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Purpose: Impaired gut barrier function is associated with systemic inflammation and many chronic diseases. Undigested dietary proteins are fermented in the colon by the gut microbiota which produces nitrogenous metabolites shown to reduce barrier function in vitro. With growing evidence of sex-based differences in gut microbiotas, we determined whether there were sex by dietary protein interactions which could differentially impact barrier function via microbiota modification., Methods: Fermentation systems were inoculated with faeces from healthy males (n = 5) and females (n = 5) and supplemented with 0.9 g of non-hydrolysed proteins sourced from whey, fish, milk, soya, egg, pea, or mycoprotein. Microbial populations were quantified using fluorescence in situ hybridisation with flow cytometry. Metabolite concentrations were analysed using gas chromatography, solid phase microextraction coupled with gas chromatography-mass spectrometry and ELISA., Results: Increased protein availability resulted in increased proteolytic Bacteroides spp (p < 0.01) and Clostridium coccoides (p < 0.01), along with increased phenol (p < 0.01), p-cresol (p < 0.01), indole (p = 0.018) and ammonia (p < 0.01), varying by protein type. Counts of Clostridium cluster IX (p = 0.03) and concentration of p-cresol (p = 0.025) increased in males, while females produced more ammonia (p = 0.02), irrespective of protein type. Further, we observed significant sex-protein interactions affecting bacterial populations and metabolites (p < 0.005)., Conclusions: Our findings suggest that protein fermentation by the gut microbiota in vitro is influenced by both protein source and the donor's sex. Should these results be confirmed through human studies, they could have major implications for developing dietary recommendations tailored by sex to prevent chronic illnesses., (© 2024. The Author(s).)

Animal hosts harbor diverse assemblages of microbial symbionts that play crucial roles in the host's lifestyle. The link between microbial symbiosis and host development remains poorly understood. In particular, little is known about the adaptive evolution of gut bacteria in host-microbe symbioses. Recently, symbiotic relationships have been categorized as open, closed, or mixed, reflecting their modes of inter-host transmission and resulting in distinct genomic features. Members of the genus Bacteroides are the most abundant human gut microbiota and possess both probiotic and pathogenic potential, providing an excellent model for studying pan-genome evolution in symbiotic systems. Here, we determined the complete genome of an novel clinical strain PL2022, which was isolated from a blood sample and performed pan-genome analyses on a representative set of Bacteroides cellulosilyticus strains to quantify the influence of the symbiotic relationship on the evolutionary dynamics. B. cellulosilyticus exhibited correlated genomic features with both open and closed symbioses, suggesting a mixed symbiosis. An open pan-genome is characterized by abundant accessory gene families, potential horizontal gene transfer (HGT), and diverse mobile genetic elements (MGEs), indicating an innovative gene pool, mainly associated with genomic islands and plasmids. However, massive parallel gene loss, weak purifying selection, and accumulation of positively selected mutations were the main drivers of genome reduction in B. cellulosilyticus. Metagenomic read recruitment analyses showed that B. cellulosilyticus members are globally distributed and active in human gut habitats, in line with predominant vertical transmission in the human gut. However, existence and/or high abundance were also detected in non-intestinal tissues, other animal hosts, and non-host environments, indicating occasional horizontal transmission to new niches, thereby creating arenas for the acquisition of novel genes. This case study of adaptive evolution under a mixed host-microbe symbiosis advances our understanding of symbiotic pan-genome evolution. Our results highlight the complexity of genetic evolution in this unusual intestinal symbiont., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Bacterial growth often alters the environment, which in turn can impact interspecies interactions among bacteria. Here, we used an in vitro batch system containing mucin beads to emulate the dynamic host environment and to study its impact on the interactions between two abundant and prevalent human gut bacteria, the primary fermenter Bacteroides thetaiotaomicron and the butyrate producer Roseburia intestinalis. By combining machine learning and flow cytometry, we found that the number of viable B. thetaiotaomicron cells decreases with glucose consumption due to acid production, while R. intestinalis survives post-glucose depletion by entering a slow growth mode. Both species attach to mucin beads, but only viable cell counts of B. thetaiotaomicron increase significantly. The number of viable co-culture cells varies significantly over time compared to those of monocultures. A combination of targeted metabolomics and RNA-seq showed that the slow growth mode of R. intestinalis represents a diauxic shift towards acetate and lactate consumption, whereas B. thetaiotaomicron survives glucose depletion and low pH by foraging on mucin sugars. In addition, most of the mucin monosaccharides we tested inhibited the growth of R. intestinalis but not B. thetaiotaomicron. We encoded these causal relationships in a kinetic model, which reproduced the observed dynamics. In summary, we explored how R. intestinalis and B. thetaiotaomicron respond to nutrient scarcity and how this affects their dynamics. We highlight the importance of understanding bacterial metabolic strategies to effectively modulate microbial dynamics in changing conditions., (© 2023. The Author(s).)

Pathological epithelial‑mesenchymal transition (EMT) has been shown to fulfill a key role in the development and progression of a variety of lung diseases. It has been demonstrated that the inflammatory microenvironment is a decisive factor in inducing pathological EMT. Hexacylated lipopolysaccharide (LPS) [or proacylated lipopolysaccharide (P‑LPS), which functions as proinflammatory lipopolysaccharide] is one of the most effective Toll‑like receptor 4 (TLR4) agonists. Furthermore, the pentacylated and tetracylated form of lipopolysaccharide (or A‑LPS, which functions as anti‑inflammatory lipopolysaccharide) has been shown to elicit competitive antagonistic effects against the pro‑inflammatory activity of P‑LPS. At present, it remains unclear whether LPS extracted from Bacteroides vulgatus (BV‑LPS) can prevent LPS extracted from Escherichia coli (EC‑LPS) from inducing pathological EMT. In the present study, A549 cells and C57BL/6 mice lung tissue were both induced by EC‑LPS (P‑LPS) and BV‑LPS (A‑LPS), either alone or in combination. The anticipated anti‑inflammatory effects of BV‑LPS were analyzed by examining the lung coefficient, lung pathology, A549 cell morphology and expression levels both of the inflammatory cytokines, IL‑1β, IL‑6 and TNF‑α and of the EMT signature proteins, epithelial cadherin (E‑cadherin), α‑smooth muscle actin (α‑SMA) and vimentin. In addition, the expression levels of TLR4, bone morphogenic protein and activin membrane‑bound inhibitor (BAMBI) and Snail were detected and the possible mechanism underlying how BV‑LPS may prevent EC‑LPS‑induced EMT was analyzed. The results obtained showed that the morphology of the A549 cells was significantly polarized, the lung index was significantly increased, the alveolar structure was collapsed and the expression levels of IL‑1β, IL‑6, TNF‑α, α‑SMA, vimentin, TLR4 and Snail in both lung tissue and A549 cells were significantly increased, whereas those of E‑cadherin and BAMBI were significantly decreased. Treatment with BV‑LPS in combination with EC‑LPS was found to reverse these changes. In conclusion, the present study demonstrated that BV‑LPS is able to effectively prevent EC‑LPS‑induced EMT in A549 cells and in mouse lung tissue and furthermore, the underlying mechanism may be associated with inhibition of the TLR4/BAMBI/Snail signaling pathway.

Background: Extensive evidence suggests that gut microbiota may interact with the kidneys and play central roles in the pathogenesis of disease. However, the association of gut microbiota-kidneys in diarrhea remains unclear., Methods: A diarrhea mouse model was constructed by combining adenine with Folium sennae . We analyzed the characteristics of the gut content microbiota and short chain fatty acids (SCFAs); and explored the potential link between gut content microbiota, SCFAs, intestinal inflammatory response and kidney function., Results: Characteristic bacteria Lactobacillus intestinalis and Bacteroides acidifaciens were enriched in the gut contents of mice. The productions of SCFAs were remarkably inhibited. Model mice presented an increased trend of creatinine (Cr), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α), a decreased trend of blood urea nitrogen (BUN) and secretory immunoglobulin A (SIgA). The pathological analysis proved obvious damage to the kidney structure. Lactobacillus intestinalis and Bacteroides acidifaciens exisited in the correlations with acetic acid, intestinal inflammatory response and kidney function., Conclusions: Adenine combined with Folium sennae -induced diarrhea, altered the structure and function of the gut content microbiota in mice, causing the enrichment of the characteristic bacteria Lactobacillus intestinalis and Bacteroides acidifaciens . The interactions between Lactobacillus intestinalis , Bacteroides acidifaciens and acetic acid, intestinal inflammation, and kidney function might be involved in the process of gut-kidney impairment in adenine, combined with Folium sennae -induced diarrhea., Competing Interests: The authors declare no conflict of interest.

