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The Human Vulvar Microbiome: A Systematic Review.
Pagan, L, Ederveen, RAM, Huisman, BW, Schoones, JW, Zwittink, RD, Schuren, FHJ, Rissmann, R, Piek, JMJ, van Poelgeest, MIE
Microorganisms. 2021;9(12)
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Vaginal microbiome composition and its link with cancer is an emerging area in research. Imbalances in the vaginal microbiome could initiate carcinogenesis by altering immunity and metabolism and accelerating inflammation. This systematic review included ten studies and assessed the vulvar microbiome in premalignant vulvar disease and healthy vulvar skin. The healthy vulvar skin showed several bacterial taxa of Lactobacillus, Corynebacterium, Staphylococcus and Prevotella of intestinal, cutaneous and vaginal origin. L. crispatus and L. iners were dominant on the vulva of most healthy women. L. gasseri dominance was non-significantly associated with vestibulodynia. Menstruation did not alter the bacterial composition. Premenarchial Lichen sclerosus may have an association with microbial dysbiosis. Further robust studies are required to identify the vaginal microbial composition due to the high heterogeneity of the studies included, small sample size and methodological limitations. Healthcare professionals can utilise the data from this study to better understand how the vulvar microbiome influences disease aetiology and its importance as a target for therapy.
Abstract
The link between cancer and the microbiome is a fast-moving field in research. There is little knowledge on the microbiome in ((pre)malignant) conditions of the vulvar skin. This systematic review aims to provide an overview of the literature regarding the microbiome composition of the healthy vulvar skin and in (pre)malignant vulvar disease. This study was performed according to the PRISMA guidelines. A comprehensive, electronic search strategy was used to identify original research articles (updated September 2021). The inclusion criteria were articles using culture-independent methods for microbiome profiling of the vulvar region. Ten articles were included. The bacterial composition of the vulva consists of several genera including Lactobacillus, Corynebacterium, Staphylococcus and Prevotella, suggesting that the vulvar microbiome composition shows similarities with the corresponding vaginal milieu. However, the vulvar microbiome generally displayed higher diversity with commensals of cutaneous and fecal origin. This is the first systematic review that investigates the relationship between microbiome and vulvar (pre)malignant disease. There are limited data and the level of evidence is low with limitations in study size, population diversity and methodology. Nevertheless, the vulvar microbiome represents a promising field for exploring potential links for disease etiology and targets for therapy.
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Modified Mediterranean-ketogenic diet modulates gut microbiome and short-chain fatty acids in association with Alzheimer's disease markers in subjects with mild cognitive impairment.
Nagpal, R, Neth, BJ, Wang, S, Craft, S, Yadav, H
EBioMedicine. 2019;47:529-542
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The exact causes of Alzheimer's disease (AD) are unknown, but there is evidence that AD is related to chronic inflammation, and it is thought that the gut bacteria (microbiome) and their metabolites can directly or indirectly affect brain functions. Diet can affect both the gut microbiome and brain health, and a ketogenic diet has been proposed to modulate processes associated with AD and is also known to affect gut microbial balance. The aim of this randomized, double-blind, crossover, pilot trial was to evaluate whether and how a modified Mediterranean-ketogenic diet (MMKD) alters the gut microbiome composition and whether this is associated with biomarkers for AD. 17 participants completed the study, 11 with mild cognitive impairment (MCI, an early stage of AD), and 6 counterparts with normal cognitive function (CN). Participants were randomly assigned to either a MMKD or an American Heart Association Diet (AHAD) for 6-weeks, followed by a 6-week washout, and then a 6-week intervention with the other diet. At baseline, participants with MCI had a microbiome composition different to that of the CN controls, with that of the MCI participants being considered less beneficial and potentially more pro-inflammatory. This difference was associated with biomarkers of AD. There was no difference in levels of microbial metabolites at baseline. Several types of bacteria were affected by the MMKD and AHAD, as were levels of faecal bacterial metabolites (short chain fatty acids). In particular, on the MMKD there was an increase in the metabolite butyrate which possesses neuroprotective actions and improves brain health. The authors conclude that the MMKD has a beneficial effect on the gut microbiome and associated AD biomarkers.
