Genetically predicted gut microbiota mediate the association between plasma lipidomics and primary sclerosing cholangitis.

BACKGROUND: Primary sclerosing cholangitis (PSC) is a complex disease with pathogenic mechanisms that remain to be elucidated. Previous observational studies with small sample sizes have reported associations between PSC, dyslipidemia, and gut microbiota dysbiosis. However, the causality of these associations is uncertain, and there has been no systematic analysis to date. METHODS: The datasets comprise data on PSC, 179 lipid species, and 412 gut microbiota species. PSC data (n = 14,890) were sourced from the International PSC Study Group, while the dataset pertaining to plasma lipidomics originated from a study involving 7174 Finnish individuals. Data on gut microbiota species were derived from the Dutch Microbiome Project study, which conducted a genome-wide association study involving 7738 participants. Furthermore, we employed a two-step Mendelian randomization (MR) analysis to quantify the proportion of the effect of gut microbiota-mediated lipidomics on PSC. RESULTS: Following a rigorous screening process, our MR analysis revealed a causal relationship between higher levels of gene-predicted Phosphatidylcholine (O-16:1_18:1) (PC O-16:1_18:1) and an increased risk of developing PSC (inverse variance-weighted method, odds ratio (OR) 1.30, 95% confidence interval (CI) 1.03-1.63). There is insufficient evidence to suggest that gene-predicted PSC impacts the levels of PC O-16:1_18:1 (OR 1.01, 95% CI 0.98-1.05). When incorporating gut microbiota data into the analysis, we found that Eubacterium rectale-mediated genetic prediction explains 17.59% of the variance in PC O-16:1_18:1 levels. CONCLUSION: Our study revealed a causal association between PC O-16:1_18:1 levels and PSC, with a minor portion of the effect mediated by Eubacterium rectale. This study aims to further explore the pathogenesis of PSC and identify promising therapeutic targets. For patients with PSC who lack effective treatment options, the results are encouraging.

Effects of prebiotic oligofructose-enriched inulin on gut-derived uremic toxins and disease progression in rats with adenine-induced chronic kidney disease.

Recent studies suggest that dysbiosis in chronic kidney disease (CKD) increases gut-derived uremic toxins (GDUT) generation, leads to systemic inflammation, reactive oxygen species generation, and poor prognosis. This study aimed to investigate the effect of oligofructose-enriched inulin supplementation on GDUT levels, inflammatory and antioxidant parameters, renal damage, and intestinal barrier function in adenine-induced CKD rats. Male Sprague-Dawley rats were divided into control group (CTL, n = 12) fed with standard diet; and CKD group (n = 16) given adenine (200 mg/kg/day) by oral gavage for 3-weeks to induce CKD. At the 4th week, CKD rats were subdivided into prebiotic supplementation (5g/kg/day) for four consecutive weeks (CKD-Pre, n = 8). Also, the control group was subdivided into two subgroups; prebiotic supplemented (CTL-Pre, n = 6) and non-supplemented group (CTL, n = 6). Results showed that prebiotic oligofructose-enriched inulin supplementation did not significantly reduce serum indoxyl sulfate (IS) but did significantly reduce serum p-Cresyl sulfate (PCS) (p = 0.002) in CKD rats. Prebiotic supplementation also reduced serum urea (p = 0.008) and interleukin (IL)-6 levels (p = 0.001), ameliorated renal injury, and enhanced antioxidant enzyme activity of glutathione peroxidase (GPx) (p = 0.002) and superoxide dismutase (SOD) (p = 0.001) in renal tissues of CKD rats. No significant changes were observed in colonic epithelial tight junction proteins claudin-1 and occludin in the CKD-Pre group. In adenine-induced CKD rats, oligofructose-enriched inulin supplementation resulted in a reduction in serum urea and PCS levels, enhancement of the antioxidant activity in the renal tissues, and retardation of the disease progression.

Candida Administration in Bilateral Nephrectomy Mice Elevates Serum (1→3)-ß-D-glucan That Enhances Systemic Inflammation Through Energy Augmentation in Macrophages.

