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1.  Can prebiotics and probiotics improve therapeutic outcomes for undernourished individuals? 
Gut Microbes  2013;5(1):74-82.
It has become clear in recent years that the human intestinal microbiota plays an important role in maintaining health and thus is an attractive target for clinical interventions. Scientists and clinicians have become increasingly interested in assessing the ability of probiotics and prebiotics to enhance the nutritional status of malnourished children, pregnant women, the elderly, and individuals with non-communicable disease-associated malnutrition. A workshop was held by the International Scientific Association for Probiotics and Prebiotics (ISAPP), drawing on the knowledge of experts from industry, medicine, and academia, with the objective to assess the status of our understanding of the link between the microbiome and under-nutrition, specifically in relation to probiotic and prebiotic treatments for under-nourished individuals. These discussions led to four recommendations:
 
(1) The categories of malnourished individuals need to be differentiated
To improve treatment outcomes, subjects should first be categorized based on the cause of malnutrition, additional health-concerns, differences in the gut microbiota, and sociological considerations.
(2) Define a baseline “healthy” gut microbiota for each category
Altered nutrient requirement (for example, in pregnancy and old age) and individual variation may change what constitutes a healthy gut microbiota for the individual.
(3) Perform studies using model systems to test the effectiveness of potential probiotics and prebiotics against these specific categories
These should illustrate how certain microbiota profiles can be altered, as members of different categories may respond differently to the same treatment.
(4) Perform robust well-designed human studies with probiotics and/or prebiotics, with appropriate, defined primary outcomes and sample size
These are critical to show efficacy and understand responder and non-responder outcomes. It is hoped that these recommendations will lead to new approaches that combat malnutrition.
This report is the result of discussion during an expert workshop titled “How do the microbiota and probiotics and/or prebiotics influence poor nutritional status?” held during the 10th Meeting of the International Scientific Association for Probiotics and Prebiotics (ISAPP) in Cork, Ireland from October 1–3, 2012. The complete list of workshop attendees is shown in Table 1.
doi:10.4161/gmic.27252
PMCID: PMC4049942  PMID: 24637591
prebiotics; probiotics; microbiota; malnutrition; undernutrition; ISAPP
2.  Inclusion of Fermented Foods in Food Guides around the World 
Nutrients  2015;7(1):390-404.
Fermented foods have been a well-established part of the human diet for thousands of years, without much of an appreciation for, or an understanding of, their underlying microbial functionality, until recently. The use of many organisms derived from these foods, and their applications in probiotics, have further illustrated their impact on gastrointestinal wellbeing and diseases affecting other sites in the body. However, despite the many benefits of fermented foods, their recommended consumption has not been widely translated to global inclusion in food guides. Here, we present the case for such inclusion, and challenge health authorities around the world to consider advocating for the many benefits of these foods.
doi:10.3390/nu7010390
PMCID: PMC4303846  PMID: 25580813
food guides; world; fermented foods; fermentation; benefits; probiotics
3.  Probiotics, prebiotics, and the host microbiome: the science of translation 
Recent advances in our understanding of the community structure and function of the human microbiome have implications for the potential role of probiotics and prebiotics in promoting human health. A group of experts recently met to review the latest advances in microbiota/microbiome research and discuss the implications for development of probiotics and prebiotics, primarily as they relate to effects mediated via the intestine. The goals of the meeting were to share recent advances in research on the microbiota, microbiome, probiotics, and prebiotics, and to discuss these findings in the contexts of regulatory barriers, evolving healthcare environments, and potential effects on a variety of health topics, including the development of obesity and diabetes; the long term consequences of exposure to antibiotics early in life to the gastrointestinal (GI) microbiota; lactose intolerance; and the relationship between the GI microbiota and the central nervous system, with implications for depression, cognition, satiety, and mental health for people living in developed and developing countries. This report provides an overview of these discussions.
doi:10.1111/nyas.12303
PMCID: PMC4013291  PMID: 24266656
microbiome; probiotics; prebiotics; intestinal microbiota; health disorders
4.  Randomized Open-Label Pilot Study of the Influence of Probiotics and the Gut Microbiome on Toxic Metal Levels in Tanzanian Pregnant Women and School Children 
mBio  2014;5(5):e01580-14.
