High-fat diet impact on intestinal cholesterol conversion by the microbiota and serum cholesterol levels.

Cholesterol-to-coprostanol conversion by the intestinal microbiota has been suggested to reduce intestinal and serum cholesterol availability, but the relationship between intestinal cholesterol conversion and the gut microbiota, dietary habits, and serum lipids has not been characterized in detail. We measured conserved proportions of cholesterol high and low-converter types in individuals with and without obesity from two distinct, independent low-carbohydrate high-fat (LCHF) dietary intervention studies. Across both cohorts, cholesterol conversion increased in previous low-converters after LCHF diet and was positively correlated with the fecal relative abundance of Eubacterium coprostanoligenes. Lean cholesterol high-converters had increased serum triacylglycerides and decreased HDL-C levels before LCHF diet and responded to the intervention with increased LDL-C, independently of fat, cholesterol, and saturated fatty acid intake. Our findings identify the cholesterol high-converter type as a microbiome marker, which in metabolically healthy lean individuals is associated with increased LDL-C in response to LCHF.

Diets differing in carbohydrate cellularity and amount similarly reduced visceral fat in people with obesity - a randomized controlled trial (CARBFUNC).

BACKGROUND & AIMS: Visceral adipose tissue (VAT) volume is associated with common lifestyle diseases. Dietary quality, including food matrix and degree of carbohydrate cellularity, as well as the carbohydrate/fat ratio, may influence VAT volume. We aimed to determine the effects of isocaloric diets differing in either "cellularity", a novel marker of dietary carbohydrate quality, or carbohydrate amount on visceral fat volume and anthropometric measures in adults with obesity. METHODS: In a randomized controlled trial of 193 people with obesity/central adiposity, we compared changes in VAT volume after 6 and 12 months, measured by abdominal computed tomography, on three isocaloric eating patterns based on "acellular" carbohydrate sources (e.g., flour-based whole-grain products; comparator arm), "cellular" carbohydrate sources (minimally processed foods with intact cellular structures such as fruits, potatoes/tubers, and rice), or low-carbohydrate high-fat (LCHF) principles. Outcomes were compared by an intention-to-treat (ITT) analysis using constrained linear mixed-effects modelling (cLMM) providing baseline-adjusted change scores and proper missing data handling without imputation. RESULTS: 78 and 57 participants completed 6 and 12 months, respectively, with similar intakes of energy (females: 1820-2060 kcal, males: 2480-2550 kcal) and protein (16-17 energy percent, E%) throughout the intervention, and only modest reductions in energy from baseline. Reported dietary intakes were 42-44, 41-42, and 11-15 E% carbohydrate and 36-38, 37-38, and 66-70 E% fat in the acellular, cellular and LCHF groups, respectively. There were no significant between-group differences in VAT volume after 6 months (cellular vs. acellular [95% CI]: -55 cm³ [-545, 436]; LCHF vs. acellular [95% CI]: -225 cm³ [-703, 253]) or after 12 months (cellular vs. acellular [95% CI]: -122 cm³ [-757, 514]; LCHF vs. acellular [95% CI]: -317 cm³ [-943, 309]). VAT volume decreased significantly within all groups by 14-18% and 12-17% after 6 and 12 months, respectively. Waist circumference was reduced to a significantly greater degree in the LCHF vs. acellular group at 6 months (LCHF vs. acellular [95% CI]: -2.78 cm [-5.54, -0.017]). CONCLUSIONS: Despite modest energy restriction, the three isocaloric eating patterns, differing in carbohydrate cellularity and amount, decreased visceral fat volume significantly and to a similar clinically relevant degree. CLINICAL TRIALS IDENTIFIER: NCT03401970. https://clinicaltrials.gov/ct2/show/NCT03401970.

The Western Diet-Microbiome-Host Interaction and Its Role in Metabolic Disease.

The dietary pattern that characterizes the Western diet is strongly associated with obesity and related metabolic diseases, but biological mechanisms supporting these associations remain largely unknown. We argue that the Western diet promotes inflammation that arises from both structural and behavioral changes in the resident microbiome. The environment created in the gut by ultra-processed foods, a hallmark of the Western diet, is an evolutionarily unique selection ground for microbes that can promote diverse forms of inflammatory disease. Recognizing the importance of the microbiome in the development of diet-related disease has implications for future research, public dietary advice as well as food production practices. Research into food patterns suggests that whole foods are a common denominator of diets associated with a low level of diet-related disease. Hence, by studying how ultra-processing changes the properties of whole foods and how these foods affect the gut microbiome, more useful dietary guidelines can be made. Innovations in food production should be focusing on enabling health in the super-organism of man and microbe, and stronger regulation of potentially hazardous components of food products is warranted.