Abstract
BACKGROUND Alzheimer's disease (AD) prevalence is increasing, but its etiology remains elusive. Gut microbes can contribute to AD pathology and may help identifying novel markers and therapies against AD. Herein, we examine how the gut microbiome differs in older adults with mild cognitive impairment compared to cognitively normal counterparts, and whether and how a modified Mediterranean-ketogenic diet (MMKD) alters the gut microbiome signature in association with cerebrospinal fluid (CSF) AD biomarkers. METHODS A randomized, double-blind, cross-over, single-center pilot study of MMKD versus American Heart Association Diet (AHAD) intervention is performed on 17 subjects (age: 64.6 ± 6.4 yr), of which 11 have mild cognitive impairment, while 6 are cognitively normal. Subjects undergo MMKD and AHAD intervention for 6-weeks separated by 6-weeks washout periods. Gut microbiome, fecal short-chain fatty acids (SCFAs), and markers of AD in CSF including amyloid β (Aβ)-40 and Aß-42, total tau, and phosphorylated tau-181 (tau-p181) are measured at before and after diet interventions. FINDINGS At baseline, subjects with normal vs. impaired cognition show no notable difference in microbiome diversity but several unique microbial signatures are detected in subjects with mild cognitive impairment. Proteobacteria correlate positively with Aβ-42: Aβ-40 while fecal propionate and butyrate correlates negatively with Aβ-42 in subjects with mild cognitive impairment. Several bacteria are differently affected by the two diets with distinct patterns between cognitively normal and impaired subjects. Notably, the abundance of Enterobacteriaceae, Akkermansia, Slackia, Christensenellaceae and Erysipelotriaceae increases while that of Bifidobacterium and Lachnobacterium reduces on MMKD, while AHAD increases Mollicutes. MMKD slightly reduces fecal lactate and acetate while increasing propionate and butyrate. Conversely, AHAD increases acetate and propionate while reducing butyrate. INTERPRETATION The data suggest that specific gut microbial signatures may depict the mild cognitive impairment and that the MMKD can modulate the gut microbiome and metabolites in association with improved AD biomarkers in CSF.
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The skin microbiome in psoriatic disease: A systematic review and critical appraisal.
Yerushalmi, M, Elalouf, O, Anderson, M, Chandran, V
Journal of translational autoimmunity. 2019;2:100009
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Psoriasis is a common inflammatory skin disease that results in patches of dry, scaly skin that can be itchy or sore. Psoriatic arthritis is an inflammatory arthritis that affects up to 30% of psoriasis patients. The role of skin bacteria (the skin microbiome) is not well understood. This systematic review summarised the literature on the microbiome in psoriatic disease. The researchers looked at nine studies: seven on psoriasis only, and two studies comparing the microbiome characteristics between psoriasis and psoriatic arthritis. Compared to healthy controls, the skin of psoriasis patients demonstrated a decreased species diversity, higher relative abundances of Firmicutes, and lower relative abundances of Actinobacteria. Less conclusive were genus-level results, which demonstrated trends towards increased Streptococcus, Staphylococcus, and Corynebacterium, and decreased Propionibacterium in the skin of psoriasis patients versus healthy controls. However, the studies’ designs and methodologies varied, and therefore the researchers concluded that further research into the role of the skin microbiome in psoriatic disease is needed.
