Publications by authors named "Lars Engstrand"

183 Publications

Use of antibiotics and risk of psychiatric disorders in newly diagnosed cancer patients: a population-based cohort study in Sweden.

Cancer Epidemiol Biomarkers Prev 2022 Jan 13. Epub 2022 Jan 13.

Clinical Epidemiology and Biostatistics, Örebro University.

Background: Antibiotic-induced dysbiosis is associated with an increased risk of depression and anxiety in the general populations. A diagnosis of cancer is associated with an immediately and dramatically elevated risk of psychiatric disorders, but the potential influence of pre-diagnostic antibiotic-induced dysbiosis is unknown.

Methods: Based on a national cohort of cancer patients in Sweden, we included 309,419 patients who were diagnosed with a first primary malignancy between July 2006 and December 2013. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of first-onset psychosis, depression, anxiety, or stress-related disorders during the first year after cancer diagnosis for antibiotic use during the year before cancer diagnosis.

Results: Compared with no antibiotic use, use of antibiotics was associated with a higher rate of the aforementioned psychiatric disorders (HR, 1.23; 95% CI, 1.16-1.30) after adjustment for sociodemographic factors, comorbidity, potential indications for antibiotics, cancer stage and type. The magnitude of the association was higher for broad-spectrum antibiotics (HR, 1.27; 95% CI, 1.18-1.37), higher doses (HR, 1.33; 95% CI, 1.22-1.44), more frequent (HR, 1.33; 95% CI, 1.21-1.46) and recent use (HR, 1.26; 95% CI, 1.17-1.35).

Conclusions: Use of antibiotics, especially of broad-spectrum type, of high dose and frequency, with recent use, was associated with an aggravated risk of psychiatric disorders, compared with no antibiotic use.

Impact: A better understanding of the microbiota-gut-brain axis may open up a wide avenue for the prevention and treatment of psychiatric disorders in cancer patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1055-9965.EPI-21-1095DOI Listing
January 2022

Novel strain of possesses traits important in gut adaptation and host-microbe interactions.

Gut Microbes 2022 Jan-Dec;14(1):2013761

Human Microbiome Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland.

Fecal microbiota transplantation (FMT) is an efficient treatment for recurrent infection and currently investigated as a treatment for other intestinal and systemic diseases. Better understanding of the species potentially transferred in FMT is needed. We isolated from a healthy fecal donor a novel strain E10-96H of , a recently described strictly anaerobic species currently represented only by the type strain. The whole genome sequence of E10-96H had over 98% similarity with the type strain. E10-96H carries 20 glycoside hydrolase encoding genes, degrades starch and thus may contribute to fiber degradation, cross-feeding of other species and butyrate production in the intestinal ecosystem. The strain carries pilus-like structures, harbors pilin genes in its genome and adheres to enterocytes but does not provoke a proinflammatory response. seems to have commensal behavior with the host epithelium, and its role in intestinal ecology should be studied further.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/19490976.2021.2013761DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8726730PMC
December 2021

Genomic and Phenotypic Characteristics in Geographically Separated Clinical ST353CC Isolates.

Microorganisms 2021 Dec 8;9(12). Epub 2021 Dec 8.

Clinical Microbiology, Department of Medical Sciences, Uppsala University, SE-75185 Uppsala, Sweden.

fecal isolates of eight international travelers, 5 of which had traveled to Ecuador and 3 to Bangladesh, were characterized, and the possible relationship between bacterial traits and clinical symptoms was further analyzed. All eight isolates belonged to the same Multi-Locus Sequence Type clonal complex (ST353CC). The three isolates from Bangladesh were all of the same sequence type (ST-9438), and when compared to isolates of various other sequence types, they had a larger quantity of unique genetic content, higher expression levels of some putative virulence genes involved in adhesion and invasion (A, B and A), and showed higher adhesion levels to human HT-29 colon cancer cells in an in vitro infection model. However, in contrast to the seemingly higher pathogenic potential of these bacterial isolates, travelers infected with the ST-9438 isolates had no or only very mild symptoms, whereas the other individuals, whose bacterial isolates seemed to have less pathogenic potential, generally reported severe symptoms. When studying the 16S rRNA gene-based fecal microbiota in samples collected prior to travel, there was an individual variation in the relative abundance of the three major bacterial phyla Actinobacteria, Bacteroidetes and Firmicutes, but there were no associations between composition and diversity of microbiota and development of severe symptoms from the infection. It remains to be confirmed by larger studies whether an individual's characteristics such as gut microbiota, might be related to the severity of symptoms in infections.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/microorganisms9122540DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8709058PMC
December 2021

Multiomics and digital monitoring during lifestyle changes reveal independent dimensions of human biology and health.

Cell Syst 2021 Nov 30. Epub 2021 Nov 30.

Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki 00290, Finland; Science for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, Stockholm 17165, Sweden. Electronic address:

We explored opportunities for personalized and predictive health care by collecting serial clinical measurements, health surveys, genomics, proteomics, autoantibodies, metabolomics, and gut microbiome data from 96 individuals who participated in a data-driven health coaching program over a 16-month period with continuous digital monitoring of activity and sleep. We generated a resource of >20,000 biological samples from this study and a compendium of >53 million primary data points for 558,032 distinct features. Multiomics factor analysis revealed distinct and independent molecular factors linked to obesity, diabetes, liver function, cardiovascular disease, inflammation, immunity, exercise, diet, and hormonal effects. For example, ethinyl estradiol, a common oral contraceptive, produced characteristic molecular and physiological effects, including increased levels of inflammation and impact on thyroid, cortisol levels, and pulse, that were distinct from other sources of variability observed in our study. In total, this work illustrates the value of combining deep molecular and digital monitoring of human health. A record of this paper's transparent peer review process is included in the supplemental information.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cels.2021.11.001DOI Listing
November 2021

Changes to human faecal microbiota after international travel.

Travel Med Infect Dis 2021 Nov-Dec;44:102199. Epub 2021 Nov 13.