ABSTRACT
Exposure to environmental toxins is a 21st century global health problem that is often the result of dietary intake. Although efforts are made to reduce dietary toxin levels, they are often unsuccessful, warranting research into novel methods to reduce host exposure. Food-grade microbes that can be delivered to the gastrointestinal tract and that are capable of sequestering toxins present a safe and cost-effective intervention. We sought to investigate the potential for probiotic-supplemented yogurt to lower heavy metal levels in at-risk populations of pregnant women and in children in Mwanza, Tanzania, and to examine the microbiome in relation to toxin levels. Two populations suspected to have high toxic metal exposures were studied. A group of 44 school-aged children was followed over 25 days, and 60 pregnant women were followed over their last two trimesters until birth. A yogurt containing 1010 CFU Lactobacillus rhamnosus GR-1 per 250 g was administered, while control groups received either whole milk or no intervention. Changes in blood metal levels were assessed, and the gut microbiomes of the children were profiled by analyzing 16S rRNA sequencing via the Ion Torrent platform. The children and pregnant women in the study were found to have elevated blood levels of lead and mercury compared to age- and sex-matched Canadians. Consumption of probiotic yogurt had a protective effect against further increases in mercury (3.2 nmol/liter; P = 0.035) and arsenic (2.3 nmol/liter; P = 0.011) blood levels in the pregnant women, but this trend was not statistically significant in the children. Elevated blood lead was associated with increases in Succinivibrionaceae and Gammaproteobacteria relative abundance levels in stool.
IMPORTANCE
Probiotic food produced locally represents a nutritious and affordable means for people in some developing countries to counter exposures to toxic metals. Further research and field trials are warranted to explore this approach in countries where communities are located near mining sites and agricultural areas, two types of areas where toxins are likely to be elevated.
doi:10.1128/mBio.01580-14
PMCID: PMC4196227  PMID: 25293764
5.  Selective Target Inactivation Rather than Global Metabolic Dormancy Causes Antibiotic Tolerance in Uropathogens 
Persister cells represent a multidrug-tolerant (MDT), physiologically distinct subpopulation of bacteria. The ability of these organisms to survive lethal antibiotic doses raises concern over their potential role in chronic disease, such as recurrent urinary tract infection (RUTI). Persistence is believed to be conveyed through global metabolic dormancy, which yields organisms unresponsive to external stimuli. However, recent studies have contested this stance. Here, various antibiotics that target different cellular processes were used to dissect the activity of transcription, translation, and peptidoglycan turnover in persister cells. Differential susceptibility patterns were found in type I and type II persisters, and responses differed between Staphylococcus saprophyticus and Escherichia coli uropathogens. Further, SOS-deficient strains were sensitized to ciprofloxacin, suggesting DNA gyrase activity in persisters and indicating the importance of active DNA repair systems for ciprofloxacin tolerance. These results indicate that global dormancy per se cannot sufficiently account for antibiotic tolerance. Rather, the activity of individual cellular processes dictates multidrug tolerance in an antibiotic-specific fashion. Furthermore, the susceptibility patterns of persisters depended on their mechanisms of onset, with subinhibitory antibiotic pretreatments selectively shutting down cognate targets and increasing the persister fraction against the same agent. Interestingly, antibiotics targeting transcription and translation enhanced persistence against multiple agents indirectly related to these processes. Conducting these assays with uropathogenic E. coli isolated from RUTI patients revealed an enriched persister fraction compared to organisms cleared with standard antibiotic therapy. This finding suggests that persister traits are either selected for during prolonged antibiotic treatment or initially contribute to therapy failure.
doi:10.1128/AAC.02552-13
PMCID: PMC4023725  PMID: 24449771
6.  A Systems Biology Approach Investigating the Effect of Probiotics on the Vaginal Microbiome and Host Responses in a Double Blind, Placebo-Controlled Clinical Trial of Post-Menopausal Women 
PLoS ONE  2014;9(8):e104511.
A lactobacilli dominated microbiota in most pre and post-menopausal women is an indicator of vaginal health. The objective of this double blinded, placebo-controlled crossover study was to evaluate in 14 post-menopausal women with an intermediate Nugent score, the effect of 3 days of vaginal administration of probiotic L. rhamnosus GR-1 and L. reuteri RC-14 (2.5×109 CFU each) on the microbiota and host response. The probiotic treatment did not result in an improved Nugent score when compared to when placebo. Analysis using 16S rRNA sequencing and metabolomics profiling revealed that the relative abundance of Lactobacillus was increased following probiotic administration as compared to placebo, which was weakly associated with an increase in lactate levels. A decrease in Atopobium was also observed. Analysis of host responses by microarray showed the probiotics had an immune-modulatory response including effects on pattern recognition receptors such as TLR2 while also affecting epithelial barrier function. This is the first study to use an interactomic approach for the study of vaginal probiotic administration in post-menopausal women. It shows that in some cases multifaceted approaches are required to detect the subtle molecular changes induced by the host to instillation of probiotic strains.