Systemic inflammation, from gut translocation of organismal molecules, might worsen uremic complications in acute kidney injury (AKI). The monitoring of gut permeability integrity and/or organismal molecules in AKI might be clinically beneficial. Due to the less prominence of Candida albicans in human intestine compared with mouse gut, C. albicans were orally administered in bilateral nephrectomy (BiN) mice. Gut dysbiosis, using microbiome analysis, and gut permeability defect (gut leakage), which was determined by fluorescein isothiocyanate-dextran and intestinal tight-junction immunofluorescent staining, in mice with BiN-Candida was more severe than BiN without Candida. Additionally, profound gut leakage in BiN-Candida also resulted in gut translocation of lipopolysaccharide (LPS) and (1→3)-ß-D-glucan (BG), the organismal components from gut contents, that induced more severe systemic inflammation than BiN without Candida. The co-presentation of LPS and BG in mouse serum enhanced inflammatory responses. As such, LPS with Whole Glucan Particle (WGP, a representative BG) induced more severe macrophage responses than LPS alone as determined by supernatant cytokines and gene expression of downstream signals (NFκB, Malt-1 and Syk). Meanwhile, WGP alone did not induced the responses. In parallel, WGP (with or without LPS), but not LPS alone, accelerated macrophage ATP production (extracellular flux analysis) through the upregulation of genes in mitochondria and glycolysis pathway (using RNA sequencing analysis), without the induction of cell activities. These data indicated a WGP pre-conditioning effect on cell energy augmentation. In conclusion, Candida in BiN mice accelerated gut translocation of BG that augmented cell energy status and enhanced pro-inflammatory macrophage responses. Hence, gut fungi and BG were associated with the enhanced systemic inflammation in acute uremia.

Blood microbiota and metabolomic signature of major depression before and after antidepressant treatment: a prospective case-control study.

Background: The microbiota interacts with the brain through the gut-brain axis, and a distinct dysbiosis may lead to major depressive episodes. Bacteria can pass through the gut barrier and be found in the blood. Using a multiomic approach, we investigated whether a distinct blood microbiome and metabolome was associated with major depressive episodes, and how it was modulated by treatment. Methods: In this case-control multiomic study, we analyzed the blood microbiome composition, inferred bacterial functions and metabolomic profile of 56 patients experiencing a current major depressive episode and 56 matched healthy controls, before and after treatment, using 16S rDNA sequencing and liquid chromatography coupled to tandem mass spectrometry. Results: The baseline blood microbiome in patients with a major depressive episode was distinct from that of healthy controls (patients with a major depressive episode had a higher proportion of Janthinobacterium and lower levels of Neisseria) and changed after antidepressant treatment. Predicted microbiome functions confirmed by metabolomic profiling showed that patients who were experiencing a major depressive episode had alterations in the cyanoamino acid pathway at baseline. High baseline levels of Firmicutes and low proportions of Bosea and Tetrasphaera were associated with response to antidepressant treatment. Based on inferred baseline metagenomic profiles, bacterial pathways that were significantly associated with treatment response were related to xenobiotics, amino acids, and lipid and carbohydrate metabolism, including tryptophan and drug metabolism. Metabolomic analyses showed that plasma tryptophan levels are independently associated with response to antidepressant treatment. Limitations: Our study has some limitations, including a lack of information on blood microbiome origin and the lack of a validation cohort to confirm our results. Conclusion: Patients with depression have a distinct blood microbiome and metabolomic signature that changes after treatment. Dysbiosis could be a new therapeutic target and prognostic tool for the treatment of patients who are experiencing a major depressive episode.

Inflammatory and Oxidative Pathways Are New Drug Targets in Multiple Episode Schizophrenia and Leaky Gut, Klebsiella pneumoniae, and C1q Immune Complexes Are Additional Drug Targets in First Episode Schizophrenia.