Clinical Microbiology, Department of Medical Sciences, Uppsala University, Uppsala, Sweden. Electronic address:

Background: The aim was to investigate whether travelling to less-resourced destinations influences the composition of faecal microbiota in generally healthy adults.

Method: In this prospective observational study, 47 adults (median age, 24 years; 73% females) travelled from Sweden to distant destinations for 1-12 weeks. Five faecal samples, two before and three after travel, were analysed by 16S amplicon massive parallel sequencing. Subjects had taken no antibiotics within three months of each sampling.

Results: The overall composition of faecal microbiota was not affected by travel. However, when looking at the relative abundance of individual bacterial taxa, Enterobacteriaceae demonstrated a 10-fold increase immediately after the trip as compared to the samples taken before travelling. Conversely, the relative abundance of Christensenellaceae had decreased equally much. Both these changes were reversible within nine weeks.

Conclusions: International travel, even to less-resourced countries, did not appear to alter the overall diversity of human faecal microbiota as studied here after travelling. However, Enterobacteriaceae bacteria, often associated with infection, inflammation, and antibiotic resistance, showed dramatically elevated levels, and Christensenellaceae, frequently associated with healthy conditions, demonstrated remarkably declined levels in relative abundance as detected immediately after travel. Both these changes returned to original pre-travel levels within nine weeks.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.tmaid.2021.102199DOI Listing
December 2021

Rapid and sensitive detection of SARS-CoV-2 infection using quantitative peptide enrichment LC-MS analysis.

Elife 2021 11 8;10. Epub 2021 Nov 8.

Science for Life Laboratory, Solna, Sweden.

Reliable, robust, large-scale molecular testing for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is essential for monitoring the ongoing coronavirus disease 2019 (COVID-19) pandemic. We have developed a scalable analytical approach to detect viral proteins based on peptide immuno-affinity enrichment combined with liquid chromatography-mass spectrometry (LC-MS). This is a multiplexed strategy, based on targeted proteomics analysis and read-out by LC-MS, capable of precisely quantifying and confirming the presence of SARS-CoV-2 in phosphate-buffered saline (PBS) swab media from combined throat/nasopharynx/saliva samples. The results reveal that the levels of SARS-CoV-2 measured by LC-MS correlate well with their correspondingreal-time polymerase chain reaction (RT-PCR) read-out (r = 0.79). The analytical workflow shows similar turnaround times as regular RT-PCR instrumentation with a quantitative read-out of viral proteins corresponding to cycle thresholds (Ct) equivalents ranging from 21 to 34. Using RT-PCR as a reference, we demonstrate that the LC-MS-based method has 100% negative percent agreement (estimated specificity) and 95% positive percent agreement (estimated sensitivity) when analyzing clinical samples collected from asymptomatic individuals with a Ct within the limit of detection of the mass spectrometer (Ct ≤ 30). These results suggest that a scalable analytical method based on LC-MS has a place in future pandemic preparedness centers to complement current virus detection technologies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.7554/eLife.70843DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8626084PMC
November 2021

[Precision diagnostics in clinical microbiology].

Lakartidningen 2021 10 25;118. Epub 2021 Oct 25.

professor, överläkare, Karolinska institutet; Karolinska universitetssjukhuset, Stockholm.

Genomic methods have had a major impact in clinical microbiology in the last decades. Microbial genomes are relatively small and therefore easier to characterise than human genomes. In both bacteriology and in virology, genomic methods have largely been used for molecular epidemiology, but also for molecular resistance testing of microorganisms. Targeted sequencing of predefined or isolated microorganisms was initially a dominant method but has gradually been supplemented with metagenomic diagnostics. Metagenomics aims at mapping all microorganisms - pathogenic as well as apathogenic - in a sample without determining in advance which agent(s) the analysis is targeting. Finally, there is also an increasing interest in mapping the significance of the microbiome, i.e. normal flora, both in health and disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
October 2021

Proton pump inhibitors and survival in patients with colorectal cancer: a Swedish population-based cohort study.

Br J Cancer 2021 09 12;125(6):893-900. Epub 2021 Jul 12.

Centre for Translational Microbiome Research, Department of Microbiology, Tumour and Cell Biology, Karolinska Institutet, Stockholm, Sweden.

Background: Proton pump inhibitors (PPIs) are associated with microbiome changes of the gut, which in turn may affect the progression of colorectal cancer (CRC). This study aims to assess the associations between PPI use and all-cause and CRC-specific mortality.

Methods: We selected all patients registered in the Swedish Prescribed Drug Registry who were diagnosed with CRC between 2006 and 2012 (N = 32,411, 54.9% PPI users) and subsequently followed them through register linkage to the Swedish Causes of Death Registry until December 2013. PPI users were patients with ≥1 post-diagnosis PPI dispensation. Time-dependent Cox-regression models were performed with PPI use as time-varying exposure.

Results: Overall 4746 (14.0%) patients died, with an aHR of 1.38 (95% CI 1.32-1.44) for all-cause mortality comparing PPI users with PPI nonusers. Higher-magnitude associations were observed among male, cancer stage 0-I, rectal cancer and patients receiving CRC surgery. The PPI-all-cause mortality association was also more pronounced comparing new users to non-users (aHR = 1.47, 95%CI 1.40-1.55) than comparing continuous users to non-users (aHR = 1.32, 95%CI 1.24-1.39). The risk estimates for CRC-specific mortality comparing PPI users to PPI nonusers were similar to those for all-cause mortality.

Conclusion: PPI use after the CRC diagnosis was associated with increased all-cause and CRC-specific mortality.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41416-021-01480-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8438017PMC
September 2021

Association Between Proton Pump Inhibitor Use and Biliary Tract Cancer Risk: A Swedish Population-Based Cohort Study.

Hepatology 2021 10 13;74(4):2021-2031. Epub 2021 Jul 13.

Centre for Translational Microbiome Research, Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.

Background And Aims: Biliary tract cancer is a group of highly aggressive malignant disorders, yet risk factors are poorly understood. In this study, we aim to assess whether prolonged use of proton pump inhibitors (PPIs) increases the risk of incident biliary tract carcinoma in a nation-wide population-based cohort in Sweden.

