Perturbations of the composition and function of the gut microbiota have been associated with metabolic disorders including obesity, insulin resistance and type 2 diabetes. Studies on mice have ...demonstrated several underlying mechanisms including host signalling through bacterial lipopolysaccharides derived from the outer membranes of Gram-negative bacteria, bacterial fermentation of dietary fibres to short-chain fatty acids and bacterial modulation of bile acids. On top of this, an increased permeability of the intestinal epithelium may lead to increased absorption of macromolecules from the intestinal content resulting in systemic immune responses, low-grade inflammation and altered signalling pathways influencing lipid and glucose metabolism. While mechanistic studies on mice collectively support a causal role of the gut microbiota in metabolic diseases, the majority of studies in humans are correlative of nature and thus hinder causal inferences. Importantly, several factors known to influence the risk of type 2 diabetes, e.g. diet and age, have also been linked to alterations in the gut microbiota complicating the interpretation of correlative studies. However, based upon the available evidence, it is hypothesised that the gut microbiota may mediate or modulate the influence of lifestyle factors triggering development of type 2 diabetes. Thus, the aim of this review is to critically discuss the potential role of the gut microbiota in the pathophysiology and pathogenesis of type 2 diabetes.
The effects of probiotic supplementation on fecal microbiota composition in healthy adults have not been well established. We aimed to provide a systematic review of the potential evidence for an ...effect of probiotic supplementation on the composition of human fecal microbiota as assessed by high-throughput molecular approaches in randomized controlled trials (RCTs) of healthy adults.
The survey of peer-reviewed papers was performed on 17 August 2015 by a literature search through PubMed, SCOPUS, and ISI Web of Science. Additional papers were identified by checking references of relevant papers. Search terms included healthy adult, probiotic, bifidobacterium, lactobacillus, gut microbiota, fecal microbiota, intestinal microbiota, intervention, and (clinical) trial. RCTs of solely probiotic supplementation and placebo in healthy adults that examined alteration in composition of overall fecal microbiota structure assessed by shotgun metagenomic sequencing, 16S ribosomal RNA sequencing, or phylogenetic microarray methods were included. Independent collection and quality assessment of studies were performed by two authors using predefined criteria including methodological quality assessment of reports of the clinical trials based on revised tools from PRISMA/Cochrane and by the Jadad score.
Seven RCTs investigating the effect of probiotic supplementation on fecal microbiota in healthy adults were identified and included in the present systematic review. The quality of the studies was assessed as medium to high. Still, no effects were observed on the fecal microbiota composition in terms of α-diversity, richness, or evenness in any of the included studies when compared to placebo. Only one study found that probiotic supplementation significantly modified the overall structure of the fecal bacterial community in terms of β-diversity when compared to placebo.
This systematic review of the pertinent literature demonstrates a lack of evidence for an impact of probiotics on fecal microbiota composition in healthy adults. Future studies would benefit from pre-specifying the primary outcome and transparently reporting the results including effect sizes, confidence intervals, and P values as well as providing a clear distinction of between-group and within-group comparisons.
Aims/hypothesis
Individuals with type 2 diabetes have an altered bacterial composition of their gut microbiota compared with non-diabetic individuals. However, these alterations may be confounded by ...medication, notably the blood-glucose-lowering biguanide, metformin. We undertook a clinical trial in healthy and previously drug-free men with the primary aim of investigating metformin-induced compositional changes in the non-diabetic state. A secondary aim was to examine whether the pre-treatment gut microbiota was related to gastrointestinal adverse effects during metformin treatment.
Methods
Twenty-seven healthy young Danish men were included in an 18-week one-armed crossover trial consisting of a pre-intervention period, an intervention period and a post-intervention period, each period lasting 6 weeks. Inclusion criteria were men of age 18–35 years, BMI between 18.5 kg/m
2
and 27.5 kg/m
2
, HbA
1c
< 39 mmol/mol (5.7%) and plasma creatinine within the normal range. No prescribed medication, including antibiotics, for 2 months prior to recruitment were allowed and no previous gastrointestinal surgery, discounting appendectomy or chronic illness requiring medical treatment. During the intervention the participants were given metformin up to 1 g twice daily. Participants were examined five times in the fasting state with blood sampling and recording of gastrointestinal symptoms. Examinations took place at Frederiksberg Hospital, Denmark before and after the pre-intervention period, halfway through and immediately after the end of intervention and after the wash-out period. Faecal samples were collected at nine evenly distributed time points, and bacterial DNA was extracted and subjected to 16S rRNA gene amplicon sequencing in order to evaluate gut microbiota composition. Subjective gastrointestinal symptoms were reported at each visit.
