The importance of the gut-brain axis in maintaining homeostasis has long been appreciated. However, the past 15 yr have seen the emergence of the microbiota (the trillions of microorganisms within ...

The Microbiota-Gut-Brain Axis

Observational findings achieved during the past two decades suggest that the intestinal microbiota may contribute to the metabolic health of the human host and, when aberrant, to the pathogenesis of various common metabolic disorders including obesity, type 2 diabetes, non-alcoholic liver disease, cardio-metabolic diseases and malnutrition. However, to gain a mechanistic understanding of how the gut microbiota affects host metabolism, research is moving from descriptive microbiota census analyses to cause-and-effect studies. Joint analyses of high-throughput human multi-omics data, including metagenomics and metabolomics data, together with measures of host physiology and mechanistic experiments in humans, animals and cells hold potential as initial steps in the identification of potential molecular mechanisms behind reported associations. In this Review, we discuss the current knowledge on how gut microbiota and derived microbial compounds may link to metabolism of the healthy host or to the pathogenesis of common metabolic diseases. We highlight examples of microbiota-targeted interventions aiming to optimize metabolic health, and we provide perspectives for future basic and translational investigations within the nascent and promising research field. In this Review, Fan and Pedersen discuss how the gut microbiota and derived microbial compounds may contribute to human metabolic health and to the pathogenesis of common metabolic diseases, and highlight examples of microbiota-targeted interventions aiming to optimize metabolic health.

Gut microbiota in human metabolic health and disease.

The Gut Microbiota in the First Decade of Life

Androgen-deprivation therapy (ADT) is a common treatment for men with prostate cancer. Although ADT is effective at suppressing prostate-specific antigen (PSA), stabilizing disease, alleviating symptoms in advanced disease, and potentially prolonging survival, it is not without serious side effects. However, to the authors' knowledge, there is lack of a systematic review of its major adverse effects to date. The authors of this report systematically reviewed and quantitatively assessed the literature on skeletal and cardiac side effects associated with ADT in men with prostate cancer. The PubMed database was searched for relevant published articles from 1966 to May 2008, and 683 articles were reviewed systematically from an original 20 different Medical Subject Heading search combinations. The focus of the review was on bone-related and cardiovascular-related outcomes. When appropriate, results were pooled from articles on specific adverse outcomes, summary risk estimates were calculated, and tests of heterogeneity were performed. Fourteen articles were identified that met inclusion criteria from the original 683 studies. Men who underwent ADT for prostate cancer had a significantly increased risk of overall fracture of 23% (summary relative risk, 1.23; 95% confidence interval [95% CI], 1.10-1.38) compared with men who had prostate cancer but who did not undergo ADT. Furthermore, men who underwent ADT had a 17% increase in cardiovascular-related mortality compared with men who did not undergo with ADT (summary hazards ratio, 1.17; 95% CI, 1.07-1.29). Significant elevations in the risk of diabetes also were observed from 2 large studies. ADT was associated with an increased risk of skeletal fracture, incident diabetes, and cardiovascular-related mortality, although the absolute risk of these events was low. Preventive measures against these adverse effects and careful assessment of patient's baseline health status should be considered. Cancer 2009. © 2009 American Cancer Society.

Review of major adverse effects of androgen-deprivation therapy in men with prostate cancer.

Low concordance between studies that examine the role of microbiota in human diseases is a pervasive challenge that limits the capacity to identify causal relationships between host-associated microorganisms and pathology. The risk of obtaining false positives is exacerbated by wide interindividual heterogeneity in microbiota composition1, probably due to population-wide differences in human lifestyle and physiological variables2 that exert differential effects on the microbiota. Here we infer the greatest, generalized sources of heterogeneity in human gut microbiota profiles and also identify human lifestyle and physiological characteristics that, if not evenly matched between cases and controls, confound microbiota analyses to produce spurious microbial associations with human diseases. We identify alcohol consumption frequency and bowel movement quality as unexpectedly strong sources of gut microbiota variance that differ in distribution between healthy participants and participants with a disease and that can confound study designs. We demonstrate that for numerous prevalent, high-burden human diseases, matching cases and controls for confounding variables reduces observed differences in the microbiota and the incidence of spurious associations. On this basis, we present a list of host variables that we recommend should be captured in human microbiota studies for the purpose of matching comparison groups, which we anticipate will increase robustness and reproducibility in resolving the members of the gut microbiota that are truly associated with human disease.

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Host variables confound gut microbiota studies of human disease.

To minimize the impact of antibiotics, gut microorganisms harbour and exchange antibiotics resistance genes, collectively called their resistome. Using shotgun sequencing-based metagenomics, we analysed the partial eradication and subsequent regrowth of the gut microbiota in 12 healthy men over a 6-month period following a 4-day intervention with a cocktail of 3 last-resort antibiotics: meropenem, gentamicin and vancomycin. Initial changes included blooms of enterobacteria and other pathobionts, such as Enterococcus faecalis and Fusobacterium nucleatum, and the depletion of Bifidobacterium species and butyrate producers. The gut microbiota of the subjects recovered to near-baseline composition within 1.5 months, although 9 common species, which were present in all subjects before the treatment, remained undetectable in most of the subjects after 180 days. Species that harbour β-lactam resistance genes were positively selected for during and after the intervention. Harbouring glycopeptide or aminoglycoside resistance genes increased the odds of de novo colonization, however, the former also decreased the odds of survival. Compositional changes under antibiotic intervention in vivo matched results from in vitro susceptibility tests. Despite a mild yet long-lasting imprint following antibiotics exposure, the gut microbiota of healthy young adults are resilient to a short-term broad-spectrum antibiotics intervention and their antibiotics resistance gene carriage modulates their recovery processes.

