Dietary fat, bile acid metabolism and colorectal cancer.

Colorectal cancer (CRC) risk is predominantly driven by environmental factors, in particular diet. A high intake of dietary fat has been implicated as a risk factor inducing the formation of pre-neoplastic lesions (e.g., adenomatous polyps) and/or exacerbating colonic tumorigenesis. Recent data attributed the tumor-promoting activity of high-fat diets to their effects on gut microbiota composition and metabolism, in particular with regard to bile acids. Bile acids are synthesized in the liver in response to dietary fat and facilitate lipid absorption in the small intestine. The majority of bile acids is re-absorbed during small intestinal transit and subjected to enterohepatic circulation. Bile acids entering the colon undergo complex biotransformation performed by gut bacteria, resulting in secondary bile acids that show tumor-promoting activity. Excessive dietary fat leads to high levels of secondary bile acids in feces and primes the gut microbiota to bile acid metabolism. This promotes an altered overall bile acid pool, which activates or restricts intestinal and hepatic cross-signaling of the bile acid receptor, farnesoid X receptor (FXR). Recent studies provided evidence that FXR is a main regulator of bile acid-mediated effects on intestinal tumorigenesis integrating dietary, microbial and genetic risk factors for CRC. Selective FXR agonist or antagonist activity by specific bile acids depends on additional factors (e.g., bile acid concentration, composition of bile acid pool, genetic instability of cells) and, thus, may differ in healthy and tumorigenic conditions in the intestine. In conclusion, fat-mediated alterations of the gut microbiota link bile acid metabolism to CRC risk and colonic tumorigenesis, exemplifying how gut microbial co-metabolism affects colon health.

Interactions between the environmental and human microbiota in the preservation of health and genesis of disease: symposium report.

PURPOSE OF REVIEW: The purpose of this symposium was to bring thought leaders in the microbiome from the west to Africa to share their unique experiences with African investigators in order to build the foundations for scientifically rigorous explorations into the African human and environmental microbiome that may explain why disease patterns are different in Africa where the chief killers are infectious diseases, whereas noncommunicable diseases (NCDs) are the major threat to healthcare resources in the developed world. RECENT FINDINGS: The application of new high throughput technologies to the investigation of the microbiome and its metabolome has revealed mechanisms whereby a traditional African high fiber diet can suppress NCDs which include colon cancer, inflammatory bowel diseases, obesity, type 2 diabetes and atherosclosis. There is concern that with migration and westernization, NCDs are becoming more common in Africa and that food security is becoming impaired by unbalanced obesogenic foods rather than inadequate food intake. SUMMARY: There is an urgent need for the formation of combined African-Western research programs to identify what is good and bad in the African diet-microbiome axis to develop strategies to prevent the incidence of NCDs rising to western levels in Africa, at the same time offering novel prevention strategies against the #1 healthcare threat in the developed world.

A simplified method for the quantitation of short-chain fatty acids in human stool.

A one-vial extraction method for the quantitation of short-chain fatty acids (SCFAs) in human stool was developed. Samples were extracted with an acidified aqueous internal standard solution, sodium sulfate, and diethyl ether, followed by analysis with GC-FID. Accuracy, in terms of relative recovery, was typically between 90 and 110% for most analytes; without internal standard, the accuracy was about 5-34%; the linear dynamic range (LDR) was 0.05-50 µmol per gram; the limit of detection (LOD) was less than or equal to 0.05 µmol per gram; and the (lower) limit of quantitation (LOQ) was 1 µmol per gram. The method is suitable for quantitating acetic acid, propanoic acid, isobutyric acid, butyric acid, isovaleric acid, valeric acid, isohexanoic acid, hexanoic acid, and heptanoic acid. It is not suitable for the quantitation of formic acid. Application to human biological research was tested by the measurement of SCFA in heathy humans. This confirmed that the method performed adequately, and even better than expected, with values up to 150 µmol per gram.

Weak Microbial Metabolites: a Treasure Trove for Using Biomimicry to Discover and Optimize Drugs.

