (LBP) in serum. Expression of three genes (Adamdec1, Ednrb and Ptgs1/Cox1) was up-regulated in the intestinal mucosa of the obese rats compared with that in the rats when they were still lean. Probiotic administration down-regulated expression of Adamdec1 and Ednrb at the mRNA and protein levels and that of Ptgs1/Cox1 at the mRNA level, and this effect was in part mediated by a decrease in both macrophage and dendritic cell populations. Probiotic treatment also increased secretory IgA content and diminished the LBP concentration. Based on results reported in this work and else where, we propose a possible mechanism of action for these bacterial strains.

Effects of Probiotics and Synbiotics on Obesity, Insulin Resistance Syndrome, Type 2 Diabetes and Non-Alcoholic Fatty Liver Disease: A Review of Human Clinical Trials.

The use of probiotics and synbiotics in the prevention and treatment of different disorders has dramatically increased over the last decade. Both probiotics and synbiotics are well known ingredients of functional foods and nutraceuticals and may provide beneficial health effects because they can influence the intestinal microbial ecology and immunity. The present study reviews the effects of probiotics and synbiotics on obesity, insulin resistance syndrome (IRS), type 2 diabetes (T2D) and non-alcoholic fatty liver disease (NAFLD) in human randomized clinical trials. Select probiotics and synbiotics provided beneficial effects in patients with obesity, mainly affecting the body mass index and fat mass. Some probiotics had beneficial effects on IRS, decreasing the cell adhesion molecule-1 levels, and the synbiotics decreased the insulin resistance and plasma lipid levels. Moreover, select probiotics improved the carbohydrate metabolism, fasting blood glucose, insulin sensitivity and antioxidant status and also reduced metabolic stress in subjects with T2D. Some probiotics and synbiotics improved the liver and metabolic parameters in patients with NAFLD. The oral intake of probiotics and synbiotics as co-adjuvants for the prevention and treatment of obesity, IRS, T2D and NAFLD is partially supported by the data shown in the present review. However, further studies are required to understand the precise mechanism of how probiotics and synbiotics affect these metabolic disorders.

Pyrosequencing analysis reveals changes in intestinal microbiota of healthy adults who received a daily dose of immunomodulatory probiotic strains.

The colon microbiota plays a crucial role in human gastrointestinal health. Current attempts to manipulate the colon microbiota composition are aimed at finding remedies for various diseases. We have recently described the immunomodulatory effects of three probiotic strains (Lactobacillus rhamnosus CNCM I-4036, Lactobacillus paracasei CNCM I-4034, and Bifidobacterium breve CNCM I-4035). The goal of the present study was to analyze the compositions of the fecal microbiota of healthy adults who received one of these strains using high-throughput 16S ribosomal RNA gene sequencing. Bacteroides was the most abundant genus in the groups that received L. rhamnosus CNCM I-4036 or L. paracasei CNCM I-4034. The Shannon indices were significantly increased in these two groups. Our results also revealed a significant increase in the Lactobacillus genus after the intervention with L. rhamnosus CNCM I-4036. The initially different colon microbiota became homogeneous in the subjects who received L. rhamnosus CNCM I-4036. While some orders that were initially present disappeared after the administration of L. rhamnosus CNCM I-4036, other orders, such as Sphingobacteriales, Nitrospirales, Desulfobacterales, Thiotrichales, and Synergistetes, were detected after the intervention. In summary, our results show that the intake of these three bacterial strains induced changes in the colon microbiota.

The role of probiotic lactic acid bacteria and bifidobacteria in the prevention and treatment of inflammatory bowel disease and other related diseases: a systematic review of randomized human clinical trials.