Results
Data from participants who completed visit 1 (
n
=23) are included in analyses. For the primary outcome the relative abundance of 11 bacterial genera significantly changed during the intervention but returned to baseline levels after treatment cessation. In line with previous reports, we observed a reduced abundance of
Intestinibacter
spp. and
Clostridium
spp., as well as an increased abundance of
Escherichia/Shigella
spp. and
Bilophila wadsworthia
. The relative abundance at baseline of 12 bacterial genera predicted self-reported gastrointestinal adverse effects.
Conclusions/interpretation
Intake of metformin changes the gut microbiota composition in normoglycaemic young men. The microbiota changes induced by metformin extend and validate previous reports in individuals with type 2 diabetes. Secondary analyses suggest that pre-treatment gut microbiota composition may be a determinant for development of gastrointestinal adverse effects following metformin intake. These results require further investigation and replication in larger prospective studies.
Trial registration
Clinicaltrialsregister.eu 2015-000199-86 and ClinicalTrials.gov NCT02546050
Funding
This project was funded by Danish Diabetes Association and The Novo Nordisk Foundation
The aim of this review is to summarize present evidence of an association between circulating levels of C-reactive protein (CRP) and cancer risk, and to evaluate whether elevated circulating CRP ...levels cause cancer. Additionally, the review provides background information on the acute-phase response, chronic inflammation, the molecular biology, function and measurement of CRP, circulating levels of CRP in health and disease, the principle of Mendelian randomization, the association between circulating levels of CRP and cancer prognosis, and cancer biomarkers.
In the Copenhagen General Population Study of approximately 63,500 individuals, the distribution of circulating levels of CRP was markedly skewed to the right with 97% of the participants having CRP levels <10 mg/L. The median plasma CRP concentration was 1.53 mg/L (IQR, 1.14-2.51) and 34% of the participants had circulating CRP levels of ≥ 2 mg/L.
Epidemiologic studies suggest that in patients with several types of solid cancers, elevated circulating levels of CRP are associated with poor prognosis, whereas in apparently healthy individuals from the general population, elevated levels of CRP are associated with increased future risk of cancer of any type, lung cancer, and possibly colorectal cancer, but not breast or prostate cancer. The robust association between circulating levels of CRP and cancer risk may be due to (1) causality: elevated CRP levels cause cancer, (2) reverse causality: occult cancer increases CRP levels, (3) or confounding: a third factor, e.g. inflammation, increases both CRP levels and the risk of cancer. Genetic epidemiologic studies (Mendelian randomization studies), which have examined the association between genetic polymorphisms influencing circulating levels of CRP and cancer risk suggest that circulating levels of CRP do not cause cancer.
A lack of causality between elevated CRP levels and increased cancer risk does, however, not invalidate the potential clinical use of slightly increased CRP levels to predict risk of certain cancer types, and to improve staging and treatment allocation in patients diagnosed with cancer. Indeed, in a study of the general population, individuals with CRP levels in the highest versus the lowest quintile had a 1.3-fold increased risk of cancer of any type and a 2-fold increased risk of lung cancer. Among individuals diagnosed with cancer during the study period, individuals with a high baseline CRP (>3 mg/L) had an 80% greater risk of early death compared with those with low CRP levels (<1 mg/L). Accordingly, patients with invasive breast cancer and CRP levels >3 mg/L at diagnosis had a 1.7-fold increased risk of death from breast cancer compared to patients with CRP levels <1 mg/L at diagnosis.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK, VSZLJ
We tested the hypothesis that baseline plasma levels of C-reactive protein (CRP) are associated with risk of incident cancer in the general population and early death in patients with cancer.
A total ...of 10,408 individuals from the Danish general population who had CRP measured at baseline were observed for up to 16 years; 1,624 developed cancer, and of these, 998 patients died during follow-up. Follow-up was 100% complete. We excluded individuals with a cancer diagnosis at baseline.