Approach And Results: Using nation-wide registries, we identified all adults who received maintenance PPIs (≥180 days) according to the Swedish Prescribed Drug Register from 2005 through 2012. Data on incident biliary tract cancer were retrieved from the Swedish Cancer, Death and Outpatient Registers. Risk of biliary tract cancer in persons who received PPI treatment was compared with the general population of the corresponding age, sex, and calendar year yielding standardized incidence ratios (SIRs) with 95% CIs. Of 738,881 PPI users (median follow-up of 5.3 years), 206 (0.03%) developed gallbladder cancer and 265 (0.04%) extrahepatic and 131 (0.02%) intrahepatic bile duct cancer corresponding to SIRs of 1.58 (95% CI, 1.37-1.81), 1.77 (95% CI, 1.56-2.00), and 1.88 (95% CI, 1.57-2.23), respectively. In sensitivity analyses restricted to persons without a history of gallstones or chronic liver or pancreatic diseases, SIRs were 1.36 (95% CI, 1.17-1.57) and 1.47 (95% CI, 1.19-1.80) for extra- and intrahepatic duct cancer, respectively. The risk remained higher than the corresponding general population with ≥5 years of PPIs use, ruling out confounding by indication.

Conclusions: In this study, long-term use of PPIs was associated with an increased risk of gallbladder, intrahepatic, and extrahepatic bile duct cancer compared with the general population.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/hep.31914DOI Listing
October 2021

A MicroRNA Gene Panel Predicts the Vaginal Microbiota Composition.

mSystems 2021 May 4;6(3). Epub 2021 May 4.

Department of Microbiology, Tumor and Cell Biology, Centre for Translational Microbiome Research (CTMR), Karolinska Institutet, Stockholm, Sweden

The vaginal microbiota plays an essential role in vaginal health. The vaginas of many reproductive-age women are dominated by one of the species. However, the vaginas of a large number of women are characterized by the colonization of several other anaerobes. Notably, some women with the non--dominated vaginal microbiota develop bacterial vaginosis, which has been correlated with sexually transmitted infections and other adverse outcomes. However, interactions and mechanisms linking the vaginal microbiota to host response are still under investigation. There are studies suggesting a link between human microRNAs and gut microbiota, but limited analysis has been carried out on the interplay of microRNAs and vaginal microbiota. In this study, we performed a microRNA expression array profiling on 67 vaginal samples from young Swedish women. MicroRNAs were clustered into distinct groups according to vaginal microbiota composition. Interestingly, 182 microRNAs were significantly elevated in their expression in the non--dominated community, suggesting an antagonistic relationship between and microRNAs. Of the elevated microRNAs, 10 microRNAs displayed excellent diagnostic potential, visualized by receiver operating characteristics analysis. We further validated our findings in 34 independent samples where expression of top microRNA candidates strongly separated the -dominated community from the non--dominated community in the vaginal microbiota. Notably, the -dominated community showed the most profound differential microRNA expression compared with the non--dominated community. In conclusion, we demonstrate a strong relationship between the vaginal microbiota and numerous genital microRNAs, which may facilitate a deeper mechanistic interplay in this biological niche. Vaginal microbiota is correlated with women's health, where a non--dominated community predisposes women to a higher risk of disease, including human papillomavirus (HPV). However, the molecular relationship between the vaginal microbiota and host is largely unexplored. In this study, we investigated a link between the vaginal microbiota and host microRNAs in a group of young women. We uncovered an inverse correlation of the expression of microRNAs with the abundance of species in the vaginal microbiota. Particularly, the expression of microRNA miR-23a-3p and miR-130a-3p, displaying significantly elevated levels in non--dominated communities, predicted the bacterial composition of the vaginal microbiota in an independent validation group. Since targeting of microRNAs is explored in the clinical setting, our results warrant investigation of whether microRNA modulation could be used for treating vaginosis recurrence and vaginosis-related diseases. Conversely, commensal bacteria could be used for treating diseases with microRNA aberrations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1128/mSystems.00175-21DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8269211PMC
May 2021

Fecal microbiota in children with juvenile idiopathic arthritis treated with methotrexate or etanercept.

Pediatr Rheumatol Online J 2021 Apr 26;19(1):55. Epub 2021 Apr 26.

Department of Women's and Children's Health, Uppsala University, Uppsala, Sweden.

Background: Alterations in the composition of the fecal microbiota in children with juvenile idiopathic arthritis (JIA) have been observed in several studies, but it has not been determined whether the standard treatment for JIA changes the composition or function of the microbiota. The first-line disease-modifying anti-rheumatic drug for treatment of JIA is usually methotrexate, followed or supplemented by anti-tumor necrosis factor alpha drugs, such as etanercept. The aim of this study was to investigate the effects of methotrexate and etanercept treatments on the fecal microbiota and the fecal short-chain fatty acids (SCFAs) in children with JIA.

Methods: In this multicenter study, the composition of fecal microbiota from 45 treatment-naïve children with JIA was compared with that from 29 children treated with methotrexate and 12 children treated with etanercept. We also made pairwise comparisons of 15 children sampled before and during methotrexate treatment and 7 children sampled before and during etanercept treatment. The microbiota was determined using sequencing amplicons from the V3 and V4 regions of the 16S rRNA gene. Alpha-diversity, community composition, and relative abundances of bacterial taxa were analyzed in all comparisons. Analyses of fecal SCFAs, using a high-performance liquid chromatograph, were performed for the pairwise comparisons.

Results: We did not find any significant differences in α-diversity or community composition of microbiota. However, principal coordinate analysis indicated a change in community composition in 7 of the 15 paired samples before and during methotrexate and 2 of the 7 paired samples before and during etanercept. Comparisons of the relative abundance of taxa revealed minor differences before and during treatment with methotrexate or etanercept, but they were not significant after correction for multiple analyses, and the unpaired and paired analyses did not show similar changes. There were no significant differences in levels of fecal SCFAs before and during treatment with methotrexate or etanercept.