For decades, traditional drug discovery has used natural product and synthetic chemistry approaches to generate libraries of compounds, with some ending as promising drug candidates. A complementary approach has been to adopt the concept of biomimicry of natural products and metabolites so as to improve multiple drug-like features of the parent molecule. In this effort, promiscuous and weak interactions between ligands and receptors are often ignored in a drug discovery process. In this Emerging Concepts article, we highlight microbial metabolite mimicry, whereby parent metabolites have weak interactions with their receptors that then have led to discrete examples of more potent and effective drug-like molecules. We show specific examples of parent-metabolite mimics with potent effects in vitro and in vivo. Furthermore, we show examples of emerging microbial ligand-receptor interactions and provide a context in which these ligands could be improved as potential drugs. A balanced conceptual advance is provided in which we also acknowledge potential pitfalls-hyperstimulation of finely balanced receptor-ligand interactions could also be detrimental. However, with balance, we provide examples of where this emerging concept needs to be tested. SIGNIFICANCE STATEMENT: Microbial metabolite mimicry is a novel way to expand on the chemical repertoire of future drugs. The emerging concept is now explained using specific examples of the discovery of therapeutic leads from microbial metabolites.

Diet and the Human Gut Microbiome: An International Review.

This review summarizes the key results of recently published studies on the effects of dietary change and nutritional intervention on the human microbiome from around the world, focusing on the USA, Canada, Europe, Asia, and Africa. It first explores mechanisms that might explain the ability of fiber-rich foods to suppress the incidence and mortality from westernized diseases, notably cancers of the colon, breast, liver, cardiovascular, infectious, and respiratory diseases, diabetes, and obesity (O'Keefe in Lancet Gastroenterol Hepatol 4(12):984-996, 2019; Am J Clin Nutr 110:265-266, 2019). It summarizes studies from Africa which suggest that disturbance of the colonic microbiome may exacerbate chronic malnutrition and growth failure in impoverished communities and highlights the importance of breast feeding. The American section discusses the role of the microbiome in the swelling population of patients with obesity and type 2 diabetes and examines the effects of race, ethnicity, geography, and climate on microbial diversity and metabolism. The studies from Europe and Asia extoll the benefits of whole foods and plant-based diets. The Asian studies examine the worrying changes from low-fat, high-carbohydrate diets to high-fat, low-carbohydrate ones and the increasing appearance of westernized diseases as in Africa and documents the ability of high-fiber traditional Chinese diets to reverse type 2 diabetes and control weight loss. In conclusion, most of the studies reviewed demonstrate clear changes in microbe abundances and in the production of fermentation products, such as short-chain fatty acids and phytochemicals following dietary change, but the significance of the microbiota changes to human health, with the possible exception of the stimulation of butyrogenic taxa by fiber-rich foods, is generally implied and not measured. Further studies are needed to determine how these changes in microbiota composition and metabolism can improve our health and be used to prevent and treat disease.

International Cancer Microbiome Consortium consensus statement on the role of the human microbiome in carcinogenesis.

OBJECTIVE: In this consensus statement, an international panel of experts deliver their opinions on key questions regarding the contribution of the human microbiome to carcinogenesis. DESIGN: International experts in oncology and/or microbiome research were approached by personal communication to form a panel. A structured, iterative, methodology based around a 1-day roundtable discussion was employed to derive expert consensus on key questions in microbiome-oncology research. RESULTS: Some 18 experts convened for the roundtable discussion and five key questions were identified regarding: (1) the relevance of dysbiosis/an altered gut microbiome to carcinogenesis; (2) potential mechanisms of microbiota-induced carcinogenesis; (3) conceptual frameworks describing how the human microbiome may drive carcinogenesis; (4) causation versus association; and (5) future directions for research in the field.The panel considered that, despite mechanistic and supporting evidence from animal and human studies, there is currently no direct evidence that the human commensal microbiome is a key determinant in the aetiopathogenesis of cancer. The panel cited the lack of large longitudinal, cohort studies as a principal deciding factor and agreed that this should be a future research priority. However, while acknowledging gaps in the evidence, expert opinion was that the microbiome, alongside environmental factors and an epigenetically/genetically vulnerable host, represents one apex of a tripartite, multidirectional interactome that drives carcinogenesis. CONCLUSION: Data from longitudinal cohort studies are needed to confirm the role of the human microbiome as a key driver in the aetiopathogenesis of cancer.