Abstract
BACKGROUND Psoriasis affects 1-3% of the Canadian population. Psoriatic arthritis (PsA), the most common comorbidity of psoriasis, affects up to 30% of psoriasis patients. The skin microbiome is hypothesized to play a role in the pathogenesis of psoriatic disease (PsD-psoriasis and PsA). OBJECTIVE To summarize the current state of literature on the skin microbiome in PsD. METHODS A systematic review was performed using searches in Ovid, Medline, Embase, Medline Epub Ahead of Print and In-Process & Other Non-Indexed Citations, and Cochrane Central Register of Controlled Trials (CENTRAL). Search was limited to humans and English language, with no limits for date or publication type. RESULTS Of 4,032 citations identified, 9 studies met inclusion criteria (7 on psoriasis only and 2 studies compared the microbiome characteristics between psoriasis and PsA). Compared to healthy controls, lesions demonstrated a decreased alpha diversity, higher relative abundances of Firmicutes, and lower relative abundances of Actinobacteria. Less conclusive were genus-level results, which nonetheless demonstrated trends towards increased Streptococcus, Staphylococcus, and Corynebacterium and decreased Propionibacterium in lesions vs. control. LIMITATIONS Study designs were heterogeneous, including sampling technique and exclusion criteria. CONCLUSIONS Phyla- and selected genus-level characteristic of the psoriatic microbiome are presented; further research is warranted.
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Functional variants in the sucrase-isomaltase gene associate with increased risk of irritable bowel syndrome.
Henström, M, Diekmann, L, Bonfiglio, F, Hadizadeh, F, Kuech, EM, von Köckritz-Blickwede, M, Thingholm, LB, Zheng, T, Assadi, G, Dierks, C, et al
Gut. 2018;67(2):263-270
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Congenital sucrase-isomaltase deficiency (CSID) is a genetic disorder which results in a lower ability to digest certain sugars, resulting in diarrhoea, abdominal pain and bloating, which are also common symptoms of Irritable Bowel Syndrome (IBS). The objective of this study was to test sucrase-isomaltase (SI) gene variants for their potential relevance in IBS. The researchers looked at genetics in several populations with and without IBS. The researchers found that genetic mutations are associated with a 35% reduction in the activity of the SI enzymes. CSID mutations were almost twice as common in IBS patients than healthy controls. The genetic variant 15Phe was associated with diarrhoea, stool frequency and changes in the gut bacteria. The authors concluded that people with SI gene variants associated with reduced enzyme activity are more at risk of IBS. Genetic screening could help to identify individuals at increased risk of IBS, and may lead to more targeted treatment for some people with IBS.
Abstract
OBJECTIVE IBS is a common gut disorder of uncertain pathogenesis. Among other factors, genetics and certain foods are proposed to contribute. Congenital sucrase-isomaltase deficiency (CSID) is a rare genetic form of disaccharide malabsorption characterised by diarrhoea, abdominal pain and bloating, which are features common to IBS. We tested sucrase-isomaltase (SI) gene variants for their potential relevance in IBS. DESIGN We sequenced SI exons in seven familial cases, and screened four CSID mutations (p.Val557Gly, p.Gly1073Asp, p.Arg1124Ter and p.Phe1745Cys) and a common SI coding polymorphism (p.Val15Phe) in a multicentre cohort of 1887 cases and controls. We studied the effect of the 15Val to 15Phe substitution on SI function in vitro. We analysed p.Val15Phe genotype in relation to IBS status, stool frequency and faecal microbiota composition in 250 individuals from the general population. RESULTS CSID mutations were more common in patients than asymptomatic controls (p=0.074; OR=1.84) and Exome Aggregation Consortium reference sequenced individuals (p=0.020; OR=1.57). 15Phe was detected in 6/7 sequenced familial cases, and increased IBS risk in case-control and population-based cohorts, with best evidence for diarrhoea phenotypes (combined p=0.00012; OR=1.36). In the population-based sample, 15Phe allele dosage correlated with stool frequency (p=0.026) and Parabacteroides faecal microbiota abundance (p=0.0024). The SI protein with 15Phe exhibited 35% reduced enzymatic activity in vitro compared with 15Val (p<0.05). CONCLUSIONS SI gene variants coding for disaccharidases with defective or reduced enzymatic activity predispose to IBS. This may help the identification of individuals at risk, and contribute to personalising treatment options in a subset of patients.
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Post-Antibiotic Gut Mucosal Microbiome Reconstitution Is Impaired by Probiotics and Improved by Autologous FMT.
