Search

Molecular factors from the gut microbiota provide the host with the right metabolic, immunological, and neurological components to support health and well-being. However, certain circumstances can rupture the mutualistic pact with our intestinal counterpart, pushing the gut microbiome toward a dysbiotic layout, where microbiome-derived molecules may contribute to a disease state. We are now beginning to understand the microbiota–host co-regulated pathways underlying these processes, paving the way for a new era of rational piloting of the gut microbiome functions, through the design of a new generation of microbiome-targeting drugs. Microbiota-derived metabolites are emerging as promising starting hit compounds to modulate human targets, hence triggering certain pharmacological responses. In conclusion, drug discovery targeting the gut microbiota as well as the characterization of microbiota-derived metabolites can represent innovative medicinal chemistry possibilities toward the identification of novel drug candidates, targets, and more in general innovative ways for the treatment of unmet medical needs.

Recent work has indicated that there at least two distinct subtypes of psychopathy. Primary psychopathy is characterized by low anxiety and thought to result from a genetic predisposition, whereas secondary psychopathy is characterized by high anxiety and thought to develop in response to environmental adversity. Primary psychopathy is robustly associated with reduced neural activation to others’ emotions and, in particular, distress. However, it has been proposed that the secondary presentation has different neurocognitive correlates.

Trait anger, or the dispositional tendency to experience a wide range of situations as annoying or frustrating, is associated with negative mental and physical health outcomes. The experience of adversity during childhood is one risk factor for the later emergence of high trait anger. This association has been hypothesized to reflect alterations in neural circuits supporting bottom-up threat processing and top-down executive control.

We assessed the subsistence-related variation of the human gut microbiome at a fine resolution for two of the main dimensions of microbiome variation, age and geography. For this, we investigated the fecal microbiome and metabolome in rural Bassa and urbanized individuals from Nigeria, including infants, and compared data with worldwide populations practicing varying subsistence. Our data highlight specific microbiome traits that are progressively lost with urbanization, such as the dominance of pristine fiber degraders and the low inter-individual variation. For the Bassa, this last feature is the result of their subsistence-related practices favoring microbial dispersal, such as their extensive environmental contact and the usage of untreated waters from the Usuma River. The high degree of microbial dispersal observed in the Bassa meta-community nullifies the differences between infant and adult intestinal ecosystems, suggesting that the infant-type microbiome in Western populations could be the result of microbiome-associated neotenic traits favored by urbanization.

Accumulating mental-health research encourages a shift in focus toward transdiagnostic dimensional features that are shared across categorical disorders. In support of this shift, recent studies have identified a general liability factor for psychopathology—sometimes called the ‘p factor’— that underlies shared risk for a wide range of mental disorders. Identifying neural correlates of this general liability would substantiate its importance in characterizing the shared origins of mental disorders and help us begin to understand the mechanisms through which the ‘p factor’ contributes to risk. Here we believe we first replicate the ‘p factor’ using cross-sectional data from a volunteer sample of 1246 university students, and then using high-resolution multimodal structural neuroimaging, we demonstrate that individuals with higher ‘p factor’ scores show reduced structural integrity of white matter pathways, as indexed by lower fractional anisotropy values, uniquely within the pons. Whole-brain analyses further revealed that higher ‘p factor’ scores are associated with reduced gray matter volume in the occipital lobe and left cerebellar lobule VIIb, which is functionally connected with prefrontal regions supporting cognitive control. Consistent with the preponderance of cerebellar afferents within the pons, we observed a significant positive correlation between the white matter integrity of the pons and cerebellar gray matter volume associated with higher ‘p factor’ scores. The results of our analyses provide initial evidence that structural alterations in corticocerebellar circuitry supporting core functions related to the basic integration, coordination and monitoring of information may contribute to a general liability for common mental disorders.