Bacterial biofilms are communities of adhering bacteria that express distinct properties compared to their free-living counterparts, including increased antibiotic tolerance and original metabolic capabilities. Despite the potential impact of the biofilm lifestyle on the stability and function of the dense community of micro-organisms constituting the mammalian gut microbiota, the overwhelming majority of studies performed on biofilm formation by gut bacteria focused either on minor and often aerobic members of the community or on pathogenic bacteria. In this review, we discuss the reported evidence for biofilm-like structures formed by gut bacteria, the importance of considering the anaerobic nature of gut biofilms and we present the most recent advances on biofilm formation by Bacteroides, one of the most abundant genera of the human gut microbiota. Bacteroides species can be found attached to food particles and colonizing the mucus layer and we propose that Bacteroides symbionts are relevant models to probe the physiology of gut microbiota biofilms., (© The Author(s) 2021. Published by Oxford University Press on behalf of FEMS.)

The intestinal flora plays an important role in the development of many human and animal diseases. Microbiome association studies revealed the potential regulatory function of intestinal bacteria in many liver diseases, such as autoimmune hepatitis, viral hepatitis and alcoholic hepatitis. However, the key intestinal bacterial strains that affect pathological liver injury and the underlying functional mechanisms remain unclear. We found that the gut microbiota from gentamycin (Gen)-treated mice significantly alleviated concanavalin A (ConA)-induced liver injury compared to vancomycin (Van)-treated mice by inhibiting CD95 expression on the surface of hepatocytes and reducing CD95/CD95L-mediated hepatocyte apoptosis. Through the combination of microbiota sequencing and correlation analysis, we isolated 5 strains with the highest relative abundance, Bacteroides acidifaciens (BA), Parabacteroides distasonis (PD), Bacteroides thetaiotaomicron (BT), Bacteroides dorei (BD) and Bacteroides uniformis (BU), from the feces of Gen-treated mice. Only BA played a protective role against ConA-induced liver injury. Further studies demonstrated that BA-reconstituted mice had reduced CD95/CD95L signaling, which was required for the decrease in the L-glutathione/glutathione (GSSG/GSH) ratio observed in the liver. BA-reconstituted mice were also more resistant to alcoholic liver injury. Our work showed that a specific murine intestinal bacterial strain, BA, ameliorated liver injury by reducing hepatocyte apoptosis in a CD95-dependent manner. Determination of the function of BA may provide an opportunity for its future use as a treatment for liver disease.

Background: Immune checkpoint blockade (ICB) shows lasting benefits in advanced melanoma; however, not all patients respond to this treatment and many develop potentially life-threatening immune-related adverse events (irAEs). Identifying individuals who will develop irAEs is critical in order to improve the quality of care. Here, we prospectively demonstrate that the gut microbiome predicts irAEs in melanoma patients undergoing ICB., Methods: Pre-, during, and post-treatment stool samples were collected from 27 patients with advanced stage melanoma treated with IPI (anti-CTLA-4) and NIVO (anti-PD1) ICB inhibitors at NYU Langone Health. We completed 16S rRNA gene amplicon sequencing, DNA deep shotgun metagenomic, and RNA-seq metatranscriptomic sequencing. The divisive amplicon denoising algorithm (DADA2) was used to process 16S data. Taxonomy for shotgun sequencing data was assigned using MetaPhlAn2, and gene pathways were assigned using HUMAnN 2.0. Compositionally aware differential expression analysis was performed using ANCOM. The Cox-proportional hazard model was used to assess the prospective role of the gut microbiome (GMB) in irAES, with adjustment for age, sex, BMI, immune ICB treatment type, and sequencing batch., Results: Two natural GMB clusters with distinct community compositions were identified from the analysis of 16S rRNA data (R 2 = 0.16, p < 0.001). In Cox-proportional hazard modeling, these two clusters showed a near 7-fold differential risk for developing irAEs within 1 year of initiating treatment (HR = 6.89 [95% CI: 1.33-35.58]). Using shotgun metagenomics, we further identified 37 bacterial strains differentially expressed between the risk groups, with specific dominance of Bacteroides dorei within the high-risk GMB cluster and Bacteroides vulgatus in the low-risk cluster. The high-risk cluster also appeared to have elevated expression of several functional pathways, including those associated with adenosine metabolism (all FDR < 0.05). A sub-analysis of samples (n = 10 participants) at baseline and 6 and 12 weeks after the start of treatment revealed that the microbiome remained stable over the course of treatment (R 2 = 0.88, p < 0.001)., Conclusions: We identified two distinct fecal bacterial community clusters which are associated differentially with irAEs in ICB-treated advanced melanoma patients., (© 2021. The Author(s).)

This study investigated the immune mechanisms whereby administration of Bacteroides uniformis CECT 7771 reduces metabolic dysfunction in obesity. C57BL/6 adult male mice were fed a standard diet or a Western diet high in fat and fructose, supplemented or not with B. uniformis CECT 7771 for 14 weeks. B. uniformis CECT 7771 reduced body weight gain, plasma cholesterol, triglyceride, glucose, and leptin levels; and improved oral glucose tolerance in obese mice. Moreover, B. uniformis CECT 7771 modulated the gut microbiota and immune alterations associated with obesity, increasing Tregs and reducing B cells, total macrophages and the M1/M2 ratio in both the gut and epididymal adipose tissue (EAT) of obese mice. B. uniformis CECT 7771 also increased the concentration of the anti-inflammatory cytokine IL-10 in the gut, EAT and peripheral blood, and protective cytokines TSLP and IL-33, involved in Treg induction and type 2 innate lymphoid cells activation, in the EAT. It also restored the obesity-reduced TLR5 expression in the ileum and EAT. The findings indicate that the administration of a human intestinal bacterium with immunoregulatory properties on the intestinal mucosa helps reverse the immuno-metabolic dysfunction caused by a Western diet acting over the gut-adipose tissue axis.

The Mediterranean diet (MD) has been recommended for type 2 diabetes (T2D) treatment. The impact of diet in shaping the gut microbiota is well known, particularly for MD. However, the link between MD and diabetes outcome improvement is not completely clear. This study aims to evaluate the role of microbiota modulation by a nonpharmacological intervention in patients with T2D. In this 12-week single-arm pilot study, nine participants received individual nutritional counseling sessions promoting MD. Gut microbiota, biochemical parameters, body composition, and blood pressure were assessed at baseline, 4 weeks, and 12 weeks after the intervention. Adherence to MD [assessed by Mediterranean Diet Adherence Screener (MEDAS) score] increased after the intervention. Bacterial richness increased after 4 weeks of intervention and was negatively correlated with fasting glucose levels and Homeostatic Model Assessment for Insulin Resistance (HOMA-IR). Prevotella to Bacteroides ratio also increased after 4 weeks. In contrast, glycated haemoglobin (HbA1c) and HOMA-IR were only decreased at the end of study. Alkaline phosphatase activity was assessed in fecal samples and was negatively correlated with HbA1c and positively correlated with bacterial diversity. The results of this study reinforce that MD adherence results in a better glycemic control in subjects with T2D. Changes in gut bacterial richness caused by MD adherence may be relevant in mediating the metabolic impact of this dietary intervention.

Interactions of commensal bacteria within the gut microbiota and with invading pathogens are critical in determining the outcome of an infection. While murine studies have been valuable, we lack in vitro models to monitor community responses to pathogens at a single-species level. We have developed a multispecies community of nine representative gut species cultured together as a mixed biofilm and tracked numbers of individual species over time using a quantitative PCR (qPCR)-based approach. Introduction of the major nosocomial gut pathogen, Clostridioides difficile , to this community resulted in increased adhesion of commensals and inhibition of C. difficile multiplication. Interestingly, we observed an increase in individual Bacteroides species accompanying the inhibition of C. difficile Furthermore, Bacteroides dorei reduced C. difficile growth within biofilms, suggesting a role for Bacteroides spp. in prevention of C. difficile colonization. We report here an in vitro tool with excellent applications for investigating bacterial interactions within a complex community. IMPORTANCE Studying interactions between bacterial species that reside in the human gut is crucial for gaining a better insight into how they provide protection from pathogen colonization. In vitro models of multispecies bacterial communities wherein behaviors of single species can be accurately tracked are key to such studies. Here, we have developed a synthetic, trackable, gut microbiota community which reduces growth of the human gut pathogen Clostridioides difficile We report that Bacteroides spp. within this community respond by multiplying in the presence of this pathogen, resulting in reduction of C. difficile growth. Defined in vitro communities that can be tailored to include different species are well suited to functional genomic approaches and are valuable tools for understanding interbacterial interactions., (Copyright © 2021 Hassall et al.)