Suez, J, Zmora, N, Zilberman-Schapira, G, Mor, U, Dori-Bachash, M, Bashiardes, S, Zur, M, Regev-Lehavi, D, Ben-Zeev Brik, R, Federici, S, et al
Cell. 2018;174(6):1406-1423.e16
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Probiotics are commonly used to reduce the risk of antibiotic associated diarrhoea (AAD). This study, in both mice and humans, investigated the effects of an 11 strain probiotic supplement and autologous faecal microbiome transplantation (aFMT) after antibiotic treatment. (Autologous meaning the person’s own, pre-antibiotic stool was transplanted.) Gut mucosa samples along the digestive tract and stool samples were investigated for microbiome composition and activity (transcriptome). The investigators found that without antibiotics the probiotics did not colonise very well, suggesting that our native microbiome offers resistance. After antibiotics, which would kill off much of our gut bacteria,the probiotics colonise the gut mucosa much better. However, the probiotics appear to then prevent the microbiome to return to its native, pre-antibiotic state. Whilst in those with the aFMT and in those who did nothing (“watchful waiting”) the microbiome returned to pre-antibiotic state fairly quickly, in the probiotic group even after 5 months the microbiome had not returned to its native composition. In vitro experiments suggest that the delay in the probiotic group is due to substances secreted by the probiotic bacteria, in particular Lactobacilli. The authors conclude that the potential benefits in terms of reducing the risk of AAD with probiotics may be offset with a delay in reconstitution of the native microbiome, and call for more research into aFMT and a more personalised approach to probiotic therapy.
Abstract
Probiotics are widely prescribed for prevention of antibiotics-associated dysbiosis and related adverse effects. However, probiotic impact on post-antibiotic reconstitution of the gut mucosal host-microbiome niche remains elusive. We invasively examined the effects of multi-strain probiotics or autologous fecal microbiome transplantation (aFMT) on post-antibiotic reconstitution of the murine and human mucosal microbiome niche. Contrary to homeostasis, antibiotic perturbation enhanced probiotics colonization in the human mucosa but only mildly improved colonization in mice. Compared to spontaneous post-antibiotic recovery, probiotics induced a markedly delayed and persistently incomplete indigenous stool/mucosal microbiome reconstitution and host transcriptome recovery toward homeostatic configuration, while aFMT induced a rapid and near-complete recovery within days of administration. In vitro, Lactobacillus-secreted soluble factors contributed to probiotics-induced microbiome inhibition. Collectively, potential post-antibiotic probiotic benefits may be offset by a compromised gut mucosal recovery, highlighting a need of developing aFMT or personalized probiotic approaches achieving mucosal protection without compromising microbiome recolonization in the antibiotics-perturbed host.
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Personalized Gut Mucosal Colonization Resistance to Empiric Probiotics Is Associated with Unique Host and Microbiome Features.
Zmora, N, Zilberman-Schapira, G, Suez, J, Mor, U, Dori-Bachash, M, Bashiardes, S, Kotler, E, Zur, M, Regev-Lehavi, D, Brik, RB, et al
Cell. 2018;174(6):1388-1405.e21
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Evidence regarding the efficacy of probiotics in colonising the gut mucosa are sparse. The authors investigated whether probiotics colonise the gut mucosa in mice and humans, using both gut mucosa and stool samples. They found that, in both mice and humans, results from stool samples only partially correlate with colonisation of the gut mucosa as determined through gut mucosa samples. Whilst results were fairly uniform in mice, in humans a person-specific resistance to colonisation of the gut mucosa by probiotics was observed. Inter-person variation could be predicted by the composition of the pre-probiotic microbiome and host immune features.