Fiber, Fat, and Colorectal Cancer: New Insight into Modifiable Dietary Risk Factors.

PURPOSE OF REVIEW: To review recent data on the role and interactions of fiber and fat as dietary risk factors associated with colorectal cancer (CRC) risk in humans. RECENT FINDINGS: Fiber intake shows convincing and linear dose-response negative correlation with CRC risk. Dietary fiber stimulates butyrogenic activity of the gut microbiota, providing high amounts of butyrate that shows extensive anti-neoplastic effects. A high-fat diet promotes CRC risk through stimulated bile acid metabolism, facilitating bile acid conversion by the gut microbiota to tumor-promoting deoxycholic acid. Comprehensive interactions of these microbial metabolites are likely to underlie mechanisms driving diet-dependent CRC risk in different populations, but require further experimental investigation. Dietary fiber and fat shape the composition and metabolic function of the gut microbiota, resulting in altered amounts of butyrate and deoxycholic acid in the colon. Fiber supplementation and restriction of fat intake represent promising strategies to reduce CRC risk in healthy individuals.

Considerations for best practices in studies of fiber or other dietary components and the intestinal microbiome.

A 2-day workshop organized by the National Institutes of Health and U.S. Department of Agriculture included 16 presentations focused on the role of diet in alterations of the gastrointestinal microbiome, primarily that of the colon. Although thousands of research projects have been funded by U.S. federal agencies to study the intestinal microbiome of humans and a variety of animal models, only a minority addresses dietary effects, and a small subset is described in sufficient detail to allow reproduction of a study. Whereas there are standards being developed for many aspects of microbiome studies, such as sample collection, nucleic acid extraction, data handling, etc., none has been proposed for the dietary component; thus this workshop focused on the latter specific point. It is important to foster rigor in design and reproducibility of published studies to maintain high quality and enable designs that can be compared in systematic reviews. Speakers addressed the influence of the structure of the fermentable carbohydrate on the microbiota and the variables to consider in design of studies using animals, in vitro models, and human subjects. For all types of studies, strengths and weaknesses of various designs were highlighted, and for human studies, comparisons between controlled feeding and observational designs were discussed. Because of the lack of published, best-diet formulations for specific research questions, the main recommendation is to describe dietary ingredients and treatments in as much detail as possible to allow reproduction by other scientists.

High prevalence of osteoporosis in patients with chronic pancreatitis: a systematic review and meta-analysis.

BACKGROUND & AIMS: Patients with chronic pancreatitis may be at high risk for osteoporosis and osteopenia. We performed a systematic review and meta-analysis to determine the prevalence of osteoporosis and osteopenia in patients with chronic pancreatitis. METHODS: Articles were identified from MEDLINE, EMBASE, and SCOPUS databases (through October 2012) and a manual search of the literature. The primary outcome measure was bone density, measured by dual-energy X-ray absorptiometry (T-score or Z-score). When available, data on the prevalence of osteopenia, bone mineral density, and bone mineral content also were recorded. RESULTS: Ten studies including 513 patients were eligible for inclusion. Based on a random-effects model, the pooled prevalence rate for osteoporosis among patients with chronic pancreatitis was 23.4% (95% confidence interval, 16.6-32.0). The pooled prevalence for osteopenia was 39.8% (95% confidence interval, 29.1-51.6). The pooled prevalence rate for either osteoporosis or osteopenia was 65% (95% confidence interval, 54.7-74.0). CONCLUSIONS: Based on meta-analysis, almost 1 of 4 patients with chronic pancreatitis have osteoporosis, and almost two-thirds of patients have either osteoporosis or osteopenia. Osteoporosis and osteopenia are underappreciated sources of morbidity in patients with chronic pancreatitis. Bone health management guidelines are urgently required in patients with chronic pancreatitis.

Timing of enteral nutrition in acute pancreatitis: meta-analysis of individuals using a single-arm of randomised trials.