Metabolic syndrome is associated with usual dietary patterns that may be involved in enterotypes. We aimed to understand the potential relationship of enterotypes and dietary patterns to influence metabolic syndrome in the Koreans. Using the Korea National Health and Nutrition Examination Survey (KNHANES)-VI in 2014, metabolic parameters were also analyzed among the dietary patterns classified by principal component analysis in Korean adults. The fecal microbiota data of 1199 Korean adults collected in 2014 were obtained from the Korea Centers for Disease Control and Prevention. Enterotypes were classified based on Dirichlet multinomial mixtures (DMM) by Mothur v.1.36. The functional abundance of fecal bacteria was analyzed using the PICRUSt2 pipeline. Korean adults were clustered into three dietary patterns including Korean-style balanced diets (KBD, 20.4%), rice-based diets (RBD, 17.2%), and Western-style diets (WSD, 62.4%) in KNHANES. The incidence of metabolic syndrome was lowered in the order of RBD, WSD, and KBD. The participants having a KBD had lower serum C-reactive protein and triglyceride concentrations than those with RBD and WSD ( p < 0.05). Three types of fecal bacteria were classified as Ruminococcaceae type (ET-R, 28.7%), Prevotella type (ET-P, 52.2%), and Bacteroides type (ET-B, 42.1%; p < 0.05). ET-P had a higher abundance of Prevotella copri, while ET-R contained a higher abundance of Alistipes , Akkermansia muciniphila , Bifidobacterium adolescentis , and Faecalibacterium prausnitzii . ET-B had a higher abundance of the order Bilophila ( p < 0.05). Metabolism of propanoate, starch, and sucrose in fecal microbiome was higher in ET-P and ET-R, whereas fatty acid metabolism was enhanced in ET-B. Fecal microbiota in ET-P and ET-B had higher lipopolysaccharide biosynthesis activity than that in ET-R. The metabolic results of KBD and RBD were consistent with ET-R and ET-P's gut microbiota metabolism, respectively. In conclusion, Korean enterotypes of ET-P, ET-B, and ET-R were associated with RBD, WSD, and KBD, respectively. This study suggests a potential link between dietary patterns, metabolic syndrome, and enterotypes among Korean adults.

Iron is an essential nutrient for the legume-rhizobia symbiosis and nitrogen-fixing bacteroids within root nodules of legumes have a very high demand for the metal. Within the infected cells of nodules, the bacteroids are surrounded by a plant membrane to form an organelle-like structure called the symbiosome. In this review, we focus on how iron is transported across the symbiosome membrane and accessed by the bacteroids.

This study was conducted to determine the effects of supplemental dietary benzoic acid on production performance, egg quality, intestinal morphology, and intestinal microbiota of laying hens. A total of seven hundred twenty 45-wk-old Lohman pink-shell laying hens were randomly allocated to 3 dietary treatments: control (CON), diet supplemented with 1,000 mg/kg benzoic acid (BA1), and 2,000 mg/kg benzoic acid (BA2). Each treatment included 10 replicates of 24 hens; laying hens were monitored for 16 wk. Overall, the results indicate that benzoic acid supplementation had no effect on laying rate, feed intake, feed conversion ratio, and breaking rate; however, a decrease in egg weight (P < 0.01) was observed in the BA2 group. Albumen height and Haugh unit (HU) were also linearly increased in the BA1 and BA2 groups (linear effect, P < 0.05). An increase in duodenum villus height (V) (quadratic effect, P = 0.041) and crypt depth (C) (linear effect, P = 0.012) was observed in the BA2 group, whereas an increased jejunum C and decreased V/C (quadratic effect, P < 0.05) in the BA1 group. Moreover, an increase in ileum V and C (quadratic effect, P < 0.05) was observed in the BA1 group. Microbial richness and diversity were reduced in the BA2 group (P < 0.01). An increase in the abundance of Clostridia (class), Clostridiales (order), Ruminococcaceae (family), and Lachnospiraceae (family) was noted in the BA1 group, whereas an enrichment of Bacteroides caecicola (species) was observed in the BA2 group. The HU positively correlated with genus Sphaerochaeta and Enorma (r = 0.56, 0.56; P < 0.05) but negatively correlated with Romboutsia, Subdoligranulum, Helicobacter, and Mucispirillum (r = -0.58, -0.49, -0.48; -0.70; P < 0.05). In conclusion, dietary supplementation with benzoic acid had no effect on production performance, but it significantly improved egg quality. In addition, 1,000 mg/kg benzoic acid positively modulated intestinal health by improving intestinal morphology and enriching microbial composition., (Copyright © 2020. Published by Elsevier Inc.)

The functional diversity of the mammalian intestinal microbiome far exceeds that of the host organism, and microbial genes contribute substantially to the well-being of the host. However, beneficial gut organisms can also be pathogenic when present in the gut or other locations in the body. Among dominant beneficial bacteria are several species of Bacteroides , which metabolize polysaccharides and oligosaccharides, providing nutrition and vitamins to the host and other intestinal microbial residents. These topics and the specific organismal and molecular interactions that are known to be responsible for the beneficial and detrimental effects of Bacteroides species in humans comprise the focus of this review. The complexity of these interactions will be revealed.

Allergy can cause intestinal damage, including through cell apoptosis. In this study, intestinal cell apoptosis was first observed in the β-conglycinin (β-CG) allergy model, and the effect of Lactobacillus rhamnosus GG (LGG) on reducing apoptosis of cells in the intestine and its underlying mechanisms were further investigated. Allergic mice received oral LGG daily, and intestinal tissue apoptotic cells, gut microbiota, and metabolites were evaluated six and nine days after intervention. Terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) analysis revealed that LGG intervention could reduce the incidence of cell apoptosis more effectively than natural recovery (NR). The results of 16S rRNA analysis indicated that LGG intervention led to an increase in the relative abundance of Bacteroides . Metabolite analysis of intestinal contents indicated that histamine, N -acetylhistamine, N (α)-γ-glutamylhistamine, phenylalanine, tryptophan, arachidonic acid malate, and xanthine were significantly decreased, and deoxycholic acid, lithocholic acid were significantly increased after the LGG intervention on β-CG allergy; the decreases in histamine and N (α)-γ-glutamylhistamine were significant compared with those of NR. In conclusion, LGG reduces apoptosis of cells induced by β-CG allergy, which may be related to regulation of Bacteroides and the bile secretion pathway.

Overweight and obese individuals may have leaky intestinal barrier and microbiome dysbiosis. The aim of this study was to determine whether body mass reduction with diet and synbiotics in an adult person with excess body mass has an influence on the gut microbiota and zonulin concentration. The study was a single blinded trial. 60 persons with excess body mass were examined. Based on randomization, patients were qualified either to the intervention group (Synbiotic group) or to the control group (Placebo group). Anthropometric measurements, microbiological assessment of faecal samples and zonulin concentration in the stool were performed before and after observation. After 3-months, an increase in the variety of intestinal bacteria (increase in the Shannon-Weaver index and the Simpson index) and a decrease in concentration of zonulin in faecal samples were observed in the Synbiotic group. Also, statistically significant correlation between zonulin and Bifidobacterium spp. (Spearman test, R=-0.51; p=0.0040) was noticed. There were no significant relationships between the body mass, BMI and changes in the intestinal microbiota or zonulin concentrations. The use of diet and synbiotics improved the condition of the microbiota and intestinal barrier in patients in the Synbiotic group.

Background: The determinants that mediate the interactions between microRNAs and the gut microbiome impacting on obesity are scarcely understood. Thus, the aim of this study was to investigate possible interactions between circulating microRNAs and gut microbiota composition in obesity., Method: The sample comprised 78 subjects with obesity (cases, body mass index (BMI): 30-40 kg/m 2 ) and 25 eutrophic individuals (controls, BMI ≤ 25 kg/m 2 ). The expression of 96 microRNAs was investigated in plasma of all individuals using miRCURY LNA miRNA Custom PCR Panels. Bacterial DNA sequencing was performed following the Illumina 16S protocol. The FDR correction was used for multiple comparison analyses., Results: A total of 26 circulating microRNAs and 12 bacterial species were found differentially expressed between cases and controls. Interestingly, an interaction among three miRNAs (miR-130b-3p, miR-185-5p and miR-21-5p) with Bacteroides eggerthi and BMI levels was evidenced ( r 2 = 0.148, p = 0.004). Moreover, these microRNAs regulate genes that participate in metabolism-related pathways, including fatty acid degradation, insulin signaling and glycerolipid metabolism., Conclusions: This study characterized an interaction between the abundance of 4 bacterial species and 14 circulating microRNAs in relation to obesity. Moreover, the current study also suggests that miRNAs may serve as a communication mechanism between the gut microbiome and human hosts.