Trial Registration
ClinicalTrials.gov NCT02139839
doi:10.1371/journal.pone.0104511
PMCID: PMC4134203  PMID: 25127240
7.  Effect of chemotherapy on the microbiota and metabolome of human milk, a case report 
Microbiome  2014;2:24.
Background
Human milk is an important source of bacteria for the developing infant and has been shown to influence the bacterial composition of the neonatal gut, which in turn can affect disease risk later in life. Human milk is also an important source of nutrients, influencing bacterial composition but also directly affecting the host. While recent studies have emphasized the adverse effects of antibiotic therapy on the infant microbiota, the effects of maternal chemotherapy have not been previously studied. Here we report the effects of drug administration on the microbiota and metabolome of human milk.
Methods
Mature milk was collected every two weeks over a four month period from a lactating woman undergoing chemotherapy for Hodgkin’s lymphoma. Mature milk was also collected from healthy lactating women for comparison. Microbial profiles were analyzed by 16S sequencing and the metabolome by gas chromatography–mass spectrometry.
Findings
Chemotherapy caused a significant deviation from a healthy microbial and metabolomic profile, with depletion of genera Bifidobacterium, Eubacterium, Staphylococcus and Cloacibacterium in favor of Acinetobacter, Xanthomonadaceae and Stenotrophomonas. The metabolites docosahexaenoic acid and inositol known for their beneficial effects were also decreased.
Conclusion
With milk contents being critical for shaping infant immunity and development, consideration needs to be given to the impact of drugs administered to the mother and the long-term potential consequences for the health of the infant.
doi:10.1186/2049-2618-2-24
PMCID: PMC4109383  PMID: 25061513
16S rRNA gene sequencing; Human milk microbiome; Metabolome
8.  Characterization of the vaginal microbiota of healthy Canadian women through the menstrual cycle 
Microbiome  2014;2:23.
Background
The vaginal microbial community plays a vital role in maintaining women’s health. Understanding the precise bacterial composition is challenging because of the diverse and difficult-to-culture nature of many bacterial constituents, necessitating culture-independent methodology. During a natural menstrual cycle, physiological changes could have an impact on bacterial growth, colonization, and community structure. The objective of this study was to assess the stability of the vaginal microbiome of healthy Canadian women throughout a menstrual cycle by using cpn60-based microbiota analysis. Vaginal swabs from 27 naturally cycling reproductive-age women were collected weekly through a single menstrual cycle. Polymerase chain reaction (PCR) was performed to amplify the universal target region of the cpn60 gene and generate amplicons representative of the microbial community. Amplicons were pyrosequenced, assembled into operational taxonomic units, and analyzed. Samples were also assayed for total 16S rRNA gene content and Gardnerella vaginalis by quantitative PCR and screened for the presence of Mollicutes by using family and genus-specific PCR.
Results
Overall, the vaginal microbiome of most women remained relatively stable throughout the menstrual cycle, with little variation in diversity and only modest fluctuations in species richness. Microbiomes between women were more different than were those collected consecutively from individual women. Clustering of microbial profiles revealed the expected groupings dominated by Lactobacillus crispatus, Lactobacillus iners, and Lactobacillus jensenii. Interestingly, two additional clusters were dominated by either Bifidobacterium breve or a heterogeneous mixture of nonlactobacilli. Direct G. vaginalis quantification correlated strongly with its pyrosequencing-read abundance, and Mollicutes, including Mycoplasma hominis, Ureaplasma parvum, and Ureaplasma urealyticum, were detected in most samples.
Conclusions
Our cpn60-based investigation of the vaginal microbiome demonstrated that in healthy women most vaginal microbiomes remained stable through their menstrual cycle. Of interest in these findings was the presence of Bifidobacteriales beyond just Gardnerella species. Bifidobacteriales are frequently underrepresented in 16S rRNA gene-based studies, and their detection by cpn60-based investigation suggests that their significance in the vaginal community may be underappreciated.
doi:10.1186/2049-2618-2-23
PMCID: PMC4106219  PMID: 25053998
Vaginal microbiome; cpn60; Menstrual cycle; Bifidobacteriales; Bifidobacterium; Lactobacillus; Mollicutes; Mycoplasma; Ureaplasma; Gardnerella; Vaginal bacteria
9.  Microbiota of Human Breast Tissue 
Applied and Environmental Microbiology  2014;80(10):3007-3014.