Breakdown of paracellular and vascular pathways and activated neuroimmune and oxidative pathways was established in (deficit) schizophrenia. The aim of this study was to delineate (a) the differences in these pathways between stable-phase, first (FES) and multiple (MES) episode schizophrenia and (b) the pathways that determine the behavioral-cognitive-physical-psychosocial (BCPS) deterioration in FES/MES. This study included 21 FES and 58 FES patients and 40 healthy controls and measured indicants of serum C1q circulating immune complexes (CIC), leaky gut, immune activation, and oxidative stress toxicity (OSTOX). We constructed a BCPS-worsening index by extracting a latent vector from symptomatic, neurocognitive, and quality of life data. FES was associated with higher IgA CIC-C1q, IgA directed to cadherin, catenin, and plasmalemma vesicle-associated protein, and IgA/IgM to Gram-negative bacteria as compared with FES and controls. In FES patients, the BCPS-worsening score was predicted (48.7%) by IgA to Klebsiella pneumoniae and lowered paraoxonase 1 activity. In MES patients, the BCPS-worsening score was explained (42.7%) by increased tumor necrosis factor-α, OSTOX, and number of episodes. In schizophrenia, 34.0% of the variance in the BCPS-worsening score was explained by IgA to K. pneumoniae, OSTOX, and number of episodes. Increased IgA to K. pneumoniae was the single best predictor of residual psychotic symptoms in FES and MES. This study delineated different mechanistic processes in FES, including breakdown of adherens junctions, bacterial translocation, and IgA CIC-C1q formation, and MES, including immune and oxidative neurotoxic pathways. FES and MES comprise different staging subtypes, i.e., FES and MES with and without worsening.

Impact of gut microbiota on plasma oxylipins profile under healthy and obesogenic conditions.

BACKGROUND & AIMS: Oxylipins (OXLs) are bioactive lipid metabolites derived from polyunsaturated fatty acids (PUFAs) which act as signaling molecules and are involved in inflammatory processes such as those that occur in obesity. On the other hand, gut microbiota plays an essential role in regulating inflammatory responses. However, little is known about the potential impact of gut bacteria on OXLs metabolism. Thus, the objective of this study was to investigate the effect of gut microbiota dysbiosis on plasma oxylipins profile in healthy and diet-induced obese animals. METHODS: Eight-week-old male Wistar rats were fed with either a standard or cafeteria diet (CAF) for 5 weeks and administered an antibiotic cocktail (ABX) in the drinking water (Ampicillin: 1 g/ml, Vancomycin: 0.5 g/ml, Imipenem: 0.25 g/ml) for the last 2 weeks in order to induce gut microbiota dysbiosis. Metabolomics analysis of OXLs in plasma was performed by HPLC-MS analysis. No antibiotic treated animals were included as controls. RESULTS: Plasma OXLs profile was significantly altered due to both CAF feeding and ABX administration. ABX effect was more pronounced under obesogenic conditions. Several significant correlations between different bacteria taxa and these lipid mediators were observed. Among these, the positive correlation of Proteobacteria with LTB4, a proinflammatory OXL involved in obesity-related disorders, was especially remarkable. CONCLUSIONS: Gut microbiota plays a key role in regulating these lipid metabolites and, therefore, affecting oxylipins-mediated inflammatory processes. These results are the first evidence to our knowledge of gut microbiota impact on OXLs metabolism. Moreover, this can set the basis for developing new obesity markers based on OXLs and gut microbiota profiles.

Fecal Microbiota Transplantation Is a Promising Method to Restore Gut Microbiota Dysbiosis and Relieve Neurological Deficits after Traumatic Brain Injury.

BACKGROUND: Traumatic brain injury (TBI) can induce persistent fluctuation in the gut microbiota makeup and abundance. The present study is aimed at determining whether fecal microbiota transplantation (FMT) can rescue microbiota changes and ameliorate neurological deficits after TBI in rats. METHODS: A controlled cortical impact (CCI) model was used to simulate TBI in male Sprague-Dawley rats, and FMT was performed for 7 consecutive days. 16S ribosomal RNA (rRNA) sequencing of fecal samples was performed to analyze the effects of FMT on gut microbiota. Modified neurological severity score and Morris water maze were used to evaluate neurobehavioral functions. Metabolomics was used to screen differential metabolites from the rat serum and ipsilateral brains. The oxidative stress indices were measured in the brain. RESULTS: TBI induced significance changes in the gut microbiome, including the alpha- and beta-bacterial diversity, as well as the microbiome composition at 8 days after TBI. On the other hand, FMT could rescue these changes and relieve neurological deficits after TBI. Metabolomics results showed that the level of trimethylamine (TMA) in feces and the level of trimethylamine N-oxide (TMAO) in the ipsilateral brain and serum was increased after TBI, while FMT decreased TMA levels in the feces, and TMAO levels in the ipsilateral brain and serum. Antioxidant enzyme methionine sulfoxide reductase A (MsrA) in the ipsilateral hippocampus was decreased after TBI but increased after FMT. In addition, FMT elevated SOD and CAT activities and GSH/GSSG ratio and diminished ROS, GSSG, and MDA levels in the ipsilateral hippocampus after TBI. CONCLUSIONS: FMT can restore gut microbiota dysbiosis and relieve neurological deficits possibly through the TMA-TMAO-MsrA signaling pathway after TBI.