In addition to their established functions in host defense, accumulating evidence has suggested an emerging role for antimicrobial proteins (AMPs) in shaping commensal microbiota. However, the role of α-defensins, the most abundant AMPs of intestine, in regulating microbial ecology remains inconclusive. Here, we report that α-defensins promote commensal Bacteroides colonization by enhancing bacterial adhesion to the mucosal reservoir. Experiments utilizing mice deficient in matrix metalloproteinase 7 (MMP7), the α-defensin-activating enzyme, with rigorous littermate controls showed that α-defensin deficiency did not significantly influence steady-state intestinal microbiota. In contrast, α-defensins are essential for replenishment of commensal Bacteroides from the mucosal reservoir following antibiotics-induced dysbiosis, shown by markedly compromised recovery of Bacteroides in Mmp7 -/- animals. Mechanistically, α-defensins promote Bacteroides colonization on epithelial surfaces in vivo and adhesion to epithelial cells in vitro . Moreover, α-defensins unexpectedly does not show any microbicidal activities against Bacteroides . Together, we propose that α-defensins promote commensal bacterial colonization and recovery to maintain microbial diversity upon environmental challenges., (Copyright © 2020 Ou, Liang, Guo and Hu.)

Background: Patients with pelvic malignancies often receive radiosensitising chemotherapy with radiotherapy to improve survival; however, this is at the expense of increased normal tissue toxicity, particularly in elderly patients. Here, we explore if an alternative, low-cost, and non-toxic approach can achieve radiosensitisation in mice transplanted with human bladder cancer cells. Other investigators have shown slower growth of transplanted tumours in mice fed high-fibre diets. We hypothesised that mice fed a high-fibre diet would have improved tumour control following ionising radiation (IR) and that this would be mediated through the gut microbiota., Results: We investigated the effects of four different diets (low-fibre, soluble high-fibre, insoluble high-fibre, and mixed soluble/insoluble high-fibre diets) on tumour growth in immunodeficient mice implanted with human bladder cancer flank xenografts and treated with ionising radiation, simultaneously investigating the composition of their gut microbiomes by 16S rRNA sequencing. A significantly higher relative abundance of Bacteroides acidifaciens was seen in the gut (faecal) microbiome of the soluble high-fibre group, and the soluble high-fibre diet resulted in delayed tumour growth after irradiation compared to the other groups. Within the soluble high-fibre group, responders to irradiation had significantly higher abundance of B. acidifaciens than non-responders. When all mice fed with different diets were pooled, an association was found between the survival time of mice and relative abundance of B. acidifaciens. The gut microbiome in responders was predicted to be enriched for carbohydrate metabolism pathways, and in vitro experiments on the transplanted human bladder cancer cell line suggested a role for microbial-generated short-chain fatty acids and/or other metabolites in the enhanced radiosensitivity of the tumour cells., Conclusions: Soluble high-fibre diets sensitised tumour xenografts to irradiation, and this phenotype was associated with modification of the microbiome and positively correlated with B. acidifaciens abundance. Our findings might be exploitable for improving radiotherapy response in human patients.

Several factors affect the composition of species that inhabit our intestinal tract, including mode of delivery, genetics and nutrition. Antimicrobial peptides and proteins secreted in the gastrointestinal tract are powerful tools against bacteria. Lactoferrin (LF) inhibits the growth of several bacterial species, such as Enterobacteriaceae, but may stimulate probiotic bacteria. Activity of LF against gut symbiotic species of the Bacteroides genus could give us insights on how these species colonize the gut. We investigated the effects of the antimicrobial protein lactoferrin and its derived peptide, lactoferricin B on two species of strict anaerobes, opportunistic pathogens that cause diseases in both adults and children, commonly found in the microbiota of the human gastrointestinal tract, Bacteroides fragilis and B. thetaiotaomicron., In vitro biofilm formation and binding to laminin were strongly inhibited by a low concentration of lactoferrin (12.5 μg/ml). Conversely, the growth of the strains in a micro-dilution assay in minimal media with different iron sources was not affected by physiological concentrations (2 mg/ml) of apo-lactoferrin or holo-lactoferrin. The combination of lactoferrin with antibiotics in synergism assays was also negative. The lactoferricin B fragment was also unable to inhibit growth in a similar test with concentrations of up to 32 μg/ml. Resistance to lactoferrin could confer an advantage to these species, even when high amount of this protein is present in the gastrointestinal tract. However, colonization is hampered by the binding and biofilm inhibitiory effect of lactoferrin, which may explain the low prevalence of Bacteroides in healthy babies. Resistance to this antimicrobial protein may help understand the success of these opportunistic pathogens during infection in the peritoneum., Competing Interests: Declaration of competing interest The authors declare no conflict of interests., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Gut microbes are linked to host metabolism, but specific mechanisms remain to be uncovered. Ceramides, a type of sphingolipid (SL), have been implicated in the development of a range of metabolic disorders from insulin resistance (IR) to hepatic steatosis. SLs are obtained from the diet and generated by de novo synthesis in mammalian tissues. Another potential, but unexplored, source of mammalian SLs is production by Bacteroidetes, the dominant phylum of the gut microbiome. Genomes of Bacteroides spp. and their relatives encode serine palmitoyltransfease (SPT), allowing them to produce SLs. Here, we explore the contribution of SL-production by gut Bacteroides to host SL homeostasis. In human cell culture, bacterial SLs are processed by host SL-metabolic pathways. In mouse models, Bacteroides-derived lipids transfer to host epithelial tissue and the hepatic portal vein. Administration of B. thetaiotaomicron to mice, but not an SPT-deficient strain, reduces de novo SL production and increases liver ceramides. These results indicate that gut-derived bacterial SLs affect host lipid metabolism.

Gestational diabetes mellitus (GDM) is significantly associated with allergen sensitization in early childhood, and this may influence the gut microbiome and immune system of the children. In addition to mother-to-child transmission of microbes, milk glycans play a pivotal role in shaping the gut microbiome of infants. A previous study has demonstrated alterations in the major milk N-glycans of mothers with GDM. However, the impact of these changes on the gut microbiome and immune response of the neonates has yet to be studied. Here, we aimed to compare the glycosylation levels of various milk glycans between normal and GDM mice, and to characterize the intestinal microbiome and immune responses of the offspring after weaning. We found that GDM mouse milk contained significantly higher concentrations of fucosylated and sialylated N-glycans than control mice, but there was no difference in the concentration of milk oligosaccharides between the groups. The differences in milk N-glycans had direct effects on the intestinal microbiome of the offspring, which in turn affected their immune response upon challenge with ovalbumin (OVA), with disruptions in the Th1/Th2 and Th17/Treg cell balances. This study lays the foundation for further research and development of specific nutritional care for the offspring of GDM mothers., (© 2020 Federation of American Societies for Experimental Biology.)

B cells fulfill multifaceted functions that influence immune responses during health and disease. In autoimmune diseases, such as inflammatory bowel disease, multiple sclerosis and rheumatoid arthritis, depletion of functional B cells results in an aggravation of disease in humans and respective mouse models. This could be due to a lack of a pivotal B cell subpopulation: regulatory B cells (Bregs). Although Bregs represent only a small proportion of all immune cells, they exhibit critical properties in regulating immune responses, thus contributing to the maintenance of immune homeostasis in healthy individuals. In this study, we report that the induction of Bregs is differentially triggered by the immunogenicity of the host microbiota. In comparative experiments with low immunogenic Bacteroides vulgatus and strong immunogenic Escherichia coli , we found that the induction and longevity of Bregs depend on strong Toll-like receptor activation mediated by antigens of strong immunogenic commensals. The potent B cell stimulation via E. coli led to a pronounced expression of suppressive molecules on the B cell surface and an increased production of anti-inflammatory cytokines like interleukin-10. These bacteria-primed Bregs were capable of efficiently inhibiting the maturation and function of dendritic cells (DCs), preventing the proliferation and polarization of T helper (Th)1 and Th17 cells while simultaneously promoting Th2 cell differentiation in vitro . In addition, Bregs facilitated the development of regulatory T cells (Tregs) resulting in a possible feedback cooperation to establish immune homeostasis. Moreover, the colonization of germfree wild type mice with E. coli but not B. vulgatus significantly reduced intestinal inflammatory processes in dextran sulfate sodium (DSS)-induced colitis associated with an increase induction of immune suppressive Bregs. The quantity of Bregs directly correlated with the severity of inflammation. These findings may provide new insights and therapeutic approaches for B cell-controlled treatments of microbiota-driven autoimmune disease., (Copyright © 2020 Maerz, Trostel, Lange, Parusel, Michaelis, Schäfer, Yao, Löw and Frick.)