ObjectiveThe engagement of the gut microbiota in the development of symptoms and complications of diverticular disease has been frequently hypothesised. Our aim was to explore colonic immunocytes, gut microbiota and the metabolome in patients with diverticular disease in a descriptive, cross-sectional, pilot study.DesignFollowing colonoscopy with biopsy and questionnaire phenotyping, patients were classified into diverticulosis or symptomatic uncomplicated diverticular disease; asymptomatic subjects served as controls. Mucosal immunocytes, in the diverticular region and in unaffected sites, were quantified with immunohistochemistry. Mucosa and faecal microbiota were analysed by the phylogenetic platform high taxonomic fingerprint (HTF)-Microbi.Array, while the metabolome was assessed by 1H nuclear magnetic resonance.ResultsCompared with controls, patients with diverticula, regardless of symptoms, had a >70% increase in colonic macrophages. Their faecal microbiota showed depletion of Clostridiumcluster IV. Clostridiumcluster IX, Fusobacteriumand Lactobacillaceae were reduced in symptomatic versus asymptomatic patients. A negative correlation was found between macrophages and mucosal Clostridiumcluster IV and Akkermansia. Urinary and faecal metabolome changes in diverticular disease involved the hippurate and kynurenine pathways. Six urinary molecules allowed to discriminate diverticular disease and control groups with >95% accuracy.ConclusionsPatients with colonic diverticular disease show depletion of microbiota members with anti-inflammatory activity associated with mucosal macrophage infiltration. Metabolome profiles were linked to inflammatory pathways and gut neuromotor dysfunction and showed the ability to discriminate diverticular subgroups and controls. These data pave the way for further large-scale studies specifically aimed at identifying microbiota signatures with a potential diagnostic value in patients with diverticular disease.

To measure the perception of obstetric violence among health sciences students.

ABSTRACTThe healthy vaginal microbiota is generally dominated by lactobacilli that confer antimicrobial protection and play a crucial role in health. Bacterial vaginosis (BV) is the most prevalent lower genital tract infection in women in reproductive age and is characterized by a shift in the relative abundances of Lactobacillusspp. to a greater abundance of strictly anaerobic bacteria. In this study, we designed a new phylogenetic microarray-based tool (VaginArray) that includes 17 probe sets specific for the most representative bacterial groups of the human vaginal ecosystem. This tool was implemented using the ligase detection reaction-universal array (LDR-UA) approach. The entire probe set properly recognized the specific targets and showed an overall sensitivity of 6 to 12 ng per probe. The VaginArray was applied to assess the efficacy of rifaximin vaginal tablets for the treatment of BV, analyzing the vaginal bacterial communities of 22 BV-affected women treated with rifaximin vaginal tablets at a dosage of 25 mg/day for 5 days. Our results showed the ability of rifaximin to reduce the growth of various BV-related bacteria (Atopobium vaginae, Prevotella, Megasphaera, Mobiluncus, and Sneathiaspp.), with the highest antibiotic susceptibility for A. vaginaeand Sneathiaspp. Moreover, we observed an increase of Lactobacillus crispatuslevels in the subset of women who maintained remission after 1 month of therapy, opening new perspectives for the treatment of BV.

ABSTRACTBacterial vaginosis (BV) is a common vaginal disorder characterized by the decrease of lactobacilli and overgrowth of Gardnerella vaginalisand resident anaerobic vaginal bacteria. In the present work, the effects of rifaximin vaginal tablets on vaginal microbiota and metabolome of women affected by BV were investigated by combining quantitative PCR and a metabolomic approach based on 1H nuclear magnetic resonance. To highlight the general trends of the bacterial communities and metabolomic profiles in response to the antibiotic/placebo therapy, a multivariate statistical strategy was set up based on the trajectories traced by vaginal samples in a principal component analysis space. Our data demonstrated the efficacy of rifaximin in restoring a health-like condition in terms of both bacterial communities and metabolomic features. In particular, rifaximin treatment was significantly associated with an increase in the lactobacillus/BV-related bacteria ratio, as well as with an increase in lactic acid concentration and a decrease of a pool of metabolites typically produced by BV-related bacteria (acetic acid, succinate, short-chain fatty acids, and biogenic amines). Among the tested dosages of rifaximin (100 and 25 mg for 5 days and 100 mg for 2 days), 25 mg for 5 days was found to be the most effective.