Restructuring the Gut Microbiota by Intermittent Fasting Lowers Blood Pressure.

[Figure: see text].

Synbiotics Alleviate the Gut Indole Load and Dysbiosis in Chronic Kidney Disease.

Chronic kidney disease (CKD) has long been known to cause significant digestive tract pathology. Of note, indoxyl sulfate is a gut microbe-derived uremic toxin that accumulates in CKD patients. Nevertheless, the relationship between gut microbiota, fecal indole content, and blood indoxyl sulfate level remains unknown. In our study, we established an adenine-induced CKD rat model, which recapitulates human CKD-related gut dysbiosis. Synbiotic treatment in CKD rats showed a significant reduction in both the indole-producing bacterium Clostridium and fecal indole amount. Furthermore, gut microbiota diversity was reduced in CKD rats but was restored after synbiotic treatment. Intriguingly, in our end-stage kidney disease (ESKD) patients, the abundance of indole-producing bacteria, Bacteroides, Prevotella, and Clostridium, is similar to that of healthy controls. Consistently, the fecal indole tends to be higher in the ESKD patients, but the difference did not achieve statistical significance. However, the blood level of indoxyl sulfate was significantly higher than that of healthy controls, implicating that under an equivalent indole production rate, the impaired renal excretion contributes to the accumulation of this notorious uremic toxin. On the other hand, we did identify two short-chain fatty acid-producing bacteria, Faecalibacterium and Roseburia, were reduced in ESKD patients as compared to the healthy controls. This may contribute to gut dysbiosis. We also identified that three genera Fusobacterium, Shewanella, and Erwinia, in the ESKD patients but not in the healthy controls. Building up gut symbiosis to treat CKD is a novel concept, but once proved effective, it will provide an additional treatment strategy for CKD patients.

Gut microbiota and the periodontal disease: role of hyperhomocysteinemia.

Periodontal disease is one of the most common conditions resulting from poor oral hygiene and is characterized by a destructive process in the periodontium that essentially includes gingiva, alveolar mucosa, cementum, periodontal ligament, and alveolar bone. Notably, the destructive event in the alveolar bone has been linked to homocysteine (Hcy) metabolism; however, it has not been fully investigated. Therefore; the implication of Hcy towards initiation, progression, and maintenance of the periodontal disease remains incompletely understood. Higher levels of Hcy (also known as hyperhomocysteinemia (HHcy)) exerts deleterious effects on gum health and teeth in distinct ways. Firstly, increased production of proinflammatory cytokines such as TNF-α, IL-1ß, IL-6, and IL-8 leads to an inflammatory cascade of events that affect methionine (Met) and Hcy metabolism (i.e., 1-carbon metabolism) leading to HHcy. Secondly, metabolic dysregulation during chronic medical conditions increases systemic inflammation leading to a decrease in vitamins, more specifically B6, B12, and folic acid, that play important roles as cofactors in Hcy metabolism. Also, given the folate level in the HHcy state that is important during dysbiosis, these two conditions appear to be intimately related, and in this context, HHcy-induced dysbiosis may be one of the potential causes of periodontal disease. This paper sums up the link between periodontitis and HHcy, with a special emphasis on the "oral-gut microbiome axis" and the potential probiotic intervention towards warding off some of the serious periodontal disease conditions.

Intermittent Fasting Improves Lipid Metabolism Through Changes in Gut Microbiota in Diet-Induced Obese Mice.

BACKGROUND The mechanism of how intermittent fasting (IF) improves metabolism is not fully understood. Our study aimed to explore the effect of IF on lipid metabolism in obese mice, specifically on the intestinal flora. MATERIAL AND METHODS Diet-induced obese (DIO) mice were subjected to ad libitum (AL) feeding or IF (alternate-day fasting) for 30 days. We examined the lipid metabolism, fat distribution, gene expression of lipid metabolism, and intestinal flora in the mice. RESULTS Despite having access to the same high-fat diet as the AL-fed groups, IF mice displayed pronounced weight loss, and their lipid metabolism significantly improved, mainly reflected in lower serum lipid levels and ameliorated liver steatosis. IF also reduced metabolic endotoxemia in DIO mice. The 16S ribosomal deoxyribonucleic acid gene amplicon sequencing suggested that IF did not change the community richness but had a tendency to increase community diversity in the intestinal flora. In addition, IF significantly reduced the ratio of Firmicutes to Bacteroidetes and increased the relative abundance of Allobaculum in the intestinal flora. CONCLUSIONS IF can improve fat metabolism, reduce fat accumulation, promote white fat conversion to beige, and improve gut microbiota.