Background: Bacteroides caccae is a ubiquitous, anaerobic bacteria, but it is not a common cause of pathologic bloodstream infection. Diabetic patients are at increased risk of developing anaerobic bacteria infection. Here, we report a repeated fever case caused by Bacteroides caccae in a diabetic patient. The aim of this study was to describe the clinical characteristics and manifestations of Bacteroides caccae., Methods: The pathogenic bacteria isolated from patient blood was identified as Bacteroides caccae. Identification of the Bacteroides caccae was done by 16s rDNA sequencing and matrix-assisted laser desorption/ionization-time of light spectrometry. The infection was cured by one-week combined therapy of intravenous Piperacillin tazobactam and oral Ornidazole tablet., Results: After treatment had been completed, no episodes of fever occurred during the follow-up to date., Conclusions: Bacteroides caccae is regarded as an intestinal, opportunistic pathogenic bacteria. It can invade the mucosa of the intestine and cause various abdominal suppurative infections. Sequencing and matrix-assisted laser desorption/ionization-time of flight spectrometry could have a role for Bacteroides caccae diagnosis. The curative effect of using first generation cephalosporines therapy was unsatisfactory. Using intravenous Piperacillin tazobactam and ornidazole tablet might obtain certain curative effect. Early diagnosis and appropriate anti-infection therapy were necessary to improve the outcome of patients with Bacteroides caccae bloodstream infection.

The human gut microbiota, which underpins nutrition and systemic health, is compositionally sensitive to the availability of complex carbohydrates in the diet. The Bacteroidetes comprise a dominant phylum in the human gut microbiota whose members thrive on dietary and endogenous glycans by employing a diversity of highly specific, multi-gene polysaccharide utilization loci (PUL), which encode a variety of carbohydrases, transporters, and sensor/regulators. PULs invariably also encode surface glycan-binding proteins (SGBPs) that play a central role in saccharide capture at the outer membrane. Here, we present combined biophysical, structural, and in vivo characterization of the two SGBPs encoded by the Bacteroides ovatus mixed-linkage β-glucan utilization locus (MLGUL), thereby elucidating their key roles in the metabolism of this ubiquitous dietary cereal polysaccharide. In particular, molecular insight gained through several crystallographic complexes of SGBP-A and SGBP-B with oligosaccharides reveals that unique shape complementarity of binding platforms underpins specificity for the kinked MLG backbone vis-à-vis linear β-glucans. Reverse-genetic analysis revealed that both the presence and binding ability of the SusD homolog BoSGBP MLG -A are essential for growth on MLG, whereas the divergent, multi-domain BoSGBP MLG -B is dispensable but may assist in oligosaccharide scavenging from the environment. The synthesis of these data illuminates the critical role SGBPs play in concert with other MLGUL components, reveals new structure-function relationships among SGBPs, and provides fundamental knowledge to inform future (meta)genomic, biochemical, and microbiological analyses of the human gut microbiota.

Objective: To investigate whether diets differing in fat content alter the gut microbiota and faecal metabolomic profiles, and to determine their relationship with cardiometabolic risk factors in healthy adults whose diet is in a transition from a traditional low-fat diet to a diet high in fat and reduced in carbohydrate., Methods: In a 6-month randomised controlled-feeding trial, 217 healthy young adults (aged 18-35 years; body mass index <28 kg/m 2 ; 52% women) who completed the whole trial were included. All the foods were provided during the intervention period. The three isocaloric diets were: a lower-fat diet (fat 20% energy), a moderate-fat diet (fat 30% energy) and a higher-fat diet (fat 40% energy). The effects of the dietary interventions on the gut microbiota, faecal metabolomics and plasma inflammatory factors were investigated., Results: The lower-fat diet was associated with increased α-diversity assessed by the Shannon index (p=0.03), increased abundance of Blautia (p=0.007) and Faecalibacterium (p=0.04), whereas the higher-fat diet was associated with increased Alistipes (p=0.04), Bacteroides (p<0.001) and decreased Faecalibacterium (p=0.04). The concentration of total short-chain fatty acids was significantly decreased in the higher-fat diet group in comparison with the other groups (p<0.001). The cometabolites p-cresol and indole, known to be associated with host metabolic disorders, were decreased in the lower-fat diet group. In addition, the higher-fat diet was associated with faecal enrichment in arachidonic acid and the lipopolysaccharide biosynthesis pathway as well as elevated plasma proinflammatory factors after the intervention., Conclusion: Higher-fat consumption by healthy young adults whose diet is in a state of nutrition transition appeared to be associated with unfavourable changes in gut microbiota, faecal metabolomic profiles and plasma proinflammatory factors, which might confer adverse consequences for long-term health outcomes., Trial Registration Number: NCT02355795; Results., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Background/purpose: Gut microbiota has been associated with liver cirrhosis and, possibly, hepatic encephalopathy. However, only a few studies have examined the link between mucosa-associated microbiota (MAM) and minimal hepatic encephalopathy (MHE). Our aim was to investigate this relationship., Methods: Twenty-four patients with cirrhosis underwent colon biopsies at our institution, between January 2014 and April 2015. Patterns of microbial colonization were examined using 16S rRNA gene sequences. MHE was diagnosed using the Neuropsychological Test., Results: Ten (41.7%) of the 24 patients were diagnosed as having MHE. There was no significant difference in the diversity of gut microbiota by sampling locations between those with and without MHE. However, the diversity of the gut microbiota and the proportion of the genus Bacteroides decreased as a function of declining liver function. We divided patients into those with the highest proportion of the genus Bacteroides (Bacteroides-dominant group; n = 9) and into a Bacteroides non-dominant group (n = 15). In the Bacteroides-dominant group, only 1 patient (11.1%) was diagnosed as having MHE, with the incidence rate of MHE being significantly lower in the Bacteroides-dominant group than in the non-dominant group (p = 0.019). The Child-Pugh score (p = 0.05) and use of proton-pump inhibitors (p = 0.015) were negatively correlated to the proportion of Bacteroides. Furthermore, the proportion of the family Clostridiaceae was significantly higher in the Bacteroides-dominant group than in the non-dominant group (p = 0.078)., Conclusions: The decrease in microbial diversity and genus Bacteroides in MAM is a risk factor for MHE in patients with liver cirrhosis.

Musa basjoo is a kind of popular slimming fruit in southern China. However, even though the trophic component and physiological effect are well studied, its internal mechanism in reconstructing gut microbiota remains unclear. In this study, maturity of M. basjoo were divided into four levels. Results indicated that M. basjoo in level Ⅱ (with 35% maturity) represented the greatest increase in the growth in vitro of probiotics, Lactobacillus plantarum FMNP01 and Lactobacillus casei FMNP02. After feeding M. basjoo with the middle dose (2.67 g/kg·BW) to mice for 21 days, gut microbiota from mice feces was isolated and sequenced. Results of 16SrDNA sequencing showed that the scattered genera of gut microbiota were significantly gathered. The amounts of different pathogens were decreased, while probiotics such as genera Bacteroides and Roseburia were significantly increased (p < 0.05). Results of function prediction indicated that the reconstruction of gut microbiota may due to the change in carbohydrate transportation, biosynthesis of cell wall, cell membrane, and cell envelope. This study has drawn a basic mechanism in reconstructing gut microbiota by feeding M. basjoo and lay out a foundation for further reach on the interaction between human as diner and M. basjoo as food., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

This study examined the effect of an exercise intervention on the composition of the intestinal microbiota in healthy elderly women. Thirty-two sedentary women that were aged 65 years and older participated in a 12-week, non-randomized comparative trial. The subjects were allocated to two groups receiving different exercise interventions, trunk muscle training (TM), or aerobic exercise training (AE). AE included brisk walking, i.e., at an intensity of ≥ 3 metabolic equivalents (METs). The composition of the intestinal microbiota in fecal samples was determined before and after the training period. We also assessed the daily physical activity using an accelerometer, trunk muscle strength by the modified Kraus-Weber (K-W) test, and cardiorespiratory fitness by a 6-min. walk test (6MWT). K-W test scores and distance achieved during the 6MWT (6MWD) improved in both groups. The relative abundance of intestinal Bacteroides only significantly increased in the AE group, particularly in subjects showing increases in the time spent in brisk walking. Overall, the increases in intestinal Bacteroides following the exercise intervention were associated with increases in 6MWD. In conclusion, aerobic exercise training that targets an increase of the time spent in brisk walking may increase intestinal Bacteroides in association with improved cardiorespiratory fitness in healthy elderly women., Competing Interests: The authors declare no conflict of interest.