INTRODUCTION: In acute pancreatitis, enteral nutrition (EN) reduces the rate of complications, such as infected pancreatic necrosis, organ failure, and mortality, as compared to parenteral nutrition (PN). Starting EN within 24 h of admission might further reduce complications. METHODS: A literature search for trials of EN in acute pancreatitis was performed. Authors of eligible trials were requested to provide the data of all patients in the EN-arm of their trials. A meta-analysis of individual patient data was performed. The cohort of patients with EN was divided into patients receiving EN within 24 h or after 24 h of admission. Multivariable logistic regression, adjusting for predicted disease severity and trial, was used to study the effect of timing of EN on a composite endpoint of infected pancreatic necrosis, organ failure, or mortality. RESULTS: Observational data from 165 individuals from 8 randomised trials were obtained; 100 patients with EN within 24 h and 65 patients with EN after 24 h of admission. In the multivariable model, EN started within 24 h of admission compared to EN started after 24 h of admission, reduced the composite endpoint from 45% to 19% (adjusted odds ratio [OR] of 0.44; 95% confidence interval [CI] 0.20-0.96). Within the composite endpoint, organ failure was reduced from 42% to 16% (adjusted OR 0.42; 95% CI 0.19-0.94). CONCLUSIONS: In this meta-analysis of observational data from individuals with acute pancreatitis, starting EN within 24 h after hospital admission, compared with after 24 h, was associated with a reduction in complications.

Fibre-rich Foods to Treat Obesity and Prevent Colon Cancer trial study protocol: a randomised clinical trial of fibre-rich legumes targeting the gut microbiome, metabolome and gut transit time of overweight and obese patients with a history of noncancerous adenomatous polyps.

INTRODUCTION: Recently published studies support the beneficial effects of consuming fibre-rich legumes, such as cooked dry beans, to improve metabolic health and reduce cancer risk. In participants with overweight/obesity and a history of colorectal polyps, the Fibre-rich Foods to Treat Obesity and Prevent Colon Cancer randomised clinical trial will test whether a high-fibre diet featuring legumes will simultaneously facilitate weight reduction and suppress colonic mucosal biomarkers of colorectal cancer (CRC). METHODS/DESIGN: This study is designed to characterise changes in (1) body weight; (2) biomarkers of insulin resistance and systemic inflammation; (3) compositional and functional profiles of the faecal microbiome and metabolome; (4) mucosal biomarkers of CRC risk and (5) gut transit. Approximately 60 overweight or obese adults with a history of noncancerous adenomatous polyps within the previous 3 years will be recruited and randomised to one of two weight-loss diets. Following a 1-week run-in, participants in the intervention arm will receive preportioned high-fibre legume-rich entrées for two meals/day in months 1-3 and one meal/day in months 4-6. In the control arm, entrées will replace legumes with lean protein sources (eg, chicken). Both groups will receive in-person and written guidance to include nutritionally balanced sides with energy intake to lose 1-2 pounds per week. ETHICS AND DISSEMINATION: The National Institutes of Health fund this ongoing 5-year study through a National Cancer Institute grant (5R01CA245063) awarded to Emory University with a subaward to the University of Pittsburgh. The study protocol was approved by the Emory Institutional Review Board (IRB approval number: 00000563). TRIAL REGISTRATION NUMBER: NCT04780477.

Safety and efficacy of teduglutide after 52 weeks of treatment in patients with short bowel intestinal failure.

BACKGROUND & AIMS: Although home parenteral nutrition (PN) can save the lives of patients with massive bowel loss that results in short-bowel syndrome and intestinal failure, quality of life is impaired by PN and its complications. We examined the 12-month tolerability and efficacy of teduglutide to reduce PN dependency. METHODS: Patients who received teduglutide (0.05 or 0.10 mg/kg/d) for 24 weeks in a randomized controlled trial were eligible for a 28-week double-blind extension study; 52 patients were given 52 weeks of the same doses of teduglutide. We investigated the safety, tolerability, and clinical efficacy (defined as a clinically meaningful ≥20% reduction in weekly PN volume from baseline) at week 52. RESULTS: The most common adverse events reported included headache (35%), nausea (31%), and abdominal pain (25%); 7 patients withdrew because of adverse events (gastrointestinal disorders in 4). Both groups had progressive reduction in PN. At week 52, 68% of the 0.05-mg/kg/d and 52% of the 0.10-mg/kg/d dose group had a ≥20% reduction in PN, with a reduction of 1 or more days of PN dependency in 68% and 37%, respectively. Four patients achieved complete independence from PN. CONCLUSIONS: For patients with short-bowel syndrome intestinal failure, the efficacy of teduglutide was maintained over 52 weeks and the safety profile was sufficient for it to be considered for long-term use. Further studies are needed to determine whether these effects will translate into improved quality of life and reduced PN complications. ClinicalTrials.gov number, NCT00172185.