Microbe-microbe and host-microbe interactions drive microbiome dysbiosis and inflammatory processes.

An extensive microbiome comprised of bacteria, viruses, bacteriophages, and fungi is now understood to persist in nearly every human body site, including tissue and blood. The genomes of these microbes continually interact with the human genome in order to regulate host metabolism. Many components of this microbiome are capable of both commensal and pathogenic activity. They are additionally able to persist in both 'acute' and chronic forms. Inflammatory conditions historically studied separately (autoimmune, neurological and malignant) are now repeatedly tied to a common trend: imbalance or dysbiosis of these microbial ecosystems. Population-based studies of the microbiome can shed light on this dysbiosis. However, it is the collective activity of the microbiome that drives inflammatory processes via complex microbe-microbe and host-microbe interactions. Many microbes survive as polymicrobial entities in order to evade the immune response. Pathogens in these communities alter their gene expression in ways that promote community-wide virulence. Other microbes persist inside the cells of the immune system, where they directly interfere with host transcription, translation, and DNA repair mechanisms. The numerous proteins and metabolites expressed by these pathogens further dysregulate human gene expression in a manner that promotes imbalance and immunosuppression. Molecular mimicry, or homology between host and microbial proteins, complicates the nature of this interference. When taken together, these microbe-microbe and host-microbe interactions are capable of driving the large-scale failure of human metabolism characteristic of many different inflammatory conditions.

Immunostimulation in the treatment for chronic fatigue syndrome/myalgic encephalomyelitis.

Chronic fatigue syndrome (CFS)/myalgic encephalomyelitis (ME) has long been associated with the presence of infectious agents, but no single pathogen has been reliably identified in all patients with the disease. Recent studies using metagenomic techniques have demonstrated the presence of thousands of microbes in the human body that were previously undetected and unknown to science. More importantly, such species interact together by sharing genes and genetic function within communities. It follows that searching for a singular pathogen may greatly underestimate the microbial complexity potentially driving a complex disease like CFS/ME. Intracellular microbes alter the expression of human genes in order to facilitate their survival. We have put forth a model describing how multiple species-bacterial, viral, and fungal-can cumulatively dysregulate expression by the VDR nuclear receptor in order to survive and thus drive a disease process. Based on this model, we have developed an immunostimulatory therapy that is showing promise inducing both subjective and objective improvement in patients suffering from CFS/ME.

Balanced caloric macronutrient composition downregulates immunological gene expression in human blood cells-adipose tissue diverges.

Cardiovascular disease, obesity, and type 2 diabetes are conditions characterized by low-grade systemic inflammation, strongly influenced by lifestyle, but the mechanisms that link these characteristics are poorly understood. Our first objective was to investigate if a normocaloric diet with a calorically balanced macronutrient composition influenced immunological gene expression. Findings regarding the suitability of blood as biological material in nutrigenomics and gene expression profiling have been inconclusive. Our second objective was to compare blood and adipose tissue sample quality in terms of adequacy for DNA-microarray analyses, and to determine tissue-specific gene expression patterns. Blood and adipose tissue samples were collected for gene expression profiling from three obese men before, during, and after a 28-day normocaloric diet intervention where each meal contained an approximately equal caloric load of macronutrients. Time series analyses of blood gene expression revealed a cluster of downregulated genes involved in immunological processes. Blood RNA quality and yield were satisfactory, and DNA-microarray analysis reproducibility was similar in blood and adipose tissue. Gene expression correlation between blood and adipose tissue varied according to gene function, and was especially low for genes involved in immunological and metabolic processes. This suggests that diet composition is of importance in inflammatory processes in blood cells. The findings also suggest that a systems biology approach, in which tissues are studied in parallel, should be employed to fully understand the impact of dietary challenges on the human body.

Immunostimulation in the era of the metagenome.

Microbes are increasingly being implicated in autoimmune disease. This calls for a re-evaluation of how these chronic inflammatory illnesses are routinely treated. The standard of care for autoimmune disease remains the use of medications that slow the immune response, while treatments aimed at eradicating microbes seek the exact opposite-stimulation of the innate immune response. Immunostimulation is complicated by a cascade of sequelae, including exacerbated inflammation, which occurs in response to microbial death. Over the past 8 years, we have collaborated with American and international clinical professionals to research a model-based treatment for inflammatory disease. This intervention, designed to stimulate the innate immune response, has required a reevaluation of disease progression and amelioration. Paramount is the inherent conflict between palliation and microbicidal efficacy. Increased microbicidal activity was experienced as immunopathology-a temporary worsening of symptoms. Further studies are needed, but they will require careful planning to manage this immunopathology.