The investigation of the immunogenic potential of commensal bacteria on the host immune system is one essential component when studying intestinal host-microbe interactions. It is well established that different commensals exhibit a different potential to stimulate the host intestinal immune system. Such investigations involve vertebrate animals, especially rodents. Since increasing ethical concerns are linked with experiments involving vertebrates, there is a high demand for invertebrate replacements models. Here, we provide a Galleria mellonella oral administration model using commensal non-pathogenic bacteria and the possible assessment of the immunogenic potential of commensals on the G. mellonella immune system. We demonstrate that G. mellonella is a useful alternative invertebrate replacement model that allows the analysis of commensals with different immunogenic potential such as Bacteroides vulgatus and Escherichia coli. Interestingly, the bacteria exhibited no killing effect on the larvae, which is similar to mammals. The immune responses of G. mellonella were comparable with vertebrate innate immune responses and involve recognition of the bacteria and production of antimicrobial molecules. We propose that G. mellonella was able to restore previous microbiota balance, which is well known from healthy mammalian individuals. Although providing comparable innate immune responses in both G. mellonella and vertebrates, G. mellonella does not harbor an adaptive immune system. Since the investigated components of the innate immune system are evolutionary conserved, the model allows a prescreening and first analysis of bacterial immunogenic properties.

Mammalian hosts constantly interact with diverse exogenous microbes, but only a subset of the microbes manage to colonize due to selective colonization resistance exerted by host genetic factors as well as the native microbiota of the host. An important question in microbial ecology and medical science is if such colonization resistance can discriminate closely related microbial species, or even closely related strains of the same species. Using human-mouse fecal microbiota transplantation and metagenomic shotgun sequencing, we reconstructed colonization patterns of human fecal microbes in mice with different genotypes (C57BL6/J vs. NSG) and with or without an intact gut microbiota. We found that mouse genotypes and the native mouse gut microbiota both exerted different selective pressures on exogenous colonizers: human fecal Bacteroides successfully established in the mice gut, however, different species of Bacteroides selectively enriched under different gut conditions, potentially due to a multitude of functional differences, ranging from versatility in nutrient acquisition to stress responses. Additionally, different clades of Bacteroides cellulosilyticus strains were selectively enriched in different gut conditions, suggesting that the fitness of conspecific microbial strains in a novel host environment could differ.

Probiotics play important roles on sustaining or reconstructing the homeostasis of intestinal microbiota, which is one of the key factors in alleviating diseases and maintaining the healthy condition of the host. Preclinical trials indicate that Bacteroides genus is widely considered as source of novel beneficial candidates for attenuating inflammation by regulating lymphocytes and cytokine expression, controlling metabolism and preventing cancer. Furthermore, the first case of authorization of Bacteroides xylanisolvens in food by the European Commission opens the gate for further investigation and application of this promising community. With this paper, we summarized current investigations of discovering beneficial Bacteroides strains, exploring their interaction mechanisms with the host, and evaluating the potential safety risks during commercialization., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background and aims : Bacteriotherapy aimed at addressing dysbiosis may be therapeutic for Inflammatory Bowel Diseases (IBDs). We sought to determine if defined Bacteroides -based bacteriotherapy could be an effective and consistent alternative to fecal microbiota transplantation (FMT) in a murine model of IBD. Methods : We induced experimental colitis in 8- 12-week-old C57BL/6 mice using 2-3% dextran sodium sulfate. Mice were simultaneously treated by oral gavage with a triple- Bacteroides cocktail, individual Bacteroides strains, FMT using stool from healthy donor mice, or their own stool as a control. Survival, weight loss and markers of inflammation (histology, serum amyloid A, cytokine production) were correlated to 16S rRNA gene profiling of fecal and mucosal microbiomes. Results : Triple- Bacteroides combination therapy was more protective against weight loss and mortality than traditional FMT therapy. B. ovatus ATCC8483 was more effective than any individual strain, or a combination of strains, in preventing weight loss, decreasing histological damage, dampening inflammatory response, and stimulating epithelial recovery. Irrespective of the treatment group, overall Bacteroides abundance associated with treatment success and decreased cytokine production while the presence of Akkermansia correlated with treatment failure. However, the therapeutic benefit associated with high Bacteroides abundance was negated in the presence of Streptococcus . Conclusions : Bacteroides ovatus monotherapy was more consistent and effective than traditional FMT at ameliorating colitis and stimulating epithelial recovery in a murine model of IBD. Given the tolerability of Bacteroides ovatus ATCC 8483 in an active, on-going human study, this therapy may be repurposed for the management of IBD in a clinically expedient timeline.

Background/objectives: Individuals with high pre-treatment bacterial Prevotella-to-Bacteroides (P/B) ratio have been reported to lose more body weight on diets high in fiber than subjects with a low P/B ratio. Therefore, the aim of the present study was to examine potential differences in dietary weight loss responses between participants with low and high P/B., Subjects/methods: Eighty overweight participants were randomized (52 completed) to a 500 kcal/d energy deficit diet with a macronutrient composition of 30 energy percentage (E%) fat, 52 E% carbohydrate and 18 E% protein either high (≈1500 mg calcium/day) or low ( ≤ 600 mg calcium/day) in dairy products for 24 weeks. Body weight, body fat, and dietary intake (by 7-day dietary records) were determined. Individuals were dichotomized according to their pre-treatment P/B ratio derived from 16S rRNA gene sequencing of collected fecal samples to test the potential modification of dietary effects using linear mixed models., Results: Independent of the randomized diets, individuals with high P/B lost 3.8 kg (95%CI, 1.8,5.8; P < 0.001) more body weight and 3.8 kg (95% CI, 1.1, 6.5; P = 0.005) more body fat compared to individuals with low P/B. After adjustment for multiple covariates, individuals with high P/B ratio lost 8.3 kg (95% CI, 5.8;10.9, P < 0.001) more body weight when consuming above compared to below 30 g fiber/10MJ whereas this weight loss was 3.2 kg (95% CI, 0.8;5.5, P = 0.008) among individuals with low P/B ratio [Mean difference: 5.1 kg (95% CI, 1.7;8.6, P = 0.003)]. Partial correlation coefficients between fiber intake and weight change was 0.90 (P < 0.001) among individuals with high P/B ratio and 0.25 (P = 0.29) among individuals with low P/B ratio., Conclusions: Individuals with high P/B lost more body weight and body fat compared to individuals with low P/B, confirming that individuals with a high P/B are more susceptible to weight loss on a diet rich in fiber.

Human gut microbiota consist of numerous microorganisms, but the most abundant species are Bacteroides and Firmicutes. Each human possesses a specific gut microbiota, which can be altered by diet, antibiotics, lifestyle, and genetic background. Gut microbiota perform vital functions, but in this article, we aimed to elaborate the effects of modified composition of microbiota on host metabolism. Ligands for G protein coupled receptors (GPCRs) are short-chain fatty acids (SCFAs) located on endocrine glands, epithelial cells, and adipocytes. SCFAs are produced in the distal gut by bacterial fermentation of nondigestible polysaccharides; they induce the various beneficial effects including decrease serum glucose level, insulin resistance, as well as inflammation; and they increase glucagon-like peptide-1 (GLP-1) secretion. Fasting-induced adipose factor (FIAF) is suppressed by gut microbiota and results in the increased storage of fatty acids in the adipose tissues and liver. An increased lipopolysaccharide level due to altered gut microflora cause the initiation of inflammation associated with type 2 diabetes mellitus (T2DM). Intestinal dysbiosis and metabolic endotoxemia are considered key mechanisms that seem to be associated with the development of T2DM and obesity. Therapeutic interventions that can be used for the treatment of diabetes include metformin, dietary modulation, probiotics, prebiotics, fecal microbiota transplantation and bariatric surgery.

The transcriptional activity of Bradyrhizobium diazoefficens isolated from soybean nodules was monitored over the period from symbiosis to late plant nodule senescence. The bacteria retained a near constant level of RNA throughout this period, and the variation in genes demonstrating increased, decreased, and/or patterned transcriptional activity indicates that the bacteria are responding to the changing environment within the nodule as the plant cells progress from an organized cellular structure to an unorganized state of internal decay. The transcriptional variation and persistence of the bacteria suggest that the bacteria are adapting to their environment and acting similar to hemibiotrophs, which survive both as saprophytes on live plant tissues and then as necrophytes on decaying plant tissues. The host plant restrictions of symbiosis make B . diazoefficiens a highly specialized, restricted hemibiotroph.