Gut microbiome dysbiosis alleviates the progression of osteoarthritis in mice.

Gut microbiota dysbiosis has been studied under the pathological conditions of osteoarthritis (OA). However, the effect of antibiotic-induced gut flora dysbiosis on OA remains incompletely understood at present. Herein, we used a mouse (8 weeks) OA model of destabilization of the medial meniscus (DMM) and gut microbiome dysbiosis induced by antibiotic treatment with ampicillin and neomycin for 8 weeks. The results show that antibiotic-induced intestinal microbiota dysbiosis reduced the serum level of lipopolysaccharide (LPS) and the inflammatory response, such as suppression of the levels of tumour necrosis factor-α (TNF-α) and interleukin-6 (IL-6), which can lead to decreased matrix metalloprotease-13 (MMP-13) expression and improvement of OA after joint injury. In addition, trabecular thickness (Tb.Th) and osteophyte scores were increased significantly in antibiotic-induced male mice compared with female mice. We further used network correlation analysis to verify the effect of gut microbiota dysbiosis on OA. Therefore, the present study contributes to our understanding of the gut-joint axis in OA and reveals the relationship between the inflammatory response, sex and gut microbiota, which may provide new strategies to prevent the symptoms and long-term sequelae of OA. Conclusion: Our data showed that gut microbiome dysbiosis alleviates the progression of OA.

Bilberry Anthocyanins Ameliorate NAFLD by Improving Dyslipidemia and Gut Microbiome Dysbiosis.

Non-alcoholic fatty liver disease (NAFLD) is a manifestation of metabolic syndrome closely linked to dyslipidemia and gut microbiome dysbiosis. Bilberry anthocyanins (BA) have been reported to have preventive effects against metabolic syndrome. This study aimed to investigate the protective effects and mechanisms of BA in a Western diet (WD)-induced mouse model. The results revealed that supplementation with BA attenuated the serum levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), low-density lipoprotein cholesterol (LDL-c), fat content in liver, 2-thiobarbituric acid reactive substances (TBARS) and α-smooth muscle actin (α-SMA) caused by WD. Furthermore, gut microbiota characterized by 16S rRNA sequencing revealed that BA reduced remarkably the ratio of Firmicutes/Bacteroidetes (F/B) and modified gut microbiome. In particular, BA increased the relative abundance of g_Akkermansia and g_Parabacteroides. Taken together, our data demonstrated that BA might ameliorate WD-induced NAFLD by attenuating dyslipidemia and gut microbiome dysbiosis.

Chronic exposure to ambient particulate matter induces gut microbial dysbiosis in a rat COPD model.

BACKGROUND: The role of the microbiota in the pathogenesis of chronic obstructive pulmonary disease (COPD) following exposure to ambient particulate matter (PM) is largely unknown. METHODS: Fifty-four male Sprague-Dawley rats were exposed to clean air, biomass fuel (BMF), or motor vehicle exhaust (MVE) for 4, 12, and 24 weeks. We performed pulmonary inflammation evaluation, morphometric measurements, and lung function analysis in rat lung at three different times points during exposure. Lung and gut microbial composition was assessed by 16S rRNA pyrosequencing. Serum lipopolysaccharide levels were measured and short-chain fatty acids in colon contents were quantified. RESULTS: After a 24-week PM exposure, rats exhibited pulmonary inflammation and pathological changes characteristic of COPD. The control and PM exposure (BMF and MVE) groups showed similar microbial diversity and composition in rat lung. However, the gut microbiota after 24 weeks PM exposure was characterized by decreased microbial richness and diversity, distinct overall microbial composition, lower levels of short-chain fatty acids, and higher serum lipopolysaccharide. CONCLUSION: Chronic exposure to ambient particulate matter induces gut microbial dysbiosis and metabolite shifts in a rat model of chronic obstructive pulmonary disease.

Gut Microbiota-Induced Changes in ß-Hydroxybutyrate Metabolism Are Linked to Altered Sociability and Depression in Alcohol Use Disorder.