Abstract
Empiric probiotics are commonly consumed by healthy individuals as means of life quality improvement and disease prevention. However, evidence of probiotic gut mucosal colonization efficacy remains sparse and controversial. We metagenomically characterized the murine and human mucosal-associated gastrointestinal microbiome and found it to only partially correlate with stool microbiome. A sequential invasive multi-omics measurement at baseline and during consumption of an 11-strain probiotic combination or placebo demonstrated that probiotics remain viable upon gastrointestinal passage. In colonized, but not germ-free mice, probiotics encountered a marked mucosal colonization resistance. In contrast, humans featured person-, region- and strain-specific mucosal colonization patterns, hallmarked by predictive baseline host and microbiome features, but indistinguishable by probiotics presence in stool. Consequently, probiotics induced a transient, individualized impact on mucosal community structure and gut transcriptome. Collectively, empiric probiotics supplementation may be limited in universally and persistently impacting the gut mucosa, meriting development of new personalized probiotic approaches.
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Long-term Lactobacillus rhamnosus BMX 54 application to restore a balanced vaginal ecosystem: a promising solution against HPV-infection.
Palma, E, Recine, N, Domenici, L, Giorgini, M, Pierangeli, A, Panici, PB
BMC infectious diseases. 2018;18(1):13
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There is increasing interest in the role that the vaginal microbiome (the bacterial profile) plays in women’s health. Lactobacilli are the most dominant vaginal bacteria present in healthy women and it is known that when the bacteria get out of balance (a state called dysbiosis), disorders such as vaginosis and sexually transmitted diseases such as the Human Papilloma Virus (HPV) increase. This randomised pilot study aimed to investigate whether long-term use of Lactobacillus rhamnosus in women with dysbiosis and HPV-infection had an impact on treatment outcomes. 117 women with diagnosed vaginosis or vaginitis and HPV-infection were treated with standard antibiotic therapy and then randomly assigned to receive either 2-months or 6 months of vaginal Lactobacillus. At the median follow-up of 14 months post treatment, more than double the number of women in the 6-month probiotic treatment group received a negative HPV-pap smear, when compared to the 2-month treatment group. Randomised controlled trials are required to further this research, however Nutrition Practitioners working with women with vaginosis/vaginitis may want to consider the possible use of probiotics to support a healthy vaginal microbiome.
Abstract
BACKGROUND Over recent years, a growing interest has developed in microbiota and in the concept of maintaining a special balance between Lactobacillus and other bacteria species in order to promote women's well-being. The aim of our study was to confirm that vaginal Lactobacilli long-lasting implementation in women with HPV-infections and concomitant bacterial vaginosis or vaginitis might be able to help in solving the viral infection, by re-establishing the original eubiosis. METHODS A total of 117 women affected by bacterial vaginosis or vaginitis with concomitant HPV-infections were enrolled at Department of Gynecological Obstetrics and Urological Sciences, La Sapienza University, Rome, Italy between February 2015 and March 2016. Women were randomized in two groups, standard treatment (metronidazole 500 mg twice a day for 7 days or fluconazole 150 mg orally once a day for 2 consecutive days) plus short-term (3 months) vaginal Lactobacillus implementation (group 1, short probiotics treatment protocol group, n = 60) versus the same standard treatment plus long-lasting (6 months) vaginal Lactobacillus rhamnosus BMX 54 administration (group 2, treatment group, n = 57). RESULTS After a median follow up of 14 months (range 9-30 months) the chance to solve HPV-related cytological anomalies was twice higher in probiotic long-term users (group 2) versus short probiotics implementation group (group 1) (79.4% vs 37.5%, p = 0.041). Moreover, a total HPV-clearance was shown in 11.6% of short schedule probiotics implementation patients compared to a percentage of 31.2% in vaginal Lactobacilli long term users (p = 0.044), assessed as negative HPV-DNA test documented at the end of the study period. CONCLUSIONS The consistent percentage of clearance of PAP-smear abnormalities and HPV-clearance obtained in long-term treatment group has been interestingly high and encouraging. Obviously, larger and randomized studies are warranted to confirm these encouraging results, but we believe that eubiosis re-establishment is the key to tackle effectively even HPV-infection. TRIAL REGISTRATION Retrospectively registered on PRS NCT03372395 (12/12/2017).