In recent years, a greater appreciation for the microbes inhabiting human body sites has emerged. In the female mammary gland, milk has been shown to contain bacterial species, ostensibly reaching the ducts from the skin. We decided to investigate whether there is a microbiome within the mammary tissue. Using 16S rRNA sequencing and culture, we analyzed breast tissue from 81 women with and without cancer in Canada and Ireland. A diverse population of bacteria was detected within tissue collected from sites all around the breast in women aged 18 to 90, not all of whom had a history of lactation. The principal phylum was Proteobacteria. The most abundant taxa in the Canadian samples were Bacillus (11.4%), Acinetobacter (10.0%), Enterobacteriaceae (8.3%), Pseudomonas (6.5%), Staphylococcus (6.5%), Propionibacterium (5.8%), Comamonadaceae (5.7%), Gammaproteobacteria (5.0%), and Prevotella (5.0%). In the Irish samples the most abundant taxa were Enterobacteriaceae (30.8%), Staphylococcus (12.7%), Listeria welshimeri (12.1%), Propionibacterium (10.1%), and Pseudomonas (5.3%). None of the subjects had signs or symptoms of infection, but the presence of viable bacteria was confirmed in some samples by culture. The extent to which these organisms play a role in health or disease remains to be determined.
doi:10.1128/AEM.00242-14
PMCID: PMC4018903  PMID: 24610844
10.  Harnessing microbiome and probiotic research in sub-Saharan Africa: recommendations from an African workshop 
Microbiome  2014;2:12.
To augment capacity-building for microbiome and probiotic research in Africa, a workshop was held in Nairobi, Kenya, at which researchers discussed human, animal, insect, and agricultural microbiome and probiotics/prebiotics topics. Five recommendations were made to promote future basic and translational research that benefits Africans.
doi:10.1186/2049-2618-2-12
PMCID: PMC3996947  PMID: 24739094
11.  Exploring a Road Map to Counter Misconceptions About the Cervicovaginal Microbiome and Disease 
Reproductive Sciences  2012;19(11):1154-1162.
Urogenital diseases, especially infection and cancer, are major causes of death and morbidity in females. Yet, millions of women in the developing world have no access to basic urogynecological care, and the diagnosis and treatment of widespread aberrant bacterial conditions (bacterial vaginosis [BV] and aerobic vaginitis [AV]) remain suboptimal the world over. Samples from women living in resource-disadvantaged and developed countries have been analyzed by high-throughput sequencing to reveal the diversity of bacteria in the vagina, how rapidly the bacterial population fluctuates over time, and how rapidly the switch occurs between healthy and aberrant conditions. Unfortunately, clinical diagnostic methods are inefficient and too often outdated therapies are administered. The net result is suboptimal care and recurrent disease that adversely affects the quality of life. This viewpoint outlines a scientific and translational road map designed to improve the cervicovaginal health and treatment of disease. This comprises (1) improving education of women and physicians on the vaginal microbiota; (2) having agencies target funding for research to improve diagnosis and test new therapies; and (3) making sure that new approaches are accessible in developing countries, empowering to women, and are acceptable and appropriate for different populations.
doi:10.1177/1933719112446075
PMCID: PMC4051403  PMID: 22614624
cervicovagina; bacteria; vaginosis; diagnosis; gardnerella; lactobacillus; Nugent; Amsel; microbiome
12.  Influence of the Vaginal Microbiota on Toxic Shock Syndrome Toxin 1 Production by Staphylococcus aureus 
Menstrual toxic shock syndrome (TSS) is a serious illness that afflicts women of premenopausal age worldwide and arises from vaginal infection by Staphylococcus aureus and concurrent production of toxic shock syndrome toxin-1 (TSST-1). Studies have illustrated the capacity of lactobacilli to reduce S. aureus virulence, including the capacity to suppress TSST-1. We hypothesized that an aberrant microbiota characteristic of pathogenic bacteria would induce the increased production of TSST-1 and that this might represent a risk factor for the development of TSS. A S. aureus TSST-1 reporter strain was grown in the presence of vaginal swab contents collected from women with a clinically healthy vaginal status, women with an intermediate status, and those diagnosed with bacterial vaginosis (BV). Bacterial supernatant challenge assays were also performed to test the effects of aerobic vaginitis (AV)-associated pathogens toward TSST-1 production. While clinical samples from healthy and BV women suppressed toxin production, in vitro studies demonstrated that Streptococcus agalactiae and Enterococcus spp. significantly induced TSST-1 production, while some Lactobacillus spp. suppressed it. The findings suggest that women colonized by S. aureus and with AV, but not BV, may be more susceptible to menstrual TSS and would most benefit from prophylactic treatment.
doi:10.1128/AEM.02908-12
PMCID: PMC3592239  PMID: 23315732
13.  ANOVA-Like Differential Expression (ALDEx) Analysis for Mixed Population RNA-Seq 
PLoS ONE  2013;8(7):e67019.