IBS is a prevalent functional gastrointestinal disorder, in which the microbiota has been demonstrated to play a role. An increasing number of studies have suggested how probiotics may alleviate IBS symptoms and several mechanisms of action have been proposed. In the present study we characterized the intestinal microbiota of 19 subjects suffering from diagnosed IBS using a fully validated High Taxonomic Fingerprint Microbiota Array (HTF-Microbi.Array). We demonstrated that the IBS microbiota is different from that of healthy individuals due to an unbalance in a number of commensal species, with an increase in relative abundance of lactobacilli, B. cereusand B. clausii, bifidobacteria, Clostridium cluster IX and E. rectale,and a decrease in abundance of Bacteroides/Prevotella group and Veillonella genus. Additionally, we demonstrated that some bacterial groups of the human intestinal microbiota, recently defined as pathobionts, are increased in concentration in the IBS microbiota.Furthermore, we aimed at investigating if the daily administration of a novel probiotic yogurt containing B. animalissubsp lactisBb12 and K. marxianusB0399, recently demonstrated to have beneficial effects in the management of IBS symptoms, could impact on the biostructure of IBS microbiota, modulating its composition to counteract putative dysbiosis found in IBS subjects. Notably, we demonstrated that the beneficial effects associated to the probiotic preparation are not related to significant modifications in the composition of the human intestinal microbiota.

ABSTRACTBacterial vaginosis (BV) is a common vaginal disorder characterized by an alteration of the vaginal bacterial morphotypes, associated with sexually transmitted infections and adverse pregnancy outcomes. The purpose of the present study was to evaluate the impact of different doses of rifaximin vaginal tablets (100 mg/day for 5 days, 25 mg/day for 5 days, and 100 mg/day for 2 days) on the vaginal microbiota of 102 European patients with BV enrolled in a multicenter, double-blind, randomized, placebo-controlled study. An integrated molecular approach based on quantitative PCR (qPCR) and PCR-denaturing gradient gel electrophoresis (PCR-DGGE) was used to investigate the effects of vaginal tablets containing the antibiotic. An increase in members of the genus Lactobacillusand a decrease in the BV-related bacterial groups after the antibiotic treatment were demonstrated by qPCR. PCR-DGGE profiles confirmed the capability of rifaximin to modulate the composition of the vaginal microbial communities and to reduce their complexity. This molecular analysis supported the clinical observation that rifaximin at 25 mg/day for 5 days represents an effective treatment to be used in future pivotal studies for the treatment of BV.

In a clinical trial, 10 patients suffering from irritable bowel syndrome or functional diarrhea were administered the probiotic preparation VSL-3. Preliminary results indicated that administration of VSL-3 improved the clinical picture and changed the composition and biochemistry of fecal microbiota. Titer variations of intestinal bacterial groups were evaluated by culture and PCR techniques. A significant increase in lactobacilli, bifidobacteria and Streptococcus thermophilus was observed as a consequence of probiotic treatment, while enterococci, coliforms, Bacteroides and Clostridium perfringens did not change significantly. The strains Bifidobacterium infantis Y1 and Bifidobacterium breve Y8, included in VSL-3, were specifically detected in feces of patients treated with the probiotic by using strain-specific PCR primers. In addition, fecal β -galactosidase increased and urease activities decreased as a result of changes in the intestinal microbiota induced by VSL-3 administration.

Ten strains of lactobacilli were evaluated for the administration of viable microorganisms to restore the normal indigenous flora in the treatment of urogenital tract infections (UTI) in women. As the strains considered are facultative anaerobes, optimization of the production process was particularly critical to preserve bacterial viability. The microorganisms were formulated in single- and double-layer vaginal tablets. The two layers were characterized by different release properties: one is an effervescent composition that ensures a rapid and complete distribution of the active ingredient over the whole vaginal surface; while the second is a sustained release composition capable of releasing the lactobacilli over a longer period of time. Three different retarding polymers were tested, and all the formulations and tablets were evaluated in terms of technological processability, bacterial viability and stability, and cell adhesion properties of the microorganisms. From the results obtained, three out of ten strains appear particularly suitable for their application in the treatment of UTI. A larger batch of tablets made with a mixture of the three strains was then evaluated, confirming the feasibility of their industrial production and a good bacterial viability in the final dosage form.