Patients with alcohol use disorder (AUD) present with important emotional, cognitive, and social impairments. The gut microbiota has been recently shown to regulate brain functions and behavior but convincing evidence of its role in AUD is lacking. Here, we show that gut dysbiosis is associated with metabolic alterations that affect behavioral (depression, sociability) and neurobiological (myelination, neurotransmission, inflammation) processes involved in alcohol addiction. By transplanting the gut microbiota from AUD patients to mice, we point out that the production of ethanol by specific bacterial genera and the reduction of lipolysis are associated with a lower hepatic synthesis of ß-hydroxybutyrate (BHB), which thereby prevents the neuroprotective effect of BHB. We confirm these results in detoxified AUD patients, in which we observe a persisting ethanol production in the feces as well as correlations among low plasma BHB levels and social impairments, depression, or brain white matter alterations.

The maternal microbiome modulates fetal neurodevelopment in mice.

'Dysbiosis' of the maternal gut microbiome, in response to challenges such as infection1, altered diet2 and stress3 during pregnancy, has been increasingly associated with abnormalities in brain function and behaviour of the offspring4. However, it is unclear whether the maternal gut microbiome influences neurodevelopment during critical prenatal periods and in the absence of environmental challenges. Here we investigate how depletion and selective reconstitution of the maternal gut microbiome influences fetal neurodevelopment in mice. Embryos from antibiotic-treated and germ-free dams exhibited reduced brain expression of genes related to axonogenesis, deficient thalamocortical axons and impaired outgrowth of thalamic axons in response to cell-extrinsic factors. Gnotobiotic colonization of microbiome-depleted dams with a limited consortium of bacteria prevented abnormalities in fetal brain gene expression and thalamocortical axonogenesis. Metabolomic profiling revealed that the maternal microbiome regulates numerous small molecules in the maternal serum and the brains of fetal offspring. Select microbiota-dependent metabolites promoted axon outgrowth from fetal thalamic explants. Moreover, maternal supplementation with these metabolites abrogated deficiencies in fetal thalamocortical axons. Manipulation of the maternal microbiome and microbial metabolites during pregnancy yielded adult offspring with altered tactile sensitivity in two aversive somatosensory behavioural tasks, but no overt differences in many other sensorimotor behaviours. Together, our findings show that the maternal gut microbiome promotes fetal thalamocortical axonogenesis, probably through signalling by microbially modulated metabolites to neurons in the developing brain.

Alterations in Circulating Fatty Acid Are Associated With Gut Microbiota Dysbiosis and Inflammation in Multiple Sclerosis.

Background: Butyric acid (BA) is a short-chain fatty acid (SCFA) with anti-inflammatory properties, which promotes intestinal barrier function. Medium-chain fatty acids (MCFA), including caproic acid (CA), promote TH1 and TH17 differentiation, thus supporting inflammation. Aim: Since most SCFAs are absorbed in the cecum and colon, the measurement of BA in peripheral blood could provide information on the health status of the intestinal ecosystem. Additionally, given the different immunomodulatory properties of BA and CA the evaluation of their serum concentration, as well as their ratio could be as a simple and rapid biomarker of disease activity and/or treatment efficacy in MS. Methods: We evaluated serum BA and CA concentrations, immune parameters, intestinal barrier integrity and the gut microbiota composition in patients with multiple sclerosis (MS) comparing result to those obtained in healthy controls. Results: In MS, the concentration of BA was reduced and that of CA was increased. Concurrently, the microbiota was depleted of BA producers while it was enriched in mucin-degrading, pro-inflammatory components. The reduced serum concentration of BA seen in MS patients correlated with alterations of the barrier permeability, as evidenced by the higher plasma concentrations of lipopolysaccharide and intestinal fatty acid-binding protein, and inflammation. Specifically, CA was positively associated with CD4+/IFNγ+ T lymphocytes, and the BA/CA ratio correlated positively with CD4+/CD25high/Foxp3+ and negatively with CD4+/IFNγ+ T lymphocytes. Conclusion: The gut microbiota dysbiosis found in MS is possibly associated with alterations of the SCFA/MCFA ratio and of the intestinal barrier; this could explain the chronic inflammation that characterizes this disease. SCFA and MCFA quantification could be a simple biomarker to evaluate the efficacy of therapeutic and rehabilitation procedures in MS.