Inflammatory bowel disease (IBD), which includes Crohn's disease (CD) and ulcerative colitis (UC), is a chronic inflammation of the small intestine and colon caused by a dysregulated immune response to host intestinal microbiota in genetically susceptible subjects. A number of fermented dairy products contain lactic acid bacteria (LAB) and bifidobacteria, some of which have been characterized as probiotics that can modify the gut microbiota and may be beneficial for the treatment and the prevention of IBD. The objective of this review was to carry out a systematic search of LAB and bifidobacteria probiotics and IBD, using the PubMed and Scopus databases, defined by a specific equation using MeSH terms and limited to human clinical trials. The use of probiotics and/or synbiotics has positive effects in the treatment and maintenance of UC, whereas in CD clear effectiveness has only been shown for synbiotics. Furthermore, in other associated IBD pathologies, such as pouchitis and cholangitis, LAB and bifidobacteria probiotics can provide a benefit through the improvement of clinical symptoms. However, more studies are needed to understand their mechanisms of action and in this way to understand the effect of probiotics prior to their use as coadjuvants in the therapy and prevention of IBD conditions.

Effects of Lactobacillus paracasei CNCM I-4034, Bifidobacterium breve CNCM I-4035 and Lactobacillus rhamnosus CNCM I-4036 on hepatic steatosis in Zucker rats.

We have previously described the safety and immunomodulatory effects of Lactobacillus paracasei CNCM I-4034, Bifidobacterium breve CNCM I-4035 and Lactobacillus rhamnosus CNCM I-4036 in healthy volunteers. The scope of this work was to evaluate the effects of these probiotic strains on the hepatic steatosis of obese rats. We used the Zucker rat as a genetic model of obesity. Zucker-Lepr(fa/fa) rats received one of three probiotic strains, a mixture of L. paracasei CNCM I-4034 and B. breve CNCM I-4035, or a placebo for 30 days. An additional group of Zucker-lean+/fa rats received a placebo for 30 days. No alterations in intestinal histology, in the epithelial, lamina propria, muscular layers of the ileal or colonic mucosa, or the submucosae, were observed in any of the experimental groups. Triacylglycerol content decreased in the liver of Zucker-Lepr(fa/fa) rats that were fed L. rhamnosus, B. breve, or the mixture of B. breve and L. paracasei. Likewise, the area corresponding to neutral lipids was significantly smaller in the liver of all four groups of Zucker-Lepr(fa/fa) rats that received probiotics than in rats fed the placebo. Zucker-Lepr(fa/fa) rats exhibited significantly greater serum LPS levels than Zucker-lean+/fa rats upon administration of placebo for 30 days. In contrast, all four groups of obese Zucker-Lepr(fa/fa) rats that received LAB strains exhibited serum LPS concentrations similar to those of Zucker-lean+/fa rats. Serum TNF-α levels decreased in the Zucker-Lepr(fa/fa) rats that received B. breve, L. rhamnosus, or the mixture, whereas L. paracasei feeding decreased IL-6 levels in the serum of Zucker-Lepr(fa/fa) rats. In conclusion, the probiotic strains reduced hepatic steatosis in part by lowering serum LPS, and had an anti-inflammatory effect in obese Zucker rats.

Transplantation of human CD34+ stem cells from umbilical cord blood to rats with thioacetamide-induced liver cirrhosis.

BACKGROUND: Liver fibrosis results from accumulation of extracellular matrix components and is associated with many chronic hepatic diseases. There is to date no specific therapy for this disease, and patients receive treatment for its associated complications. Specific progenitor cells, known as oval cells, are present in the liver. As oval cells express markers such as CD34, they are thought to arise from a hematopoietic precursor. The aim of this work was to investigate whether transplantation of hematopoietic CD34(+) stem cells could improve hepatic fibrosis by their differentiation into hepatocytes. METHODS: CD34(+) stem cells from human umbilical cord blood were purified, transduced with a lentiviral vector containing the green fluorescent protein (GFP) gene and injected via portal vein into rats with liver cirrhosis induced by the 4-month administration of thioacetamide. Rats were killed 15 and 60 days post-transplantation. RESULTS: Up to 37% and 22% fluorescent cells were observed in the blood of control and cirrhotic rats, respectively, at 15 days post-transplantation. At 60 days post-transplantation, however, fluorescent cells were completely absent from the blood. Fluorescence was not detected in liver sections at either 15 or 60 days post-transplantation. Polymerase chain-reaction study to detect the GFP gene ruled out silencing of the transgene. CONCLUSIONS: These results suggest that the transplanted cells did not engraft in the liver and were eliminated from the rats.