For PCR specific detection of the strains Bifidobacterium longumY 10, B. infantisY 1 and B. breveY 8 used in a new probiotic product (VSL-3), strains-specific rDNA primers have been developed. Spacer regions between the 16S and 23S rRNA genes (ITS) of the three strains were amplified by PCR with conserved primers and the nucleotide sequence of these ITSs were determined. On the basis of their comparison with the rDNA sequences retrieved from GenBank, we designed new primers which specifically recognize the species B. breveand the two strains B. infantisY 1 and B. breveY 8. Specificity of these primers was confirmed through the analysis of 60 bifidobacteria strains belonging to the more representative human species. The feasibility of this PCR method was investigated in commercial VSL-3 product and fecal samples collected from 4 patients affected by inflammatory bowel deseases and two healthy subjects before and after the VSL-3 administration. By PCR analysis of different VSL-3 commercial batches we were successful in differentiating and quantifying the strains B. longumY 10, B. infantisY 1 and B. breveY 8. B. infantisY 1 and B. breveY 8 could be detected at high concentration in fecal specimens of both patients and subjects treated with the probiotic preparation, showing a different colonization behaviour. Seven days after the VSL-3 treatment suspension, no patients and subjects harbored B. infantisY 1 and B. breveY 8, indicating a transient presence of these exogenous strains.

Background & Aims:Pouchitis is the major long-term complication after ileal pouch–anal anastomosis for ulcerative colitis. Most patients have relapsing disease, and no maintenance treatment study has been performed. We evaluated the efficacy of a probiotic preparation (VSL#3) containing 5 × 1011per gram of viable lyophilized bacteria of 4 strains of lactobacilli, 3 strains of bifidobacteria, and 1 strain of Streptococcus salivariussubsp. thermophiluscompared with placebo in maintenance of remission of chronic pouchitis. Methods:Forty patients in clinical and endoscopic remission were randomized to receive either VSL#3, 6 g/day, or an identical placebo for 9 months. Patients were assessed clinically every month and endoscopically and histologically every 2 months or in the case of a relapse. Fecal samples were collected for stool culture before and after antibiotic treatment and each month during maintenance treatment. Results:Three patients (15%) in the VSL#3 group had relapses within the 9-month follow-up period, compared with 20 (100%) in the placebo group (P< 0.001). Fecal concentration of lactobacilli, bifidobacteria, and S. thermophilusincreased significantly from baseline levels only in the VSL#3-treated group (P< 0.01). Conclusions:These results suggest that oral administration of this new probiotic preparation is effective in preventing flare-ups of chronic pouchitis.

Single-agent monoclonal antibodies targeting the immune checkpoint PD1 (programmed death 1) are an efficient and safe therapeutic option in patients with relapsed/refractory B-cell lymphoma. However, many patients progress or lose response to anti-PD1. Recent studies have highlighted the role of the gut microbiota (GM) in influencing the response to chemo-immunotherapeutic agents. Here we hypothesize that the GM dynamics in B-cell lymphoma patients during anti-PD1 therapy correlate with treatment response.

The optimal culture conditions for Bacillus stearothermophilus NUB3621 (BGSC 9A5) in chemostat were studied. The results obtained showed that the optimal culture conditions in terms of biomass concentration and maximum growth rate were 65°C, pH 6.8 to 7.2. Dissolved oxygen became growth limiting at pO2 levels below 10%. Furthermore, this strain was transformed with three new hybrid vectors (pPAM2, pPCH2, or pPLY2) constructed by cloning in pRP9, a plasmid based on the thermophilic replicon, pBC1, and three heterologous genes: the α-amylase gene from Bacillus licheniformis, the cholesterol oxidase gene from Streptomyces sp., and the lipase gene from Pseudomonas fluorescens. The influence of several fermentative conditions on segregational and structural stability of the recombinant B. stearothermophilus NUB3621 transformants was studied. The parameters of plasmid loss, that is, rate of plasmid loss (R) and specific growth rate difference (δμ), were calculated. B. stearothermophilus NUB3621 carrying pRP9 showed great segregational stability in all the assayed conditions, exceeding more than 300 generations without significant plasmid loss, whereas NUB3621 carrying pPAM2, pPCH2, or pPLY2 exhibited relatively low plasmid stability. The segregational instability of the recombinant constructs increased by increasing the fermentation temperature, decreased by increasing the dilution rate, and was not affected by the level of dissolved oxygen. On the other hand, plasmid maintenance decreased in minimal medium if compared with the results obtained in complex medium. Restriction analyses carried out on cultures of NUB3621 carrying pRP9, pPAM2, pPCH2, or pPLY2, grown for 200 generations on nonselective media, revealed that all the clones tested contained the parental plasmids. These results indicate that the heterologous inserts did not affect the structural stability of the recombinant plasmids. © 1997 John Wiley & Sons, Inc. Biotechnol Bioeng 53: 507–514, 1997.