Teduglutide reduces need for parenteral support among patients with short bowel syndrome with intestinal failure.

BACKGROUND & AIMS: Teduglutide, a glucagon-like peptide 2 analogue, might restore intestinal structural and functional integrity by promoting growth of the mucosa and reducing gastric emptying and secretion. These factors could increase fluid and nutrient absorption in patients with short bowel syndrome with intestinal failure (SBS-IF). We performed a prospective study to determine whether teduglutide reduces parenteral support in patients with SBS-IF. METHODS: We performed a 24-week study of patients with SBS-IF who were given subcutaneous teduglutide (0.05 mg/kg/d; n = 43) or placebo (n = 43) once daily. Parenteral support was reduced if 48-hour urine volumes exceeded baseline values by ≥ 10%. The primary efficacy end point was number of responders (patients with >20% reduction in parenteral support volume from baseline at weeks 20 and 24). RESULTS: There were significantly more responders in the teduglutide group (27/43 [63%]) than the placebo group (13/43 [30%]; P = .002). At week 24, the mean reduction in parenteral support volume in the teduglutide group was 4.4 ± 3.8 L/wk (baseline 12.9 ± 7.8 L/wk) compared with 2.3 ± 2.7 L/wk (baseline 13.2 ± 7.4 L/wk) in the placebo group (P < .001). The percentage of patients with a 1-day or more reduction in the weekly need for parenteral support was greater in the teduglutide group (21/39 [54%]) than in the placebo group (9/39 [23%]; P = .005). Teduglutide increased plasma concentrations of citrulline, a biomarker of mucosal mass. The distribution of treatment-emergent adverse events that led to study discontinuation was similar between patients given teduglutide (n = 2) and placebo (n = 3). CONCLUSIONS: Twenty-four weeks of teduglutide treatment was generally well tolerated in patients with SBS-IF. Treatment with teduglutide reduced volumes and numbers of days of parenteral support for patients with SBS-IF; ClinicalTrials.gov Number, NCT00798967.

Is Salt at Fault? Dietary Salt Consumption and Inflammatory Bowel Disease.

Epidemiological trends have led to a growing consensus that diet plays a central role in the etiopathogenesis of inflammatory bowel diseases (IBD). A Western diet high in ultra-processed foods has been associated with an increased prevalence of IBD worldwide. Much attention has focused on components of the Western diet, including the high fat content, lack of fiber, added sugars, and use of additives, such as carrageenan and other emulsifiers. Less attention has been paid to the impact of high salt intake, an integral component of ultra-processed foods, which has increased dramatically in the US diet over the past 50 years. We review a growing body of literature linking the rise in dietary salt intake with the epidemiology of IBD, increased consumption of salt as a component of ultra-processed foods, high salt intake and imbalances in immune homeostasis, the effects of a high-salt diet on other inflammatory disorders, salt's impact on animal colitis models, salt as an underrecognized component in diet modification-induced remission of IBD, and directions for future investigation.

Recent studies have shown that high dietary salt intake is proinflammatory and contributes to chronic inflammatory conditions. Combined with investigations demonstrating low-salt exclusive enteral nutrition induced Crohn's remission, salt intake is likely a contributory factor to inflammatory bowel diseases' pathogenesis and severity.

Association between low colonic short-chain fatty acids and high bile acids in high colon cancer risk populations.