Experimental variance is a major challenge when dealing with high-throughput sequencing data. This variance has several sources: sampling replication, technical replication, variability within biological conditions, and variability between biological conditions. The high per-sample cost of RNA-Seq often precludes the large number of experiments needed to partition observed variance into these categories as per standard ANOVA models. We show that the partitioning of within-condition to between-condition variation cannot reasonably be ignored, whether in single-organism RNA-Seq or in Meta-RNA-Seq experiments, and further find that commonly-used RNA-Seq analysis tools, as described in the literature, do not enforce the constraint that the sum of relative expression levels must be one, and thus report expression levels that are systematically distorted. These two factors lead to misleading inferences if not properly accommodated. As it is usually only the biological between-condition and within-condition differences that are of interest, we developed ALDEx, an ANOVA-like differential expression procedure, to identify genes with greater between- to within-condition differences. We show that the presence of differential expression and the magnitude of these comparative differences can be reasonably estimated with even very small sample sizes.
doi:10.1371/journal.pone.0067019
PMCID: PMC3699591  PMID: 23843979
14.  A Canadian Working Group report on fecal microbial therapy: Microbial ecosystems therapeutics 
A working group from across Canada comprised of clinician and basic scientists, epidemiologists, ethicists, Health Canada regulatory authorities and representatives of major funding agencies (Canadian Institutes of Health Research and the Crohn’s and Colitis Foundation of Canada) met to review the current experience with fecal microbial therapy and to identify the key areas of study required to move this field forward. The report highlights the promise of fecal microbial therapy and related synthetic stool therapy (together called ‘microbial ecosystems therapeutics’) for the treatment of Clostridium difficile colitis and, possibly, other disorders. It identifies pressing clinical issues that need to be addressed as well as social, ethical and regulatory barriers to the use of these important therapies.
PMCID: PMC3395448  PMID: 22803022
Clostridium difficile; Fecal microbial therapy; Microbiome
15.  Persistence of the Oral Probiotic Streptococcus salivarius M18 Is Dose Dependent and Megaplasmid Transfer Can Augment Their Bacteriocin Production and Adhesion Characteristics 
PLoS ONE  2013;8(6):e65991.
Bacteriocin-producing probiotic Streptococcus salivarius M18 offers beneficial modulatory capabilities within the oral microbiome, apparently through potent inhibitory activity against potentially deleterious bacteria, such as Streptococcus pyogenes. The oral cavity persistence of S. salivarius M18 was investigated in 75 subjects receiving four different doses for 28 days. Sixty per cent of the subjects already had some inhibitor-producing S. salivarius in their saliva prior to probiotic intervention. Strain M18’s persistence was dependent upon the dose, but not the period of administration. Culture analysis indicated that in some individuals the introduced strain had almost entirely replaced the indigenous S. salivarius, though the total numbers of the species did not increase. Selected subjects showing either high or low probiotic persistence had their salivary populations profiled using Illumina sequencing of the V6 region of the 16S rRNA gene. Analysis indicated that while certain bacterial phenotypes were markedly modulated, the overall composition of the oral microbiome was not modified by the probiotic treatment. Megaplasmids encoding bacteriocins and adhesion factors were transferred in vitro to generate a transconjugant S. salivarius exhibiting enhanced antimicrobial production and binding capabilities to HEp-2 cells. Since no widespread perturbation of the existing indigenous microbiota was associated with oral instillation and given its antimicrobial activity against potentially pathogenic streptococci, it appears that application of probiotic strain M18 offers potential low impact alternative to classical antibiotic prophylaxis. For candidate probiotic strains having relatively poor antimicrobial or adhesive properties, unique derivatives displaying improved probiotic performance may be engineered in vitro by megaplasmid transfer.
doi:10.1371/journal.pone.0065991
PMCID: PMC3681767  PMID: 23785463
16.  Comparative meta-RNA-seq of the vaginal microbiota and differential expression by Lactobacillus iners in health and dysbiosis 
Microbiome  2013;1:12.
Background
Bacterial vaginosis (BV), the most common vaginal condition of reproductive-aged women, is associated with a highly diverse and heterogeneous microbiota. Here we present a proof-of-principle analysis to uncover the function of the microbiota using meta-RNA-seq to uncover genes and pathways that potentially differentiate healthy vaginal microbial communities from those in the dysbiotic state of bacterial vaginosis (BV).
