James Kinross

Host-Gut Microbiota Metabolic Interactions

The composition and activity of the gut microbiota codevelop with the host from birth and is subject to a complex interplay that depends on the host genome, nutrition, and life-style. The gut microbiota is involved in the regulation of multiple host metabolic pathways, giving rise to interactive host-microbiota metabolic, signaling, and immune-inflammatory axes that physiologically connect the gut, liver, muscle, and brain. A deeper understanding of these axes is a prerequisite for optimizing therapeutic strategies to manipulate the gut microbiota to combat disease and improve health.

The gut microbiota and host health: a new clinical frontier

Over the last 10–15 years, our understanding of the composition and functions of the human gut microbiota has increased exponentially. To a large extent, this has been due to new ‘omic’ technologies that have facilitated large-scale analysis of the genetic and metabolic profile of this microbial community, revealing it to be comparable in influence to a new organ in the body and offering the possibility of a new route for therapeutic intervention. Moreover, it might be more accurate to think of it like an immune system: a collection of cells that work in unison with the host and that can promote health but sometimes initiate disease. This review gives an update on the current knowledge in the area of gut disorders, in particular metabolic syndrome and obesity-related disease, liver disease, IBD and colorectal cancer. The potential of manipulating the gut microbiota in these disorders is assessed, with an examination of the latest and most relevant evidence relating to antibiotics, probiotics, prebiotics, polyphenols and faecal microbiota transplantation.

Metabolic surgery profoundly influences gut microbial–host metabolic cross-talk

Background and aims Bariatric surgery is increasingly performed worldwide to treat morbid obesity and is also known as metabolic surgery to reflect its beneficial metabolic effects especially with respect to improvement in type 2 diabetes. Understanding surgical weight loss mechanisms and metabolic modulation is required to enhance patient benefits and operative outcomes. Methods The authors applied a parallel and statistically integrated bacterial profiling and metabonomic approach to characterise Roux-en-Y gastric bypass (RYGB) effects in a non-obese rat model. Results Substantial shifts of the main gut phyla towards higher concentrations of Proteobacteria (52-fold), specifically Enterobacter hormaechei, are shown. Low concentrations of Firmicutes (4.5-fold) and Bacteroidetes (twofold) in comparison with sham-operated rats were also found. Faecal extraction studies revealed a decrease in faecal bile acids and a shift from protein degradation to putrefaction through decreased faecal tyrosine with concomitant increases in faecal putrescine and diaminoethane. Decreased urinary amines and cresols were found and indices of modulated energy metabolism were demonstrated after RYGB, including decreased urinary succinate, 2-oxoglutarate, citrate and fumarate. These changes could also indicate renal tubular acidosis, which is associated with increased flux of mitochondrial tricarboxylic acid cycle intermediates. A surgically induced effect on the gut–brain–liver metabolic axis is inferred from modulated faecal γ-aminobutyric acid and glutamate. Conclusion This profound co-dependence of mammalian and microbial metabolism, which is systematically altered after RYGB surgery, suggests that RYGB exerts local and global metabolic effects. The effect of RYGB surgery on the host metabolic–microbial cross-talk augments our understanding of the metabolic phenotype of bariatric procedures and can facilitate enhanced treatments for obesity-related diseases.

Metabolic phenotyping in clinical and surgical environments

Metabolic phenotyping involves the comprehensive analysis of biological fluids or tissue samples. This analysis allows biochemical classification of a persons physiological or pathological states that relate to disease diagnosis or prognosis at the individual level and to disease risk factors at the population level. These approaches are currently being implemented in hospital environments and in regional phenotyping centres worldwide. The ultimate aim of such work is to generate information on patient biology using techniques such as patient stratification to better inform clinicians on factors that will enhance diagnosis or the choice of therapy. There have been many reports of direct applications of metabolic phenotyping in a clinical setting.