Conclusions: Treatment with methotrexate or etanercept had minor, but no significant or consistent changes either on composition of microbiota or on levels of SCFAs, suggesting that these changes are not related to the therapeutic effects of methotrexate or etanercept.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12969-021-00542-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8077782PMC
April 2021

Prediagnostic use of estrogen-only therapy is associated with improved colorectal cancer survival in menopausal women: a Swedish population-based cohort study.

Acta Oncol 2021 Jul 16;60(7):881-887. Epub 2021 Apr 16.

Department of Microbiology, Tumor and Cell Biology, Centre for Translational Microbiome Reseaarch (CTMR), Stockholm, Sweden.

Background: Menopausal hormone therapy (MHT) reduces the risk of developing colorectal cancer (CRC), yet it is largely unclear whether it could also influence survival in women with CRC. Therefore, we aimed to investigate the influence of prediagnostic MHT use on CRC-specific and all-cause mortality in women with CRC.

Methods: This nationwide nested cohort study, within a large population-based matched cohort, included all women diagnosed with incident CRC between January 2006 and December 2012 (N = 7814). A total of 1529 women had received at least one dispensed prescription of systemic MHT before CRC diagnosis, and 6285 CRC women with CRC did not receive MHT during the study period, as ascertained from the Swedish Prescribed Drug Registry. Multivariable Cox regression models provided adjusted hazard ratios (HRs) with 95% confidence intervals (CIs) for CRC-specific mortality and all-cause mortality.

Results: Past use of prediagnostic estrogen-only therapy (E-MHT) was associated with lower CRC-specific (HR = 0.67, 95%CI 0.44-0.99) and all-cause mortality (HR = 0.68, 95%CI 0.59-0.93). However, all-cause mortality (HR = 1.23, 95%CI 1.02-1.48) was elevated among current prediagnostic E-MHT users who were 70+ years at diagnosis. Current estrogen combined progestin therapy (EP-MHT) was associated with higher CRC-specific mortality (HR = 1.61, 95%CI 1.06-2.44) in older women, but no association was shown for all-cause mortality.

Conclusions: Our findings suggest that E-MHT, but not EP-MHT use, might be associated with improved CRC survival, indicating a potential role of estrogens in sex hormone-related cancers. However, association of MHT use with grade of cancer remains unclear.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/0284186X.2021.1909747DOI Listing
July 2021

Menopausal hormone therapies and risk of colorectal cancer: a Swedish matched-cohort study.

Aliment Pharmacol Ther 2021 06 15;53(11):1216-1225. Epub 2021 Apr 15.

Stockholm, Sweden.

Background: Menopausal hormone therapy (MHT) has been associated with various malignancies.

Aims: To investigate the association of various MHT regimens with the risk of colorectal cancer (CRC).

Methods: All MHT ever-users (n = 290 186) were included through the Swedish Prescribed Drug Registry, with a 1:3 group-level matching to non-users. Ever-users were defined as women who received ≥1 dispensed prescription of systemic MHT during 2005-2012 in Sweden. All CRC cases after drug initiation were extracted from the Swedish Cancer Registry. The association was assessed by multivariable conditional logistic and Cox regression models, presented as odds ratios (ORs) or hazard ratios (HRs) with 95% confidence intervals (CIs) considering different regimens, duration and age at treatment initiation.

Results: Compared with non-users, MHT users had an overall reduced odds for colon (OR = 0.67, 95% CI 0.63-0.72) and rectal adenocarcinoma (OR = 0.66, 95% CI 0.60-0.73), especially among women aged 40-60 years. Current users of oestrogen-only preparations (E-MHT) showed a reduced odds (colon OR = 0.73, 95% CI 0.65-0.82; rectal OR = 0.76, 95% CI 0.64-0.90) compared to non-users, particularly with oestradiol and oestriol. Past E-MHT use showed stronger odds reductions (colon OR = 0.49, 95% CI 0.43-0.56; rectal OR = 0.36, 95% CI 0.28-0.45). Current use of oestrogen combined progestin therapy (EP-MHT) indicated a less prominent odds reduction (colon adenocarcinoma OR 0.62, 95% CI 0.54-0.72; rectal adenocarcinoma OR = 0.60, 95% CI 0.49-0.74) than past users. Tibolone showed an increased risk of left-sided colorectal adenocarcinoma. Oral and cutaneous MHT usage showed similar patterns.

Conclusions: MHT use may decrease colorectal adenocarcinoma risk, for both E-MHT and EP-MHT, and especially in past users.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/apt.16362DOI Listing
June 2021

Dysbiosis of the Human Oral Microbiome During the Menstrual Cycle and Vulnerability to the External Exposures of Smoking and Dietary Sugar.

Front Cell Infect Microbiol 2021 19;11:625229. Epub 2021 Mar 19.

Centre for Translational Microbiome Research, Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.

Physiological hormonal fluctuations exert endogenous pressures on the structure and function of the human microbiome. As such, the menstrual cycle may selectively disrupt the homeostasis of the resident oral microbiome, thus compromising oral health. Hence, the aim of the present study was to structurally and functionally profile the salivary microbiome of 103 women in reproductive age with regular menstrual cycle, while evaluating the modifying influences of hormonal contraceptives, sex hormones, diet, and smoking. Whole saliva was sampled during the menstrual, follicular, and luteal phases (n = 309) of the cycle, and the participants reported questionnaire-based data concerning their life habits and oral or systemic health. No significant differences in alpha-diversity or phase-specific clustering of the overall microbiome were observed. Nevertheless, the salivary abundances of genera , , , and varied throughout the cycle, and a higher species-richness was observed during the luteal phase. While the overall community structure maintained relatively intact, its functional properties were drastically affected. In particular, 11 functional modules were differentially abundant throughout the menstrual cycle, including pentose phosphate metabolism, and biosynthesis of cobalamin and neurotransmitter gamma-aminobutyric acid. The menstrual cycle phase, but not oral contraceptive usage, was accountable for greater variations in the metabolic pathways of the salivary microbiome. Further co-risk factor analysis demonstrated that and were increased in current smokers, whereas high dietary sugar consumption modified the richness and diversity of the microbiome during the cycle. This is the first large study to systematically address dysbiotic variations of the oral microbiome during the course of menstrual cycle, and document the additive effect of smoking and sugar consumption as environmental risk factors. It reveals the structural resilience and functional adaptability of the oral microbiome to the endogenous hormonal pressures of the menstrual cycle, while revealing its vulnerability to the exogenous exposures of diet and smoking.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fcimb.2021.625229DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8018275PMC
July 2021

Pancreatic cancer cachexia: three dimensions of a complex syndrome.