Recovery of gut microbiota of healthy adults following antibiotic exposure

This section opens with a nationwide Danish study on the risk of fractures in prostate cancer, as well as assessing the impact of exposure to androgen deprivation. The authors found that there was a marked increase in the risk of fractures, especially of the hip.



Authors from the USA address the outcome of cytoreductive nephrectomy for metastatic RCC, finding that it can be predicted by the fraction of tumour volume removed. They give an informative review of the topic and describe their experience in this type of surgery.



Treatment options for hormonerefractory prostate cancer are rather limited and authors from the USA present the results of a phase II trial into the use of gefitinib as a single therapy in patients with non-metastatic refractory disease. They found an absence of PSA response but confirmed the well-established favourable tolerability profile of this agent.



OBJECTIVE

To assess the risk of fracture attributable to prostate cancer, and the impact of exposure to prescribed gonadotrophin-releasing hormone agonists and antiandrogens on this risk in a nationwide, population-based case-control study.



PATIENTS AND METHODS

Data from the Danish National Hospital Discharge Register, the National Bureau of Statistics, and the National Prescriptions Database were merged. The analysis covered 15 716 men aged >50 years presenting with a fracture at any hospital in Denmark in 2000, and 47 149 age-matched control men. A previous diagnosis of prostate cancer had been recorded in 1.3% of controls and 2.5% of those with a fracture.



RESULTS

Prostate cancer was associated with an increased odds ratio (95% confidence interval) for all fractures of 1.8 (1.6–2.1), for hip fractures of 3.7 (3.1–4.4), but no increased risk of vertebral fractures. The increased fracture risk became apparent early after diagnosis and remained pronounced even in long-term survivors. Androgen deprivation therapy (ADT) with an odds ratio of 1.7  (1.2–2.5; P  50 years are attributable to prostate cancer.



CONCLUSION

Prostate cancer, orchidectomy and the use of ADT are associated with a markedly greater risk of fractures, especially of the hip. The risk of hip fracture is not confined to the very old, neither is the risk made negligible by the excess mortality in patients with advanced prostate cancer.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1464-410X.2007.07163.x

Fracture risk in Danish men with prostate cancer: a nationwide register study.

Systematic studies of autosomal dominant osteopetrosis (ADO) were followed by the identification of underlying mutations giving unique possibilities to perform translational studies. What was previously designated ADO1 turned out to be a high bone mass phenotype caused by a missense mutation in the first propeller of LRP5, a region of importance for binding inhibitory proteins. Thereby, ADO1 cannot be regarded as a classical form of osteopetrosis but must now be considered a disease of LRP5 activation. ADO (Albers-Schonberg disease, or previously ADO2) is characterized by increased number of osteoclasts and a defect in the chloride transport system (ClC-7) of importance for acidification of the resorption lacuna (a form of Chloride Channel 7 Deficiency Osteopetrosis). Ex vivo studies of osteoclasts from ADO have shown that cells do form normally but have reduced resorption capacity and an expanded life span. Bone formation seems normal despite decreased osteoclast function. Uncoupling of formation from resorption makes ADO of interest for new strategies for treatment of osteoporosis. Recent studies have integrated bone metabolism in whole-body energy homeostasis. Patients with ADO may have decreased insulin levels indicating importance beyond bone metabolism. There seems to be a paradigm shift in the treatment of osteoporosis. Targeting ClC-7 might introduce a new principle of dual action. Drugs affecting ClC-7 could be antiresorptive, still allowing ongoing bone formation. Inversely, drugs affecting the inhibitory site of LRP5 might stimulate bone formation and inhibit resorption. Thereby, these studies have highlighted several intriguing treatment possibilities, employing novel modes of action, which could provide benefits to the treatment of osteoporosis.

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Autosomal dominant osteopetrosis revisited: lessons from recent studies.

/pdf/use-of-antibiotics-and-risk-of-type-2-diabetes-a-population-1kfp7qc360.pdf

Use of antibiotics and risk of type 2 diabetes: a population-based case control study

New gene sequencing-based techniques and the large worldwide sequencing capacity have introduced a new era within the field of gut microbiota. Animal and human studies have shown that obesity and type 2 diabetes are associated with changes in the composition of the gut microbiota and that prebiotics, antibiotics or faecal transplantation can alter glucose and lipid metabolism. This paper summarizes the latest research regarding the association between gut microbiota, diabetes and obesity and some of the mechanisms by which gut bacteria may influence host metabolism.

Morten Frost Munk Nielsen

Papers

Recovery of gut microbiota of healthy adults following antibiotic exposure

Fracture risk in Danish men with prostate cancer: a nationwide register study.

Autosomal dominant osteopetrosis revisited: lessons from recent studies.

Use of antibiotics and risk of type 2 diabetes: a population-based case control study

Gut microbiota may have influence on glucose and lipid metabolism