Fat, fibre and cancer risk in African Americans and rural Africans

Rates of colon cancer are much higher in African Americans (65:100,000) than in rural South Africans (<5:100,000). The higher rates are associated with higher animal protein and fat and lower fiber consumption, higher colonic secondary bile acids, lower colonic short chain fatty acid quantities and higher mucosal proliferative biomarkers of cancer risk in otherwise healthy middle aged volunteers. Here we investigate further the role of fat and fiber in this association. We performed two-week food exchanges in subjects from the same populations, where African Americans were fed a high-fiber, lowfat African-style diet, and rural Africans a high-fat low-fiber western-style diet under close supervision. In comparison to their usual diets, the food changes resulted in remarkable reciprocal changes in mucosal biomarkers of cancer risk and in aspects of the microbiota and metabolome known to affect cancer risk, best illustrated by increased saccharolytic fermentation and butyrogenesis and suppressed secondary bile acid synthesis in the African Americans.

Intraoperative Tissue Identification Using Rapid Evaporative Ionization Mass Spectrometry

A mass spectrometric approach was developed for intraoperative identification of cancerous tissue, in near–real-time. Diagnosing the Masses One of the best options for curing cancer is surgery. Yet, surgeons can leave cancerous tissue behind by not seeing the “tumor margins”—or edges of the tumor—clearly. If a surgeon isn’t sure whether tissue is normal or cancerous, the tissue is sent to a pathologist for testing. During this time (20 to 30 min), the patient remains under anesthesia, and, quite often, additional samples are required. To ensure that all malignant tissue is removed in the operating room, Balog and colleagues developed a mass spectrometry–based approach that identifies cancer during surgery. After analyzing ex vivo samples of cancerous, healthy, and benign/inflammatory tissue with rapid evaporative ionization mass spectrometry (REIMS), the authors created a database of the nearly 3000 tissue-specific mass spectra. These spectra were unique for each cancer type, with lipids such as phosphatidylcholine and phosphotidylinositol showing different ratios. Using these ratios, Balog et al. were even able to identify the origin of metastatic tumors ex vivo. To adapt this technology for use in vivo, during surgery, the authors created the “intelligent knife” (iKnife), which samples surgical smoke for mass spectrometric analysis. More than 800 spectra were acquired with the iKnife from 81 patients. These spectra, when matched against the previously created database, confirmed the results of normal histology, with low rates of false-positive and false-negative readouts. This first-in-human demonstration shows that the iKnife technology is ready for widespread use in the operating room to improve the accuracy of surgical intervention in cancer. Rapid evaporative ionization mass spectrometry (REIMS) is an emerging technique that allows near–real-time characterization of human tissue in vivo by analysis of the aerosol (“smoke”) released during electrosurgical dissection. The coupling of REIMS technology with electrosurgery for tissue diagnostics is known as the intelligent knife (iKnife). This study aimed to validate the technique by applying it to the analysis of fresh human tissue samples ex vivo and to demonstrate the translation to real-time use in vivo in a surgical environment. A variety of tissue samples from 302 patients were analyzed in the laboratory, resulting in 1624 cancerous and 1309 noncancerous database entries. The technology was then transferred to the operating theater, where the device was coupled to existing electrosurgical equipment to collect data during a total of 81 resections. Mass spectrometric data were analyzed using multivariate statistical methods, including principal components analysis (PCA) and linear discriminant analysis (LDA), and a spectral identification algorithm using a similar approach was implemented. The REIMS approach differentiated accurately between distinct histological and histopathological tissue types, with malignant tissues yielding chemical characteristics specific to their histopathological subtypes. Tissue identification via intraoperative REIMS matched the postoperative histological diagnosis in 100% (all 81) of the cases studied. The mass spectra reflected lipidomic profiles that varied between distinct histological tumor types and also between primary and metastatic tumors. Thus, in addition to real-time diagnostic information, the spectra provided additional information on divergent tumor biochemistry that may have mechanistic importance in cancer.

Therapeutic Modulation of Microbiota-Host Metabolic Interactions

Abnormal microbial-host metabolic interactions underlying disease provide new targets for therapeutic intervention. The complex metabolic relationships between the host and its microbiota change throughout life and vary extensively between individuals, affecting disease risk factors and therapeutic responses through drug metabolism. Elucidating the biochemical mechanisms underlying this human supraorganism symbiosis is yielding new therapeutic insights to improve human health, treat disease, and potentially modify human disease risk factors. Therapeutic options include targeting drugs to microbial genes or co-regulated host pathways and modifying the gut microbiota through diet, probiotic and prebiotic interventions, bariatric surgery, fecal transplants, or ecological engineering. The age-associated co-development of the host and its microbiota provides a series of windows for therapeutic intervention from early life through old age.