Baseline CRP levels more than 3 versus less than 1 mg/L were associated with multifactorially adjusted hazard ratios of 1.3 (95% CI, 1.0 to 1.6) for cancer of any type, 2.2 (95% CI, 1.0 to 4.6) for lung cancer, 1.9 (95% CI, 0.8 to 4.6) for colorectal cancer, and 0.7 (95% CI, 0.4 to 1.4) for breast cancer. Corresponding hazard ratios for the highest versus the lowest quintile of baseline CRP levels were 1.3 (95% CI, 1.0 to 1.6), 2.1 (95% CI, 1.2 to 3.8), 1.7 (95% CI, 0.8 to 3.2), and 0.9 (95% CI, 0.5 to 1.7), respectively. Multifactorially adjusted hazard ratios for early death in patients with cancer were 1.8 (95% CI, 1.2 to 2.7) for CRP more than 3 versus less than 1 mg/L and 1.4 (95% CI, 1.1 to 1.7) for the highest versus the lowest quintile. Elevated CRP levels were associated with early death in patients with cancer having localized disease, but not in those with metastases (interaction; P = .03).
Elevated levels of CRP in cancer-free individuals are associated with increased risk of cancer of any type, of lung cancer, and possibly of colorectal cancer. Moreover, elevated levels of baseline CRP associate with early death after a diagnosis of any cancer, particularly in patients without metastases.
Little is known about the effect of long-term diet patterns on the composition and functional potential of the human salivary microbiota. In the present study, we sought to contribute to the ongoing ...elucidation of dietary effects on the oral microbial community by examining the diversity, composition and functional potential of the salivary microbiota in 160 healthy vegans and omnivores using 16S rRNA gene amplicon sequencing. We further sought to identify bacterial taxa in saliva associated with host inflammatory markers. We show that compositional differences in the salivary microbiota of vegans and omnivores is present at all taxonomic levels below phylum level and includes upper respiratory tract commensals (e.g. Neisseria subflava, Haemophilus parainfluenzae, and Rothia mucilaginosa) and species associated with periodontal disease (e.g. Campylobacter rectus and Porphyromonas endodontalis). Dietary intake of medium chain fatty acids, piscine mono- and polyunsaturated fatty acids, and dietary fibre was associated with bacterial diversity, community structure, as well as relative abundance of several species-level operational taxonomic units. Analysis of imputed genomic potential revealed several metabolic pathways differentially abundant in vegans and omnivores indicating possible effects of macro- and micro-nutrient intake. We also show that certain oral bacteria are associated with the systemic inflammatory state of the host.
Inflammation and cancer are tightly linked. This study tests the hypothesis that an inflammatory score based on plasma levels of C‐reactive protein (CRP) and fibrinogen and whole blood leukocyte ...count is associated with risk of colorectal, lung, breast and prostate cancer. A score ranging from none through three elevated biomarkers was constructed in 84,000 individuals from the Danish general population. During a median follow‐up time of 4.8 years, 4,081 incident cancers occurred. Cox proportional hazards regression models were used to estimate hazard ratios (HRs) of incident cancer. Multifactor‐adjusted HRs for colorectal cancer were 1.28 (95% CI, 1.01 to 1.62), 1.79 (95% CI, 1.41 to 2.27) and 2.18 (95% CI, 1.67 to 2.86) for individuals with elevated levels of one, two and three inflammatory biomarkers compared to individuals with none elevated biomarkers. A similar stepwise increasing risk was observed for lung and breast cancer with HRs of 3.03 (95% CI, 2.25 to 4.08) and 1.42 (95% CI, 1.11 to 1.80) for three versus none elevated biomarkers. HRs were highest within the first years of follow‐up. Absolute 5‐year risk of lung cancer was 7.8 (95% CI, 6.1 to 10)% among older smokers with three elevated biomarkers compared to 3.8 (95% CI, 2.6 to 5.6)% among those with none elevated biomarkers. In conclusion, simultaneously elevated CRP, fibrinogen and leukocyte count are associated with an increased risk of colorectal, lung and breast cancer. Cancer as a promoter of inflammation may be more likely to account for our findings than low‐grade inflammation promoting cancer development.
What's new?
Inflammation and cancer are tightly linked. In this prospective study of 84,000 individuals, the authors tested the hypothesis that an inflammatory score based on plasma levels of C‐reactive protein (CRP) and fibrinogen and whole blood leukocyte count is associated with cancer risk. Simultaneously elevated CRP and fibrinogen levels and leukocyte count were associated with an increased risk of colorectal, lung and breast cancer: among those with three versus none elevated biomarkers, the risk was increased 2.2‐, 3.0‐ and 1.4‐fold, respectively. The association was strongest within the first few years after blood sampling, suggesting occult cancer eliciting inflammation as an explanation.