The ability to antagonize competing strains and species is often important for bacterial fitness in microbial communities. The extent to which intra-species antagonism drives phenotypic diversity of bacterial species is rarely examined in a comprehensive manner at both the genetic and phenotypic levels. Here we show that for nine abundant human gut Bacteroides species examined, there are only a few LPS glycan genetic types. We show that for a given Bacteroides species, there is a predominant lipopolysaccharide (LPS) glycan locus present in the majority of strains. However, other strains have replacements of glycosyltransferase-encoding genes, in most cases, adjacent to a membrane attack/perforin (MACPF) domain-encoding gene not present in the predominant type. We show that the MACPF genes present in LPS glycan biosynthesis loci of four Bacteroides species encode antimicrobial proteins and in Bacteroides vulgatus and Bacteroides dorei, we show the MACPF toxin targets the LPS of strains with the predominant LPS glycan locus. By a combination of gene deletion and replacement, we converted a MACPF toxin-producing strain into a sensitive strain. Genetic diversity of LPS glycan biosynthesis regions in Bacteroides is similar to phage serotype conversion whereby the receptor is altered to render the strain immune to infection/toxicity, and is a rare example in bacteria of toxin immunity conferred to the toxin-producing strain by replacement of genetic material to modify the receptor rather than by a cognate immunity protein.

Experimental studies of microbial communities routinely reveal that they have multiple stable states. While each of these states is generally resilient, certain perturbations such as antibiotics, probiotics, and diet shifts, result in transitions to other states. Can we reliably both predict such stable states as well as direct and control transitions between them? Here we present a new conceptual model-inspired by the stable marriage problem in game theory and economics-in which microbial communities naturally exhibit multiple stable states, each state with a different species' abundance profile. Our model's core ingredient is that microbes utilize nutrients one at a time while competing with each other. Using only two ranked tables, one with microbes' nutrient preferences and one with their competitive abilities, we can determine all possible stable states as well as predict inter-state transitions, triggered by the removal or addition of a specific nutrient or microbe. Further, using an example of seven Bacteroides species common to the human gut utilizing nine polysaccharides, we predict that mutual complementarity in nutrient preferences enables these species to coexist at high abundances.

The link between antibiotic treatment and IF-associated liver disease (IFALD) is unclear. Here, we study the effect of antibiotic treatment on bile acid (BA) metabolism and investigate the involved mechanisms. The results showed that pediatric IF patients with cholestasis had a significantly lower abundance of BA-biotransforming bacteria than patients without cholestasis. In addition, the BA composition was altered in the serum, feces, and liver of pediatric IF patients with cholestasis, as reflected by the increased proportion of primary BAs. In the ileum, farnesoid X receptor (FXR) expression was reduced in patients with cholestasis. Correspondingly, the serum FGF19 levels decreased significantly in patients with cholestasis. In the liver, the expression of the rate-limiting enzyme in bile salt synthesis, cytochrome P450 7a1 (CYP7A1), increased noticeably in IF patients with cholestasis. In mice, we showed that oral antibiotics (gentamicin, GM or vancomycin, VCM) reduced colonic microbial diversity, with a decrease in both Gram-negative bacteria (GM affected Eubacterium and Bacteroides) and Gram-positive bacteria (VCM affected Clostridium, Bifidobacterium and Lactobacillus). Concomitantly, treatment with GM or VCM decreased secondary BAs in the colonic contents, with a simultaneous increase in primary BAs in plasma. Moreover, the changes in the colonic BA profile especially that of tauro-beta-muricholic acid (TβMCA), were predominantly associated with the inhibition of the FXR and further altered BA synthesis and transport. In conclusion, the administration of antibiotics significantly decreased the intestinal microbiota diversity and subsequently altered the BA composition. The alterations in BA composition contributed to cholestasis in IF patients by regulating FXR signaling.

Background: Links between colorectal cancer (CRC) and the gut microbiome have been established, but the specific microbial species and their role in carcinogenesis remain an active area of inquiry. Our understanding would be enhanced by better accounting for tumor subtype, microbial community interactions, metabolism, and ecology., Methods: We collected paired colon tumor and normal-adjacent tissue and mucosa samples from 83 individuals who underwent partial or total colectomies for CRC. Mismatch repair (MMR) status was determined in each tumor sample and classified as either deficient MMR (dMMR) or proficient MMR (pMMR) tumor subtypes. Samples underwent 16S rRNA gene sequencing and a subset of samples from 50 individuals were submitted for targeted metabolomic analysis to quantify amino acids and short-chain fatty acids. A PERMANOVA was used to identify the biological variables that explained variance within the microbial communities. dMMR and pMMR microbial communities were then analyzed separately using a generalized linear mixed effects model that accounted for MMR status, sample location, intra-subject variability, and read depth. Genome-scale metabolic models were then used to generate microbial interaction networks for dMMR and pMMR microbial communities. We assessed global network properties as well as the metabolic influence of each microbe within the dMMR and pMMR networks., Results: We demonstrate distinct roles for microbes in dMMR and pMMR CRC. Bacteroides fragilis and sulfidogenic Fusobacterium nucleatum were significantly enriched in dMMR CRC, but not pMMR CRC. These findings were further supported by metabolic modeling and metabolomics indicating suppression of B. fragilis in pMMR CRC and increased production of amino acid proxies for hydrogen sulfide in dMMR CRC., Conclusions: Integrating tumor biology and microbial ecology highlighted distinct microbial, metabolic, and ecological properties unique to dMMR and pMMR CRC. This approach could critically improve our ability to define, predict, prevent, and treat colorectal cancers.

Antagonistic interactions are abundant in microbial communities and contribute not only to the composition and relative proportions of their members but also to the longer-term stability of a community. This Review will largely focus on bacterial antagonism mediated by ribosomally synthesized peptides and proteins produced by members of host-associated microbial communities. We discuss recent findings on their diversity, functions, and ecological impacts. These systems play key roles in ecosystem defense, pathogen invasion, spatial segregation, and diversity but also confer indirect gains to the aggressor from products released by killed cells. Investigations into antagonistic bacterial interactions are important for our understanding of how the microbiota establish within hosts, influence health and disease, and offer insights into potential translational applications., (Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

A Gram-negative, anaerobic, non-motile, non-spore-forming bacterial strain, designated YN3PY1 T , was isolated from a chloroethene-dechlorinating consortium originally enriched from river sediment. The strain enhanced the dechlorination of cis-dichloroethene to ethene by Dehalococcoides, especially at the early stages of cultivation. Strain YN3PY1 T was the first isolate of the genus Bacteroides, obtained from animal-independent environments, and its 16S rRNA gene had the highest sequence similarity (97.1%) with Bacteroides luti JCM 19020 T in the 'Coprosuis' clade of the genus Bacteroides. Strain YN3PY1 T formed a phylogenetic cluster with other phylotypes detected from sediments and paddy soil, and the cluster was affiliated with a linage of so-called free-living Bacteroides detected from animal-independent environments, suggesting specific adaptations to sediment-like environments. The strain showed typical phenotypes of Bacteroides, i.e., polysaccharolytic anaerobe having anteiso-C 15:0 as the most abundant fatty acid and MK-11 as one of the major respiratory quinones. Additionally, the strain uniquely transforms glucose to lactate and malate, has MK-12 as another major respiratory quinone, and grows at comparatively low temperatures, i.e. 10-40°C, with an optimum at 28°C. Based on the presented data, strain YN3PY1 T (= KCTC 15656 T = NBRC 113168 T ) can be proposed as a novel species of the genus Bacteroides and named as Bacteroides sedimenti sp. nov.