Lipocalin 2 deficiency-induced gut microbiota dysbiosis evokes metabolic syndrome in aged mice.

Lipocalin 2 (Lcn2) is a multifunctional innate immune protein that limits microbial overgrowth. Our previous study demonstrated that the gut microbiota directly induces intestinal Lcn2 production, and Lcn2-deficient (Lcn2-/-) mice exhibit gut dysbiosis. Coincidentally, gut dysbiosis is associated with metabolic syndrome pathogenesis, and elevated Lcn2 levels has been considered a potential clinical biomarker of metabolic syndrome. Yet whether Lcn2 mitigates or exacerbates metabolic syndrome remains inconclusive. Our objective was to determine whether Lcn2 deficiency-induced compositional changes in gut microbiota contribute to gain in adiposity in aged mice. Utilizing Lcn2-/- mice and their wild-type (WT) littermates, we measured metabolic markers, including fasting blood glucose, serum lipids, fat pad weight, and insulin resistance at ages 3, 6, and 9 mo old. Relative to WT mice, aged Lcn2-/- mice exhibited a gain in adiposity associated with numerous features of metabolic syndrome, including insulin resistance and dyslipidemia. Surprisingly, supplementation with a high-fat diet did not further aggravate metabolic syndrome that spontaneously occurs in Lcn2-/- mice by 6 mo of age. Interestingly, chow-fed Lcn2-/- mice displayed marked differences in the bacterial abundance and metabolomic profile of the gut microbiota compared with WT mice. Overall, our results demonstrate that Lcn2 is essential to maintain metabolic and gut microbiotal homeostasis, where deficiency induces spontaneous delayed onset of metabolic syndrome.

Eubiotic vs. dysbiotic human blood microbiota: the phenomenon of cell wall deficiency and disease-trigger potential of bacterial and fungal L-forms.

The current review provides data and focuses on blood as a niche for the presence of cell wall-deficient microbes (L-forms). The hypothesis for the existence of L-form microbiota in humans was tested by us using an innovative methodology for the isolation of L-form cultures from human blood. Criteria were conceived for the individual assessment of blood microbiota and recognition of two types of states -- "eubiotic" and "dysbiotic" blood microbiota. Cell wall-deficient microbes (CWD) that inhabit blood in healthy people are in natural balance with the host homeostasis, which corresponds to the "eubiotic" state. When interacting with a host, CWD bacteria or fungi employ a strategy distinctive for a latent lifestyle. In contrast to "eubiotic," "dysbiotic" blood microbiota manifests when the balance is disrupted and there is an excess of L-form variants of opportunistic microbes that invade from the external microbiota, i.e., from all body sites in contact with the external environment. Our case studies on people with multiple sclerosis (MS), Parkinson's disease, psoriasis, thyroid cancer, and diabetes revealed the appearance of "dysbiotic" blood microbiota that outlined the disease-trigger potential of opportunistic bacteria and fungi existing in blood as CWD variants. Blood microbiota assessment could be of diagnostic and prognostic importance for the pathological processes occurring within the body, as well as for understanding the microbial pathogenesis.

Colorectal cancer is associated with increased circulating lipopolysaccharide, inflammation and hypercoagulability.

Gut dysbiosis contributes to the development of a dysfunctional gut barrier, facilitating the translocation of bacteria and inflammagens, and is implicated in colorectal cancer (CRC) pathogenesis. Such 'leaky gut' conditions result in systemic inflammation, of which a hallmark is increased hypercoagulability. Fluorescence antibody confocal microscopy was used to determine circulating levels of lipopolysaccharide (LPS) in control and CRC populations. Here we showed that circulating levels of LPS are significantly elevated in the CRC population. We also showed that markers of inflammation and hypercoagulability are increased in this population. Furthermore, anomalous blood clotting and structural changes in blood components are presented. Importantly, the association between LPS levels, inflammation, and hematological dysfunction was analysed. Statistical regression models were applied to identify markers with strong association with CRC, and to investigate the correlation between markers. A core aim is enhanced biomarker discovery for CRC. We conclude that circulating LPS can promote systemic inflammation and contribute to the development of a pathological coagulation system, with resulting chronic inflammation and an activated coagulation system implicated in tumorigenesis. Blood-based screening tools are an emerging research area of interest for CRC screening. We propose the use of additional (novel) biomarkers to effectively screen for CRC.