Aims/hypothesis
Individuals with type 2 diabetes have aberrant intestinal microbiota. However, recent studies suggest that metformin alters the composition and functional potential of gut microbiota, ...thereby interfering with the diabetes-related microbial signatures. We tested whether specific gut microbiota profiles are associated with prediabetes (defined as fasting plasma glucose of 6.1–7.0 mmol/l or HbA
1c
of 42–48 mmol/mol 6.0–6.5%) and a range of clinical biomarkers of poor metabolic health.
Methods
In the present case–control study, we analysed the gut microbiota of 134 Danish adults with prediabetes, overweight, insulin resistance, dyslipidaemia and low-grade inflammation and 134 age- and sex-matched individuals with normal glucose regulation.
Results
We found that five bacterial genera and 36 operational taxonomic units (OTUs) were differentially abundant between individuals with prediabetes and those with normal glucose regulation. At the genus level, the abundance of
Clostridium
was decreased (mean log
2
fold change −0.64 (SEM 0.23),
p
adj
= 0.0497), whereas the abundances of
Dorea
,
Ruminococcus
,
Sutterella
and
Streptococcus
were increased (mean log
2
fold change 0.51 (SEM 0.12),
p
adj
= 5 × 10
−4
; 0.51 (SEM 0.11),
p
adj
= 1 × 10
−4
; 0.60 (SEM 0.21),
p
adj
= 0.0497; and 0.92 (SEM 0.21),
p
adj
= 4 × 10
−4
, respectively). The two OTUs that differed the most were a member of the order Clostridiales (OTU 146564) and
Akkermansia muciniphila
, which both displayed lower abundance among individuals with prediabetes (mean log
2
fold change −1.74 (SEM 0.41),
p
adj
= 2 × 10
−3
and −1.65 (SEM 0.34),
p
adj
= 4 × 10
−4
, respectively). Faecal transfer from donors with prediabetes or screen-detected, drug-naive type 2 diabetes to germfree Swiss Webster or conventional C57BL/6 J mice did not induce impaired glucose regulation in recipient mice.
Conclusions/interpretation
Collectively, our data show that individuals with prediabetes have aberrant intestinal microbiota characterised by a decreased abundance of the genus
Clostridium
and the mucin-degrading bacterium
A. muciniphila
. Our findings are comparable to observations in overt chronic diseases characterised by low-grade inflammation.
Aims/hypothesis
Fasting plasma levels of branched-chain amino acids (BCAAs) are associated with insulin resistance, but it remains unclear whether there is a causal relation between the two. We aimed ...to disentangle the causal relations by performing a Mendelian randomisation study using genetic variants associated with circulating BCAA levels and insulin resistance as instrumental variables.
Methods
We measured circulating BCAA levels in blood plasma by NMR spectroscopy in 1,321 individuals from the ADDITION-PRO cohort. We complemented our analyses by using previously published genome-wide association study (GWAS) results from the Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC) (
n
= 46,186) and from a GWAS of serum BCAA levels (
n
= 24,925). We used a genetic risk score (GRS), calculated using ten established fasting serum insulin associated variants, as an instrumental variable for insulin resistance. A GRS of three variants increasing circulating BCAA levels was used as an instrumental variable for circulating BCAA levels.
Results
Fasting plasma BCAA levels were associated with higher HOMA-IR in ADDITION-PRO (β 0.137 95% CI 0.08, 0.19
p
= 6 × 10
−7
). However, the GRS for circulating BCAA levels was not associated with fasting insulin levels or HOMA-IR in ADDITION-PRO (β −0.011 95% CI −0.053, 0.032
p
= 0.6 and β −0.011 95% CI −0.054, 0.031
p
= 0.6, respectively) or in GWAS results for HOMA-IR from MAGIC (β for valine-increasing GRS −0.012 95% CI −0.069, 0.045
p
= 0.7). By contrast, the insulin-resistance-increasing GRS was significantly associated with increased BCAA levels in ADDITION-PRO (β 0.027 95% CI 0.005, 0.048
p
= 0.01) and in GWAS results for serum BCAA levels (β 1.22 95% CI 0.71, 1.73
p
= 4 × 10
−6
, β 0.96 95% CI 0.45, 1.47
p
= 3 × 10
−4
, and β 0.67 95% CI 0.16, 1.18
p
= 0.01 for isoleucine, leucine and valine levels, respectively) and instrumental variable analyses in ADDITION-PRO indicated that HOMA-IR is causally related to higher circulating fasting BCAA levels (β 0.73 95% CI 0.26, 1.19
p
= 0.002).
Conclusions/interpretation
Our results suggest that higher BCAA levels do not have a causal effect on insulin resistance while increased insulin resistance drives higher circulating fasting BCAA levels.
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