Interest in manipulating the gut microbiota to treat disease has led to a need for understanding how organisms can establish themselves when introduced into a host with an intact microbial community. Here, we employ the concept of orthogonal niche engineering: a resource typically absent from the diet, seaweed, creates a customized niche for an introduced organism. In the short term, co-introduction of this resource at 1% in the diet along with an organism with exclusive access to this resource, Bacteroides plebeius DSM 17135, enables it to colonize at a median abundance of 1% and frequently up to 10 or more percent, both on pulsed and constant seaweed diets. In a two-month follow-up after the initial treatment period, B. plebeius stops responding to seaweed in mice initially on the constant seaweed diet, suggesting treatment regime will affect controllability. These results offer potential for diet-based intervention to introduce and control target organisms., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

The intestinal microbiota provides colonization resistance against pathogens, limiting pathogen expansion and transmission. These microbiota-mediated mechanisms were previously identified by observing loss of colonization resistance after antibiotic treatment or dietary changes, which severely disrupt microbiota communities. We identify a microbiota-mediated mechanism of colonization resistance against Salmonella enterica serovar Typhimurium (S. Typhimurium) by comparing high-complexity commensal communities with different levels of colonization resistance. Using inbred mouse strains with different infection dynamics and S. Typhimurium intestinal burdens, we demonstrate that Bacteroides species mediate colonization resistance against S. Typhimurium by producing the short-chain fatty acid propionate. Propionate directly inhibits pathogen growth in vitro by disrupting intracellular pH homeostasis, and chemically increasing intestinal propionate levels protects mice from S. Typhimurium. In addition, administering susceptible mice Bacteroides, but not a propionate-production mutant, confers resistance to S. Typhimurium. This work provides mechanistic understanding into the role of individualized microbial communities in host-to-host variability of pathogen transmission., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Immunoglobulin A (IgA) promotes health by regulating the composition and function of gut microbiota, but the molecular requirements for such homeostatic IgA function remain unknown. We found that a heavily glycosylated monoclonal IgA recognizing ovalbumin coats Bacteroides thetaiotaomicron ( B. theta ), a prominent gut symbiont of the phylum Bacteroidetes. In vivo, IgA alters the expression of polysaccharide utilization loci (PUL), including a functionally uncharacterized molecular family provisionally named Mucus-Associated Functional Factor (MAFF). In both mice and humans, MAFF is detected predominantly in mucus-resident bacteria, and its expression requires the presence of complex microbiota. Expression of the MAFF system facilitates symbiosis with other members of the phylum Firmicutes and promotes protection from a chemically induced model of colitis. Our data reveal a novel mechanism by which IgA promotes symbiosis and colonic homeostasis., (© 2018 Nakajima et al.)

It is unknown whether the gut microbiome affects HIV transmission. In our recent SHIV vaccine study, we found that the naive rhesus macaques from two different sources had significantly different rates of infection against repeated low-dose intrarectal challenge with SHIV SF162P4 virus. Exploring causes, we found that the more susceptible group of seven macaques had significantly more activated CD4 + CCR5 + Ki67 + T cells in the rectal mucosa than the more resistant group of 11 macaques from a different source. The prevalence of pre-challenge activated rectal CD4 T cells in the naive macaques correlated inversely with the number of challenges required to infect. Because the two naive groups came from different sources, we hypothesized that their microbiomes may differ and might explain the activation difference. Indeed, after sequencing 16s rRNA, we found differences between the two naive groups that correlated with immune activation status. Distinct gut microbiota induced different levels of immune activation ex vivo. Significantly lower ratios of Bacteroides to Prevotella, and significantly lower levels of Firmicutes were found in the susceptible cohort, which were also inversely correlated with high levels of immune activation in the rectal mucosa. Thus, host-microbiome interactions might influence HIV/SIV mucosal transmission through effects on mucosal immune activation.

The dense microbial ecosystem in the gut is intimately connected to numerous facets of human biology, and manipulation of the gut microbiota has broad implications for human health. In the absence of profound perturbation, the bacterial strains that reside within an individual are mostly stable over time 1 . By contrast, the fate of exogenous commensal and probiotic strains applied to an established microbiota is variable, generally unpredictable and greatly influenced by the background microbiota 2,3 . Therefore, analysis of the factors that govern strain engraftment and abundance is of critical importance to the emerging field of microbiome reprogramming. Here we generate an exclusive metabolic niche in mice via administration of a marine polysaccharide, porphyran, and an exogenous Bacteroides strain harbouring a rare gene cluster for porphyran utilization. Privileged nutrient access enables reliable engraftment of the exogenous strain at predictable abundances in mice harbouring diverse communities of gut microbes. This targeted dietary support is sufficient to overcome priority exclusion by an isogenic strain 4 , and enables strain replacement. We demonstrate transfer of the 60-kb porphyran utilization locus into a naive strain of Bacteroides, and show finely tuned control of strain abundance in the mouse gut across multiple orders of magnitude by varying porphyran dosage. Finally, we show that this system enables the introduction of a new strain into the colonic crypt ecosystem. These data highlight the influence of nutrient availability in shaping microbiota membership, expand the ability to perform a broad spectrum of investigations in the context of a complex microbiota, and have implications for cell-based therapeutic strategies in the gut.

Background/objectives: The gut microbiota is determined early in life, possibly including pregnancy. Pioneering data suggest vitamin D, a nutrient important for bone health, affects this microbiota. We found that high maternal vitamin D lowered circulating lipopolysaccharide (LPS), improved intestinal barrier and bone health in male but not female offspring in an obesogenic environment. This study determined if high maternal dietary vitamin D programs Bacteroides and Prevotella and whether this associates with bone mineral content, density and structure of male and female adult offspring fed an obesogenic diet., Methods: C57BL/6J females received an AIN93G diet with high or low vitamin D from before mating until weaning. Post-weaning, male and female offspring remained on their respective vitamin D level or were switched and fed a high fat and sucrose diet until killing (age 7 months). Bacteroides and Prevotella were quantified in dams' feces and offspring colonic contents. LPS concentrations, bone mineral density and content, strength and structure data were integrated from our previous studies in the same mice. Spearman correlations were completed between Bacteroides and LPS, and bone outcomes., Results: There was a maternal vitamin D effect on colonic Bacteroides but not Prevotella (dam diet: <0.001 and 0.735) in adult male offspring, independent of dams fecal Bacteroides before birth (P=0.998). In males, but not females, Bacteroides correlated with LPS (r=-0.488, P=0.018), trabecular femur peak load (r=0.362, P=0.033), vertebral trabecular separation (r=-0.605, P=0.006), trabecular number (r=0.614, P=0.005) and bone volume fraction (r=0.549, P=0.015)., Conclusions: Dietary vitamin D programs Bacteroides in male adult offspring only, which correlated negatively with systemic inflammation and positively with bone strength and structure. This may have implications on maternal diet and nutritional guidelines targeting sexes in a different manner.

Objectives: Perturbation of the choriodecidual space before the onset of spontaneous preterm birth (sPTB) could lead to a concomitant rise in both cervicovaginal fluid (CVF) cytokine and fetal fibronectin (FFN), and assessing the concentrations of both markers could improve the prediction of sPTB (delivery before 37 completed weeks of gestation). Therefore, we prospectively determined mid-trimester changes in CVF cytokine and FFN concentrations, and their predictive capacity for sPTB in asymptomatic pregnant women., Study Design: CVF collected at 20 +0 -22 +6 weeks (n = 47: Preterm-delivered = 22, Term-delivered = 25) and 26 +0 -28 +6 weeks (n = 50: Preterm-delivered = 17, Term-delivered = 33) from 63 asymptomatic pregnant women at risk of sPTB were examined. Cytokine and FFN concentrations were determined by multiplexed bead-based immunoassay and 10Q Rapid analysis (Hologic, MA, USA) respectively. The 20 +0 -22 +6 /26 +0 -28 +6 weeks ratios of cytokines and FFN concentrations were compared between preterm- and term-delivered women using Receiver Operating Characteristics curves to predict sPTB. Also, bacterial 16S rDNA from 64 samples (20 +0 -22 +6 weeks n = 36, 26 +0 -28 +6 weeks n = 28) was amplified by polymerase chain reaction to determine associations between vaginal microflora, cytokine and FFN concentrations., Results: Changes in RANTES and IL-1β concentrations between 20 +0 -22 +6 and 26 +0 -28 +6 weeks, expressed as a ratios, were predictive of sPTB, RANTES (AUC = 0.82, CI = 0.62-0.94) more so than IL-1β (AUC = 0.71, CI = 0.53-0.85) and FFN (not predictive). Combining these markers (AUC = 0.83, CI = 0.63-0.95) showed similar predictive capacity as RANTES alone. FFN concentrations at 26 +0 -28 +6 weeks correlated with IL-1β (r = 0.4, P = 0.002) and RANTES (r = 0.3, P = 0.03). In addition, there was increased prevalence of vaginal anaerobes including Bacteroides, Fusobacterium and Mobiluncus between gestational time points in women who experienced sPTB compared to the term women (P = 0.0006)., Conclusions: CVF RANTES and IL-1β in mid-trimester of pregnancy correlate with quantitative FFN. The levels of CVF RANTES and IL-1β decline significantly in women who deliver at term unlike women who deliver preterm. This observation suggests that sPTB may be characterised by sustained choriodecidual inflammation and may have clinical value in serial screening for sPTB if confirmed by larger studies., (Crown Copyright © 2018. Published by Elsevier B.V. All rights reserved.)