We propose that the influence of diet on colon cancer risk is mediated by the microbiota. To investigate how dietary fat influences risk, we compared the colonic contents of 12 adult high-risk African Americans (AAs) and 10 Caucasian Americans (CAs) who consumed a high-fat diet (123 ± 11 g/d and 129 ± 17 g/d, respectively) to 13 native Africans (NAs) who subsisted on a low-fat (38 ± 3.0 g/d) diet, all aged 50-60 yr. The colonic bile acids were measured by LC-MS and the short-chain fatty acids (SCFAs) by GC. The chief secondary colonic bile acids, deoxycholic acid and lithocholic acid, were correlated with fat intake and similar between AAs and CAs, but 3-4 times higher than in AAs (p < 0.05). The major SCFAs were lower in AAs (p < 0.001) and CAs (p < 0.001) compared to AAs, but conversely, the branched chain fatty acids (BFCA) were higher. Our results suggest that the higher risk of colon cancer in Americans may be partly explained by their high-fat and high-protein, low complex carbohydrate diet, which produces colonic residues that promote microbes to produce potentially carcinogenic secondary bile acids and less antineoplastic SCFAs. The role of BCFA in colonic carcinogenesis deserves further study.

Synthesis and biological activity of pyridopyridazin-6-one p38α MAP kinase inhibitors. Part 2.

This manuscript concludes the Structure Activity Relationship (SAR) on the pyridazinone scaffold and identifies a compound with subnanomolar p38α activity and 24h coverage in the rat arthritis efficacy model.

Disease-Related Malnutrition and Enteral Nutrition.

There are many misconceptions surrounding the diagnosing and treatment of malnutrition and around feeding people with enteral nutrition (EN). Often the decisions made by clinicians are made from anecdote or guidelines that may be out of date or supported by low-quality evidence. In this article, we will discuss different aspects of diagnosing malnutrition and delve deeper into the science and evidence behind certain recommendations. Our goal is to better equip the reader with the most current data-supported recommendation, such as indications, contraindications, complications of EN, tube and ostomy complications, types and use of specialized enteral formulas, and home management.

Parenteral Nutrition.

Parenteral nutrition (PN) is a therapy to nourish patients who cannot tolerate feeding via the gut. Though a life-saving intervention, it does have risks associated. In this article, we aim to dispel myths associated with PN. Practitioners who manage critically ill patients or patients with intestinal failure should be equipped with evidence-based knowledge of PN including the indications, contraindications, feasibility, complications, and long-term management of PN.

A chemical genetic approach reveals that p38alpha MAPK activation by diphosphorylation aggravates myocardial infarction and is prevented by the direct binding of SB203580.

The use of nonselective pharmacological inhibitors has resulted in controversy regarding the mechanism and consequences of p38 activation during myocardial infarction. Classic p38 inhibitors such as SB203580 rely on a critical "gatekeeper" threonine residue for binding. We addressed these controversies by using mice in which the p38alpha alleles were targeted to cause substitution of the gatekeeper residue and resistance to inhibition. In homozygous drug-resistant compared with wild-type hearts, SB203580 failed to inhibit the activating phosphorylation of p38 or to reduce the infarction caused by myocardial ischemia. However, BIRB796, a p38 inhibitor not reliant on the gatekeeper for binding, similarly reduced p38-activating phosphorylation and infarction in both wild-type and knock-in mice, thereby excluding a nonspecific inhibitor-dependent phenotype resulting from the targeting strategy. Furthermore, the activation during myocardial ischemia involved phosphorylation of both the threonine and tyrosine residues in the activation loop of p38 despite the phosphorylation of the threonine alone being sufficient to create the epitope for dual phosphospecific antibody binding. Finally, SB203580 failed to reduce infarction in heterozygous drug-resistant hearts, suggesting that near complete inhibition of p38alpha kinase activity is necessary to elicit protection. These results indicate that, during myocardial ischemia, p38alpha (i) is the dominant-active p38 isoform, (ii) contributes to infarction, (iii) is responsible for the cardioprotective effect of SB203580, and (iv) is activated by a mechanism consistent with autodiphosphorylation despite this necessitating the phosphorylation of a tyrosine residue by an archetypal serine/threonine kinase.