Metabolic Phenotyping and Systems Biology Approaches to Understanding Metabolic Syndrome and Fatty Liver Disease

Metabolic syndrome, a cluster of risk factors for type 2 diabetes mellitus and cardiovascular disease, is becoming an increasing global health concern. Insulin resistance is often associated with metabolic syndrome and also typical hepatic manifestations such as nonalcoholic fatty liver disease. Profiling of metabolic products (metabolic phenotyping or metabotyping) has provided new insights into metabolic syndrome and nonalcoholic fatty liver disease. Data from nuclear magnetic resonance spectroscopy and mass spectrometry combined with statistical modeling and top-down systems biology have allowed us to analyze and interpret metabolic signatures in terms of metabolic pathways and protein interaction networks and to identify the genomic and metagenomic determinants of metabolism. For example, metabolic phenotyping has shown that relationships between host cells and the microbiome affect development of the metabolic syndrome and fatty liver disease. We review recent developments in metabolic phenotyping and systems biology technologies and how these methodologies have provided insights into the mechanisms of metabolic syndrome and nonalcoholic fatty liver disease. We discuss emerging areas of research in this field and outline our vision for how metabolic phenotyping could be used to study metabolic syndrome and fatty liver disease.

Laparoscopic versus open appendectomy for complicated and uncomplicated appendicitis in children.

BackgroundAppendectomy is one of the most common emergency operations performed in the pediatric population. The aim of this pooled analysis is to compare the outcome from complicated appendicitis (CA) and uncomplicated appendicitis (UA) following laparoscopic appendectomy (LA) and open appendectomy (OA) in children.MethodsA systematic literature search was performed. Primary outcome measures were incidence of complications, intra-abdominal abscess, and wound infection. Secondary outcomes were length of operation, length of hospital stay, incidence of bowel obstruction, and readmission.ResultsSeventy-three thousand one hundred fifty appendectomies for UA and 34,474 appendectomies for CA were included. For UA, the only significant difference between the groups was a reduced length of hospital stay following LA. LA in CA was associated with reduced complications (pooled odds ratio [POR] = 0.53; P < 0.05), wound infections (POR = 0.42; P < 0.05), length of hospital stay (WMD = −0.67; P < 0.05), and bowel obstruction episodes (POR = 0.8; P < 0.05), but an increased incidence of intra-abdominal abscess and length of operation.ConclusionPooled analysis demonstrates that, in children with uncomplicated acute appendicitis, LA is associated with a reduced hospital stay but broad equivalence in postoperative morbidity when compared with the conventional approach. Although overall morbidity is reduced when the laparoscopic approach is utilized, in cases of CA, the risk of intra-abdominal abscess is increased.

Metabolic phenotyping for monitoring surgical patients.

www.thelancet.com Vol 377 May 28, 2011 1817 Many challenges remain, not least of which is the harmonisation between DSM-5 and its WHO counterpart, the ICD-11, of the categories and descriptions for specifi c disorders and not just the overall architecture of the classifi cation. The APA would also do well to think about the congruence between DSM-5 and global public health, for example by considering the forthcoming primary care version of ICD, and WHO’s Mental Health Gap Action Programme intervention guide for mental, neurological, and substance use disorders in non-specialised health settings. It is unfortunate that the APA’s President, Carol Bernstein, made no reference to the “bed net” of global mental health in her recent discussion of DSM-5’s progress. Anyone with a stake in mental health would be well advised to go to the APA’s website and take part in the ongoing consultation about DSM-5’s structure, which closes on June 15. Bernstein has likened the rewriting of the manual to “repairing a plane while keeping it fl ying”. DSM-5 now looks like it might, despite a turbulent takeoff , achieve a safe landing at the APA’s San Francisco meeting in 2013.