Results
The predominant organism, Lactobacillus iners, was present in both conditions and showed a differing expression profile in BV compared to healthy. Despite its minimal genome, L. iners differentially expressed over 10% of its gene complement. Notably, in a BV environment L. iners increased expression of a cholesterol-dependent cytolysin, and of mucin and glycerol transport and related metabolic enzymes. Genes belonging to a CRISPR system were greatly upregulated suggesting that bacteriophage influence the community. Reflective of L. iners, the bacterial community as a whole demonstrated a preference for glycogen and glycerol as carbon sources under BV conditions. The predicted end-products of metabolism under BV conditions include an abundance of succinate and other short-chain fatty-acids, while healthy conditions are predicted to largely contain lactic acid.
Conclusions
Our study underscores the importance of understanding the functional activity of the bacterial community in addition to characterizing the population structure when investigating the human microbiome.
doi:10.1186/2049-2618-1-12
PMCID: PMC3971606  PMID: 24450540
Bacterial vaginosis; Vaginal microbiome; Meta-transcriptomics; High-throughput sequencing; RNAseq
17.  Genome Sequence of Lactobacillus pentosus KCA1: Vaginal Isolate from a Healthy Premenopausal Woman 
PLoS ONE  2013;8(3):e59239.
The vaginal microbiota, in particular Lactobacillus species, play an important role in female health through modulation of immunity, countering pathogens and maintaining a pH below 4.7. We report the isolation and genome sequence of Lactobacillus pentosus strain KCA1 (formally known as L. plantarum) from the vagina of a healthy Nigerian woman. The genome was sequenced using Illumina GA II technology. The resulting 16,920,226 paired-end reads were assembled with the Velvet tool. Contigs were annotated using the RAST server, and manually curated. A comparative analysis with the available genomes of L. pentosus IG1 and L. plantarum WCFS1 showed that over 15% of the predicted functional activities are found only in this strain. The strain has a chromosome sequence of 3,418,159 bp with a G+C content of 46.4%, and is devoid of plasmids. Novel gene clusters or variants of known genes relative to the reference genomes were found. In particular, the strain has loci encoding additional putative mannose phosphotransferase systems. Clusters of genes include those for utilization of hydantoin, isopropylmalate, malonate, rhamnosides, and genes for assimilation of polyglycans, suggesting the metabolic versatility of L. pentosus KCA1. Loci encoding putative phage defense systems were also found including clustered regularly interspaced short palindromic repeats (CRISPRs), abortive infection (Abi) systems and toxin-antitoxin systems (TA). A putative cluster of genes for biosynthesis of a cyclic bacteriocin precursor, here designated as pentocin KCA1 (penA) were identified. These findings add crucial information for understanding the genomic and geographic diversity of vaginal lactobacilli.
doi:10.1371/journal.pone.0059239
PMCID: PMC3602190  PMID: 23527145
18.  Bioremediation and Tolerance of Humans to Heavy Metals through Microbial Processes: a Potential Role for Probiotics? 
Applied and Environmental Microbiology  2012;78(18):6397-6404.
The food and water we consume are often contaminated with a range of chemicals and heavy metals, such as lead, cadmium, arsenic, chromium, and mercury, that are associated with numerous diseases. Although heavy-metal exposure and contamination are not a recent phenomenon, the concentration of metals and the exposure to populations remain major issues despite efforts at remediation. The ability to prevent and manage this problem is still a subject of much debate, with many technologies ineffective and others too expensive for practical large-scale use, especially for developing nations where major pollution occurs. This has led researchers to seek alternative solutions for decontaminating environmental sites and humans themselves. A number of environmental microorganisms have long been known for their ability to bind metals, but less well appreciated are human gastrointestinal bacteria. Species such as Lactobacillus, present in the human mouth, gut, and vagina and in fermented foods, have the ability to bind and detoxify some of these substances. This review examines the current understanding of detoxication mechanisms of lactobacilli and how, in the future, humans and animals might benefit from these organisms in remediating environmental contamination of food.
doi:10.1128/AEM.01665-12
PMCID: PMC3426676  PMID: 22798364
19.  Effect of Streptococcus salivarius K12 on the In Vitro Growth of Candida albicans and Its Protective Effect in an Oral Candidiasis Model 
Oral candidiasis is often accompanied by severe inflammation, resulting in a decline in the quality of life of immunosuppressed individuals and elderly people. To develop a new oral therapeutic option for candidiasis, a nonpathogenic commensal oral probiotic microorganism, Streptococcus salivarius K12, was evaluated for its ability to modulate Candida albicans growth in vitro, and its therapeutic activity in an experimental oral candidiasis model was tested. In vitro inhibition of mycelial growth of C. albicans was determined by plate assay and fluorescence microscopy. Addition of S. salivarius K12 to modified RPMI 1640 culture medium inhibited the adherence of C. albicans to the plastic petri dish in a dose-dependent manner. Preculture of S. salivarius K12 potentiated its inhibitory activity for adherence of C. albicans. Interestingly, S. salivarius K12 was not directly fungicidal but appeared to inhibit Candida adhesion to the substratum by preferentially binding to hyphae rather than yeast. To determine the potentially anti-infective attributes of S. salivarius K12 in oral candidiasis, the probiotic was administered to mice with orally induced candidiasis. Oral treatment with S. salivarius K12 significantly protected the mice from severe candidiasis. These findings suggest that S. salivarius K12 may inhibit the process of invasion of C. albicans into mucous surfaces or its adhesion to denture acrylic resins by mechanisms not associated with the antimicrobial activity of the bacteriocin. S. salivarius K12 may be useful as a probiotic as a protective tool for oral care, especially with regard to candidiasis.