Br J Cancer 2021 05 19;124(10):1623-1636. Epub 2021 Mar 19.

Department of Clinical Science, Intervention and Technology, Karolinska Institute, Stockholm, Sweden.

Cancer cachexia is a multifactorial syndrome that is characterised by a loss of skeletal muscle mass, is commonly associated with adipose tissue wasting and malaise, and responds poorly to therapeutic interventions. Although cachexia can affect patients who are severely ill with various malignant or non-malignant conditions, it is particularly common among patients with pancreatic cancer. Pancreatic cancer often leads to the development of cachexia through a combination of distinct factors, which, together, explain its high prevalence and clinical importance in this disease: systemic factors, including metabolic changes and pathogenic signals related to the tumour biology of pancreatic adenocarcinoma; factors resulting from the disruption of the digestive and endocrine functions of the pancreas; and factors related to the close anatomical and functional connection of the pancreas with the gut. In this review, we conceptualise the various insights into the mechanisms underlying pancreatic cancer cachexia according to these three dimensions to expose its particular complexity and the challenges that face clinicians in trying to devise therapeutic interventions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41416-021-01301-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8110983PMC
May 2021

Tonsillar Microbiota: a Cross-Sectional Study of Patients with Chronic Tonsillitis or Tonsillar Hypertrophy.

mSystems 2021 Mar 9;6(2). Epub 2021 Mar 9.

Department of Medicine, Solna, Karolinska Institutet, Stockholm, Sweden.

Chronic tonsillitis (CT) and tonsillar hypertrophy (TH) are common tonsillar diseases that are related to infection and inflammation. Little is known about tonsillar microbiota and its role in CT and TH. This study aims to identify palatine tonsillar microbiota both on the surface and in the core tissues of CT and TH patients. In total, 22 palatine tonsils were removed and collected from CT and TH patients who underwent surgery. The surface and core microbiota in the tonsils of CT and TH patients were compared using 16S rRNA gene sequencing of V3-V4 regions. Differential tonsillar microbiotas were found in the CT versus TH patients and surface versus core tissues. Further, a higher relative abundance of bacterial genera, including , , , , , , and [G-2] in patients with TH and , , [G-2], , and in patients with CT, was observed. Of these, the differential genera of , , and served as key factors in the tonsillar microbiota network. Notably, four representable tonsillar microbial types were identified, with one, consisting of a higher abundance of and , exclusively detected in the TH patients. This study analyzed the different tonsillar microbiota from the surface and core tissues of CT and TH patients. Several bacteria and various microbial types related to CT and TH were identified, along with potential bacterial networks and related immune pathways. The human microbiota has been shown to be functionally connected to infectious and inflammation-related diseases. So far, only limited studies had been performed on tonsillar microbiota, although tonsils play an essential role in the human immune defense system and encountered numerous microorganisms. Our work presented different tonsillar microbiota from surface and core tissues of chronic tonsillitis (CT) and tonsillar hypertrophy (TH) patients. Notably, one tonsillar microbiota type, which contains a higher abundance of and , was only detected in the TH patients. Furthermore, certain bacteria, such as , , , and , may serve as microbial biomarkers to discriminate CT patients from TH patients. These data provide important microbiota data in the tonsillar research area and are highly useful for researchers both in the oral microbiome field and clinical field.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1128/mSystems.01302-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8547005PMC
March 2021

High Amounts of SARS-CoV-2 Precede Sickness Among Asymptomatic Health Care Workers.

J Infect Dis 2021 07;224(1):14-20

Karolinska University Hospital, Stockholm, Sweden.

Background: Whether severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) positivity among asymptomatic subjects reflects past or future disease may be difficult to ascertain.

Methods: We tested 9449 employees at Karolinska University Hospital, Stockholm, Sweden for SARS-CoV-2 RNA and antibodies, linked the results to sick leave records, and determined associations with past or future sick leave using multinomial logistic regression.

Results: Subjects with high amounts of SARS-CoV-2 virus, indicated by polymerase chain reaction (PCR) cycle threshold (Ct) value, had the highest risk for sick leave in the 2 weeks after testing (odds ratio [OR], 11.97; 95% confidence interval [CI], 6.29-22.80) whereas subjects with low amounts of virus had the highest risk for sick leave in the 3 weeks before testing (OR, 6.31; 95% CI, 4.38-9.08). Only 2.5% of employees were SARS-CoV-2 positive while 10.5% were positive by serology and 1.2% were positive in both tests. Serology-positive subjects were not at excess risk for future sick leave (OR, 1.06; 95% CI, .71-1.57).

Conclusions: High amounts of SARS-CoV-2 virus, as determined using PCR Ct values, was associated with development of sickness in the next few weeks. Results support the concept that PCR Ct may be informative when testing for SARS-CoV-2. Clinical Trials Registration. NCT04411576.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/infdis/jiab099DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7928785PMC
July 2021

Proton pump inhibitors and the risk of pancreatic cancer.

J Gastroenterol 2021 03 2;56(3):295-296. Epub 2021 Feb 2.

Department of Microbiology, Tumor and Cell Biology, Centre for Translational Microbiome Research, Karolinska Institutet, Karolinska Hospital, Biomedicum A8, Solnavägen 9, 171 65, Stockholm, Sweden.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00535-021-01761-8DOI Listing
March 2021

Ileocolonic Histopathological and Microbial Alterations in the Irritable Bowel Syndrome: A Nested Community Case-Control Study.

Clin Transl Gastroenterol 2020 12 22;12(1):e00296. Epub 2020 Dec 22.

Department of Psychology, Macquarie University, North Ryde, Australia.