doi:10.1128/AEM.07055-11
PMCID: PMC3302625  PMID: 22267663
20.  The microbes are coming 
doi:10.1503/cmaj.110126
PMCID: PMC3153528  PMID: 21670116
21.  Probiotic Interference of Lactobacillus rhamnosus GR-1 and Lactobacillus reuteri RC-14 with the Opportunistic Fungal Pathogen Candida albicans 
Candida albicans is the most important Candida species causing vulvovaginal candidiasis (VVC). VVC has significant medical and economical impact on women's health and wellbeing. While current antifungal treatment is reasonably effective, supportive and preventive measures such as application of probiotics are required to reduce the incidence of VVC. We investigated the potential of the probiotics Lactobacillus rhamnosus GR-1 and Lactobacillus reuteri RC-14 towards control of C. albicans. In vitro experiments demonstrated that lactic acid at low pH plays a major role in suppressing fungal growth. Viability staining following cocultures with lactobacilli revealed that C. albicans cells lost metabolic activity and eventually were killed. Transcriptome analyses showed increased expression of stress-related genes and lower expression of genes involved in fluconazole resistance, which might explain the increased eradication of Candida in a previous clinical study on conjoint probiotic therapy. Our results provide insights on the impact of probiotics on C. albicans survival.
doi:10.1155/2012/636474
PMCID: PMC3395238  PMID: 22811591
22.  HPV Type Distribution and Cervical Cytology among HIV-Positive Tanzanian and South African Women 
ISRN Obstetrics and Gynecology  2012;2012:514146.
Background. There are limited data on high-risk human papillomavirus (hr-HPV) genotypes among HIV-positive women in Africa, and little is known about their relationship with cervical cytology in these populations. Methods. We conducted a cross-sectional study among 194 HIV-positive women (143 from Tanzania, and 51 from South Africa) to evaluate HPV genotypes among HIV-positive women with normal and abnormal cytology. Cervical samples were genotyped for HPV types, and slides were evaluated for atypical squamous cell changes according to the Bethesda classification system. Results. Prevalence of high grade squamous intraepithelial dysplasia (HSIL) was 9%. Overall, more than half (56%) of women were infected with an hr-HPV type; 94% of women with HSIL (n = 16), 90% of women with LSIL (n = 35), and 42% of women within normal limits (WNL) (n = 58) tested positive for hr-HPV. Overall, the most prevalent hr-HPV subtypes were HPV16 (26%) and HPV52 (30%). Regional differences in the prevalence of HPV18 and HPV35 were found. Conclusion. Regional differences in HPV genotypes among African women warrant the need to consider different monitoring programmes for cervical preneoplasia. HPV-based screening tests for cervical preneoplasia would be highly inefficient unless coupled with cytology screening of the HPV-positive sample, especially in HIV-positive women.
doi:10.5402/2012/514146
PMCID: PMC3394385  PMID: 22811925
23.  Adhesion Forces and Coaggregation between Vaginal Staphylococci and Lactobacilli 
PLoS ONE  2012;7(5):e36917.
Urogenital infections are the most common ailments afflicting women. They are treated with dated antimicrobials whose efficacy is diminishing. The process of infection involves pathogen adhesion and displacement of indigenous Lactobacillus crispatus and Lactobacillus jensenii. An alternative therapeutic approach to antimicrobial therapy is to reestablish lactobacilli in this microbiome through probiotic administration. We hypothesized that lactobacilli displaying strong adhesion forces with pathogens would facilitate coaggregation between the two strains, ultimately explaining the elimination of pathogens seen in vivo. Using atomic force microscopy, we found that adhesion forces between lactobacilli and three virulent toxic shock syndrome toxin 1-producing Staphylococcus aureus strains, were significantly stronger (2.2–6.4 nN) than between staphylococcal pairs (2.2–3.4 nN), especially for the probiotic Lactobacillus reuteri RC-14 (4.0–6.4 nN) after 120 s of bond-strengthening. Moreover, stronger adhesion forces resulted in significantly larger coaggregates. Adhesion between the bacteria occurred instantly upon contact and matured within one to two minutes, demonstrating the potential for rapid anti-pathogen effects using a probiotic. Coaggregation is one of the recognized mechanisms through which lactobacilli can exert their probiotic effects to create a hostile micro-environment around a pathogen. With antimicrobial options fading, it therewith becomes increasingly important to identify lactobacilli that bind strongly with pathogens.