Introduction: Histopathological alterations in the ileum and colon in irritable bowel syndrome (IBS) are controversial, and normal values are poorly established. We hypothesized that changes in mucosal immune cells characterize IBS and key changes in immune composition are associated with the mucosa-associated microbiota (MaM).

Methods: A nested case-control study (48 IBS and 106 controls included) from 745 colonoscopy participants in a random population sample. Intraepithelial lymphocytes (IELs)/100 enterocytes and eosinophils/5 nonoverlapping high-power fields counted; mast cells identified by immunocytochemistry (CD117)/5 high-power fields. Paneth cells quantified per 5 crypts. 16S rRNA gene amplicon sequencing performed on available sigmoid MaM, n = 55 and fecal microbiota, n = 20. Microbiota profiles compared between samples with high and low IEL counts.

Results: IBS had increased IELs in the terminal ileum (relative risk ratio = 1.70, 95% confidence interval 1.08-2.76, P = 0.022 adjusted for age, sex, and smoking). Cecal IELs were increased in IBS-diarrhea (relative risk ratio = 2.03, 95% confidence interval 1.13-3.63, P = 0.017). No difference was observed in alpha diversity of MaM or fecal microbiota based on IEL count. There was no difference in beta diversity of the MaM according to IEL count in the terminal ileal (TI) (P = 0.079). High TI IEL counts associated with a significant expansion of the genus Blautia (P = 0.024) and unclassified Clostridiales (P = 0.036) in colon MaM.

Discussion: A modest but significant increase in IELs was observed in IBS vs. controls in a population-based setting. Subtle TI and cecal inflammation may play a pathogenic role in IBS but needs confirmation. Modest but discernible differences in the colonic MaM were seen according to TI IEL count but not IBS status.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.14309/ctg.0000000000000296DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8345925PMC
December 2020

Fecal Microbiota in Untreated Children With Juvenile Idiopathic Arthritis: A Comparison With Healthy Children and Healthy Siblings.

J Rheumatol 2021 10 1;48(10):1589-1595. Epub 2020 Dec 1.

A. Öman, MD, L. Berntson, MD, Associate Professor, Department of Women's and Children's Health, Uppsala University, Uppsala.

Objective: Changes in the composition of gut microbiota have been suggested to be associated with juvenile idiopathic arthritis (JIA). The objective in this study was to investigate if the diversity and composition of the fecal microbiota differed between children with JIA and healthy controls (HCs), and if the microbiota differed between children with JIA and their healthy siblings.

Methods: In this multicenter, case-control study, fecal samples were collected from 75 children with JIA and 32 HCs. Eight of the HCs were siblings to 8 children with JIA, and they were compared only pairwise with their siblings. The microbiota was determined using sequencing amplicons from the V3 and V4 regions of the 16S rRNA gene. Alpha diversity, community composition of microbiota, and relative abundances of taxa were compared between children with JIA and healthy unrelated controls as well as between children with JIA and healthy siblings.

Results: Our data revealed no significant differences in α-diversity or community composition of microbiota between children with JIA, healthy unrelated controls, or healthy siblings. Analyses of relative abundances of phyla, families, and genera identified trends of differing abundances of some taxa in children with JIA, in comparison with both HCs and healthy siblings, but none of these findings were significant after adjustment for multiple comparisons.

Conclusion: There were no significant differences in the composition of fecal microbiota in children with JIA compared with HCs. The composition of microbiota in children with JIA did not differ significantly from that in their healthy siblings.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3899/jrheum.200551DOI Listing
October 2021

Assessment of and Protocols for Sequence-Based Characterization of the Human Vaginal Microbiome.

mSphere 2020 11 18;5(6). Epub 2020 Nov 18.

Centre for Translational Microbiome Research, Department of Microbiology, Tumour and Cell Biology, Science for Life Laboratory, Karolinska Institutet, Solna, Sweden

The vaginal microbiome has been connected to a wide range of health outcomes. This has led to a thriving research environment but also to the use of conflicting methodologies to study its microbial composition. Here, we systematically assessed best practices for the sequencing-based characterization of the human vaginal microbiome. As far as 16S rRNA gene sequencing is concerned, the V1-V3 region performed best , but limitations of current sequencing technologies meant that the V3-V4 region performed equally well. Both approaches presented very good agreement with qPCR quantification of key taxa, provided that an appropriate bioinformatic pipeline was used. Shotgun metagenomic sequencing presents an interesting alternative to 16S rRNA gene amplification and sequencing but requires deeper sequencing and more bioinformatic expertise and infrastructure. We assessed different tools for the removal of host reads and the taxonomic annotation of metagenomic reads, including a new, easy-to-build and -use reference database of vaginal taxa. This curated database performed as well as the best-performing previously published strategies. Despite the many advantages of shotgun sequencing, none of the shotgun approaches assessed here agreed with the qPCR data as well as the 16S rRNA gene sequencing. The vaginal microbiome has been connected to various aspects of host health, including susceptibility to sexually transmitted infections as well as gynecological cancers and pregnancy outcomes. This has led to a thriving research environment but also to conflicting available methodologies, including many studies that do not report their molecular biological and bioinformatic methods in sufficient detail to be considered reproducible. This can lead to conflicting messages and delay progress from descriptive to intervention studies. By systematically assessing best practices for the characterization of the human vaginal microbiome, this study will enable past studies to be assessed more critically and assist future studies in the selection of appropriate methods for their specific research questions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1128/mSphere.00448-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7677004PMC
November 2020

Vaginal microbiota and human papillomavirus infection among young Swedish women.

NPJ Biofilms Microbiomes 2020 10 12;6(1):39. Epub 2020 Oct 12.

Department of Microbiology, Tumor and Cell Biology, Centre for Translational Microbiome Research (CTMR), Karolinska Institutet, Stockholm, Sweden.