doi:10.1371/journal.pone.0036917
PMCID: PMC3356358  PMID: 22629342
24.  Perceptions about Probiotic Yogurt for Health and Nutrition in the Context of HIV/AIDS in Mwanza, Tanzania 
Recently, the food and malnutrition issues have taken centre stage within the arena of HIV/AIDS epidemic, with several calls being made for context-specific health and nutrition interventions to deal with the emerging food insecurity and malnutrition issues in settings with high burdens of HIV/AIDS. The use of probiotics as nutritional supplements in HIV/AIDS-affected and resource-poor settings has also been advocated. This paper presents the results of a qualitative study on community knowledge and perceptions about probiotics and their potential impact on people's everyday life in the context of the HIV/AIDS epidemic. In-depth interviews (n=26) were conducted with residents in Mwanza, Tanzania. The results showed that people living with HIV/AIDS, who were using probiotic yogurt produced through a joint partnership of Western Heads East, Tanzania Medical Research Institute and the Tukwamune Women's Group, reported perceived beneficial effects, such as gain in weight and improved health and well-being. Yet, these beneficial effects might be resulting in growing misconceptions about probiotic yogurt being ‘medicine’ for the treatment of HIV/AIDS; this is leading some people living with HIV/AIDS to abandon taking their antiretroviral medications based on the view that the probiotic yogurt is making them feel much better. The findings illustrate the potential challenges with regard to the introduction of nutritional food supplements into new contexts plagued by malnutrition and infectious diseases. Public-health education and awareness programmes are needed when introducing novel foods into such contexts.
PMCID: PMC3312357  PMID: 22524117
Acquired immunodeficiency syndrome; Health; HIV; Nutrition; Perceptions; Probiotics; Qualitative studies; Yogurt; Tanzania
25.  Lactobacillus rhamnosus GR-1 enhances NF-kappaB activation in Escherichia coli-stimulated urinary bladder cells through TLR4 
BMC Microbiology  2012;12:15.
Background
Epithelial cells of the urinary tract recognize pathogenic bacteria through pattern recognition receptors on their surface, such as toll-like receptors (TLRs), and mount an immune response through the activation of the NF-kappaB pathway. Some uropathogenic bacteria can subvert these cellular responses, creating problems with how the host eliminates pathogens. Lactobacillus is a genus of lactic acid bacteria that are part of the microbiota and consist of many probiotic strains, some specifically for urogenital infections. Immunomodulation has emerged as an important mode of action of probiotic and commensal lactobacilli and given the importance of epithelial cells, we evaluated the effect of the urogenital probiotic Lactobacillus rhamnosus GR-1 on epithelial immune activation.
Results
Immune activation through the NF-kappaB pathway was initiated by stimulation of T24 urothelial cells with heat-killed Escherichia coli and this was further potentiated when cells were co-cultured with live L. rhamnosus GR-1. Heat-killed lactobacilli were poor activators of NF-kappaB. Concomitant stimulation of bladder cells with E. coli and L. rhamnosus GR-1 increased the levels of the pro-inflammatory cytokine TNF, whereas IL-6 and CXCL8 levels were reduced. Another probiotic, L. rhamnosus GG, was also able to potentiate NF-kappaB in these cells although at a significantly reduced level compared to the GR-1 strain. The transcript numbers and protein levels of the lipopolysaccharide receptor TLR4 were significantly increased after co-stimulation with E. coli and lactobacilli compared to controls. Furthermore, inhibition of TLR4 activation by polymixin B completely blocked the lactobacilli potentiation of NF-kappaB.
Conclusions
The immunological outcome of E. coli challenge of bladder cells was influenced by probiotic L. rhamnosus GR-1, by enhancing the activation of NF-kappaB and TNF release. Thus the urogenital probiotic L. rhamnosus GR-1 modulated the activation of the NF-kappaB through increased levels of TLR4 on the bladder cells and altered subsequent release of cytokines from urothelial cells. By influencing immunological factors such as TLR4, important in the process of fighting pathogens, lactobacilli could facilitate pathogen recognition and infection clearance.
doi:10.1186/1471-2180-12-15
PMCID: PMC3305351  PMID: 22264349

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