Human papillomavirus (HPV) infection is one of the most common sexually transmitted diseases. To define the HPV-associated microbial community among a high vaccination coverage population, we carried out a cross-sectional study with 345 young Swedish women. The microbial composition and its association with HPV infection, including 27 HPV types, were analyzed. Microbial alpha-diversity was found significantly higher in the HPV-infected group (especially with oncogenic HPV types and multiple HPV types), compared with the HPV negative group. The vaginal microbiota among HPV-infected women was characterized by a larger number of bacterial vaginosis-associated bacteria (BVAB), Sneathia, Prevotella, and Megasphaera. In addition, the correlation analysis demonstrated that twice as many women with non-Lactobacillus-dominant vaginal microbiota were infected with oncogenic HPV types, compared with L. crispatus-dominated vaginal microbiota. The data suggest that HPV infection, especially oncogenic HPV types, is strongly associated with a non-Lactobacillus-dominant vaginal microbiota, regardless of age and vaccination status.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41522-020-00146-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7552401PMC
October 2020

Antibiotic use and risk of colorectal cancer: a systematic review and dose-response meta-analysis.

Br J Cancer 2020 12 24;123(12):1825-1832. Epub 2020 Sep 24.

Centre for Translational Microbiome Research (CTMR), Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Biomedicum kvarter 8A. Solnavägen 9, SE-171 65, Stockholm, Sweden.

Background: It is understudied whether the posed association of oral antibiotics with colorectal cancer (CRC) varies between antibiotic spectrums, colorectal continuum, and if a non-linear dose-dependent relationship is present.

Design: Three electronic databases and a trial platform were searched for all relevant studies, from inception until February 2020, without restrictions. Random-effects meta-analyses provided pooled effect-sizes (ES) with 95% confidence intervals (CI). Dose-response analyses modelling the relationship between number of days exposed to antibiotics and CRC risk were extended to non-linear multivariable random-effects models.

Results: Of 6483 identified publications ten were eligible, including 4.1 million individuals and over 73,550 CRC cases. The pooled CRC risk was increased among individuals who ever-used antibiotics (ES = 1.17, 95%CI 1.05-1.30), particularly for broad-spectrum antibiotics (ES = 1.70, 95%CI 1.26-2.30), but not for narrow-spectrum antibiotic (ES = 1.11, 95% 0.93-1.32). The dose-response analysis did not provide strong evidence of any particular dose-response association, and the risk patterns were rather similar for colon and rectal cancer.

Discussion: The antibiotic use associated CRC risk seemingly differs between broad- and narrow-spectrum antibiotics, and possibly within the colorectal continuum. It remains unclear whether this association is causal, requiring more mechanistic studies and further clarification of drug-microbiome interactions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41416-020-01082-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7722751PMC
December 2020

Trial watch : the gut microbiota as a tool to boost the clinical efficacy of anticancer immunotherapy.

Oncoimmunology 2020 06 3;9(1):1774298. Epub 2020 Jun 3.

Gustave Roussy Comprehensive Cancer Institute, Villejuif, France.

Accumulating evidence demonstrates the decisive role of the gut microbiota in determining the effectiveness of anticancer therapeutics such as immunogenic chemotherapy or immune checkpoint blockade in preclinical tumor models, as well as in cancer patients. In synthesis, it appears that a normal intestinal microbiota supports therapeutic anticancer responses, while a dysbiotic microbiota that lacks immunostimulatory bacteria or contains overabundant immunosuppressive species causes treatment failure. These findings have led to the design of clinical trials that evaluate the capacity of modulation of the gut microbiota to synergize with treatment and hence limit tumor progression. Along the lines of this Trial Watch, we discuss the rationale for harnessing the gut microbiome in support of cancer therapy and the progress of recent clinical trials testing this new therapeutic paradigm in cancer patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/2162402X.2020.1774298DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7466862PMC
June 2020

Compositional and functional differences of the mucosal microbiota along the intestine of healthy individuals.

Sci Rep 2020 09 11;10(1):14977. Epub 2020 Sep 11.

Centre for Host-Microbiome Interactions, Dental Institute, King's College London, London, UK.

Gut mucosal microbes evolved closest to the host, developing specialized local communities. There is, however, insufficient knowledge of these communities as most studies have employed sequencing technologies to investigate faecal microbiota only. This work used shotgun metagenomics of mucosal biopsies to explore the microbial communities' compositions of terminal ileum and large intestine in 5 healthy individuals. Functional annotations and genome-scale metabolic modelling of selected species were then employed to identify local functional enrichments. While faecal metagenomics provided a good approximation of the average gut mucosal microbiome composition, mucosal biopsies allowed detecting the subtle variations of local microbial communities. Given their significant enrichment in the mucosal microbiota, we highlight the roles of Bacteroides species and describe the antimicrobial resistance biogeography along the intestine. We also detail which species, at which locations, are involved with the tryptophan/indole pathway, whose malfunctioning has been linked to pathologies including inflammatory bowel disease. Our study thus provides invaluable resources for investigating mechanisms connecting gut microbiota and host pathophysiology.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-020-71939-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7486370PMC
September 2020

Integration of molecular profiles in a longitudinal wellness profiling cohort.

Nat Commun 2020 09 8;11(1):4487. Epub 2020 Sep 8.

Science for Life Laboratory, Department of Protein Science, KTH Royal Institute of Technology, Stockholm, Sweden.

An important aspect of precision medicine is to probe the stability in molecular profiles among healthy individuals over time. Here, we sample a longitudinal wellness cohort with 100 healthy individuals and analyze blood molecular profiles including proteomics, transcriptomics, lipidomics, metabolomics, autoantibodies and immune cell profiling, complemented with gut microbiota composition and routine clinical chemistry. Overall, our results show high variation between individuals across different molecular readouts, while the intra-individual baseline variation is low. The analyses show that each individual has a unique and stable plasma protein profile throughout the study period and that many individuals also show distinct profiles with regards to the other omics datasets, with strong underlying connections between the blood proteome and the clinical chemistry parameters. In conclusion, the results support an individual-based definition of health and show that comprehensive omics profiling in a longitudinal manner is a path forward for precision medicine.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-020-18148-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7479148PMC
September 2020

No evidence for a placental microbiome in human pregnancies at term.

Am J Obstet Gynecol 2021 03 29;224(3):296.e1-296.e23. Epub 2020 Aug 29.

Centre for Translational Microbiome Research, Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, Stockholm, Sweden; Science for Life Laboratory, Karolinska Institutet, Stockholm, Sweden. Electronic address:

Background: The placenta plays an important role in the modulation of pregnancy immunity; however, there is no consensus regarding the existence of a placental microbiome in healthy full-term pregnancies.

Objective: This study aimed to investigate the existence and origin of a placental microbiome.

Study Design: A cross-sectional study comparing samples (3 layers of placental tissue, amniotic fluid, vernix caseosa, and saliva, vaginal, and rectal samples) from 2 groups of full-term births: 50 women not in labor with elective cesarean deliveries and 26 with vaginal deliveries. The comparisons were performed using polymerase chain reaction amplification and DNA sequencing techniques and bacterial culture experiments.

Results: There were no significant differences regarding background characteristics between women who delivered by elective cesarean and those who delivered vaginally. Quantitative measurements of bacterial content in all 3 placental layers (quantitative polymerase chain reaction of the 16S ribosomal RNA gene) did not show any significant difference among any of the sample types and the negative controls. Here, 16S ribosomal RNA gene sequencing of the maternal side of the placenta could not differentiate between bacteria in the placental tissue and contamination of the laboratory reagents with bacterial DNA. Probe-specific quantitative polymerase chain reaction for bacterial taxa suspected to be present in the placenta could not detect any statistically significant difference between the 2 groups. In bacterial cultures, substantially more bacteria were observed in the placenta layers from vaginal deliveries than those from cesarean deliveries. In addition, 16S ribosomal RNA gene sequencing of bacterial colonies revealed that most of the bacteria that grew on the plates were genera typically found in human skin; moreover, it revealed that placentas delivered vaginally contained a high prevalence of common vaginal bacteria. Bacterial growth inhibition experiments indicated that placental tissue may facilitate the inhibition of bacterial growth.

Conclusion: We found no evidence to support the existence of a placental microbiome in our study of 76 term pregnancies, which used polymerase chain reaction amplification and sequencing techniques and bacterial culture experiments. Incidental findings of bacterial species could be due to contamination or to low-grade bacterial presence in some locations; such bacteria do not represent a placental microbiome per se.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ajog.2020.08.103DOI Listing
March 2021

Liver X receptor regulates Th17 and RORγt Treg cells by distinct mechanisms.

Mucosal Immunol 2021 03 17;14(2):411-419. Epub 2020 Jul 17.

Division of Immunology and Allergy, Department of Medicine, Solna, Karolinska Institutet and University Hospital, Stockholm, Sweden.

The gastrointestinal microenvironment, dominated by dietary compounds and the commensal bacteria, is a major driver of intestinal CD4 T helper (Th) cell differentiation. Dietary compounds can be sensed by nuclear receptors (NRs) that consequently exert pleiotropic effects including immune modulation. Here, we found that under homeostatic conditions the NR Liver X receptor (LXR), a sensor of cholesterol metabolites, regulates RORγt CD4 T cells in the intestine draining mesenteric lymph node (MLN). While LXR activation led to a decrease, LXR-deficiency resulted in an increase in MLN Th17 and RORγt Tregs. Mechanistically, LXR signaling in CD11c myeloid cells was required to control RORγt Treg. By contrast, modulation of MLN Th17 was independent of LXR signaling in either immune or epithelial cells. Of note, horizontal transfer of microbiota between LXRα and WT mice was sufficient to only partially increase MLN Th17 in WT mice. Despite LXRα deficiency resulted in an increased abundance of Ruminococcaceae and Lachnospiraceae bacterial families compared to littermate controls, microbiota ablation (including SFB) was not sufficient to dampen LXRα-mediated expansion of MLN Th17. Altogether, our results suggest that LXR modulates RORγt Treg and Th17 cells in the MLN through distinct mechanisms.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41385-020-0323-5DOI Listing
March 2021

Antibiotic use and the risk of breast cancer: A systematic review and dose-response meta-analysis.

Pharmacol Res 2020 10 15;160:105072. Epub 2020 Jul 15.

Centre for Translational Microbiome Research (CTMR), Dept. of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Biomedicum Kvarter 8A, Tomtebodavägen 16, SE-171 65, Stockholm, Sweden; Science for Life Laboratory (SciLifeLab), SE-171 21 Stockholm, Sweden.

Objective: Oral antibiotics are posed as a possible risk factor for breast cancer. Evidence is insufficient to determine whether the choice of antibiotic class could effect this potential association, and non-linearity has not been studied. We aimed to fill these important knowledge gaps.

Methods: PubMed, Web of Science, Embase and a trial registry were searched from inception until January 2020, without any restrictions. Additionally, extensive manual searches were undertaken. Random-effects meta-analyses provided pooled risk estimates with 95 % confidence intervals (CI). Dose-response analyses modeling the relationship between number of antibiotic prescriptions and breast cancer risk were extended to non-linear models. Heterogeneity, publication bias and small-study effects were assessed.

Results: Of 7805 identified publications ten were eligible, including 3,719,383 individuals and 84,485 breast cancer cases. The pooled breast cancer risk was modestly increased among individuals who ever used antibiotics (relative risk RR = 1.18, 95 %CI 1.08-1.29), also after excluding the last year prior diagnosis. This excess risk was seen among penicillin (RR = 1.09, 95 %CI 1.01-1.18), tetracycline (RR = 1.13, 95 %CI 1.04-1.24) and nitrofuran users (RR = 1.26, 95 %CI 1.05-1.52), whilst nitroimidazole and metronidazole use (RR = 1.05, 95 %CI 1.00-1.11) indicated for marginal association. No apparent association was found for other antibiotics. Data suggested for a non-linear dose-dependent relationship, with a seemingly protective effect after at least 35 prescriptions. However, these findings might partly be explained by limited power of dose-response analyses.

Conclusions: The association of antibiotics with breast cancer risk appears to differ between the various antibiotic classes. Whether this association is causal remains unclear, requiring further clarification and mechanistic studies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.phrs.2020.105072DOI Listing
October 2020
-->