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Reversing some industrialization-related changes in the human gut microbiota may be risky

Domesticated animals experienced profound changes in diet, environment, and social interactions that likely shaped their gut microbiota and were potentially analogous to ecological changes experienced by humans during industrialization. Comparing the gut microbiota of wild and domesticated mammals plus chimpanzees and humans, we found a strong signal of domestication in overall gut microbial community composition and similar changes in composition with domestication and industrialization. Reciprocal diet switches within mouse and canid dyads demonstrated the critical role of diet in shaping the domesticated gut microbiota. Notably, we succeeded in recovering wild-like microbiota in domesticated mice through experimental colonization. Although fundamentally different processes, we conclude that domestication and industrialization have impacted the gut microbiota in related ways, likely through shared ecological change. Our findings highlight the utility, and limitations, of domesticated animal models for human research and the importance of studying wild animals and non-industrialized humans for interrogating signals of host-microbial coevolution.

We previously showed that C57BL/6J mice fed high-fat diet (HFD) supplemented with 1% grape polyphenols (GP) for 12 weeks developed a bloom of Akkermansia muciniphila with attenuated metabolic syndrome symptoms. Here we investigated early timing of GP-induced effects and the responsible class of grape polyphenols. Mice were fed HFD, low-fat diet (LFD) or formulations supplemented with GP (HFD-GP, LFD-GP) for 14 days. Mice fed HFD-GP, but not LFD-GP, showed improved oral glucose tolerance compared to controls. A. muciniphila bloom occurred earlier in mice fed LFD-GP than HFD-GP; however, timing was dependent on baseline A. muciniphila levels rather than dietary fat. Mice gavaged for 10 days with GP extract (GPE) or grape proanthocyanidins (PACs), each delivering 360 mg PACs/kg body weight, induced a bloom of fecal and cecal A. muciniphila, the rate of which depended on initial A. muciniphila abundance. Grape PACs were sufficient to induce a bloom of A. muciniphila independent of specific intestinal gene expression changes. Gut microbial community analysis and in vitro inhibition of A. muciniphila by GPE or PACs suggest that the A. muciniphila bloom in vivo occurs via indirect mechanisms.

Although the importance of human genetic polymorphisms in therapeutic outcomes is well established, the role of our 'second genome' (the microbiome) has been largely overlooked. In this Review, we highlight recent studies that have shed light on the mechanisms that link the human gut microbiome to the efficacy and toxicity of xenobiotics, including drugs, dietary compounds and environmental toxins. Continued progress in this area could enable more precise tools for predicting patient responses and for the development of a new generation of therapeutics based on, or targeted at, the gut microbiome. Indeed, the admirable goal of precision medicine may require us to first understand the microbial pharmacists within.

Dietary polyphenols protect against metabolic syndrome, despite limited absorption and digestion, raising questions about their mechanism of action. We hypothesized that one mechanism may involve the gut microbiota. To test this hypothesis, C57BL/6J mice were fed a high-fat diet (HFD) containing 1% Concord grape polyphenols (GP). Relative to vehicle controls, GP attenuated several effects of HFD feeding, including weight gain, adiposity, serum inflammatory markers (tumor necrosis factor [TNF]α, interleukin [IL]-6, and lipopolysaccharide), and glucose intolerance. GP lowered intestinal expression of inflammatory markers (TNFα, IL-6, inducible nitric oxide synthase) and a gene for glucose absorption (Glut2). GP increased intestinal expression of genes involved in barrier function (occludin) and limiting triglyceride storage (fasting-induced adipocyte factor). GP also increased intestinal gene expression of proglucagon, a precursor of proteins that promote insulin production and gut barrier integrity. 16S rRNA gene sequencing and quantitative PCR of cecal and fecal samples demonstrated that GP dramatically increased the growth of Akkermansia muciniphila and decreased the proportion of Firmicutes to Bacteroidetes, consistent with prior reports that similar changes in microbial community structure can protect from diet-induced obesity and metabolic disease. These data suggest that GP act in the intestine to modify gut microbial community structure, resulting in lower intestinal and systemic inflammation and improved metabolic outcomes. The gut microbiota may thus provide the missing link in the mechanism of action of poorly absorbed dietary polyphenols.

Mammals exhibit marked interindividual variations in their gut microbiota, but it remains unclear if this is primarily driven by host genetics or by extrinsic factors like dietary intake. To address this, we examined the effect of dietary perturbations on the gut microbiota of five inbred mouse strains, mice deficient for genes relevant to host-microbial interactions (MyD88(-/-), NOD2(-/-), ob/ob, and Rag1(-/-)), and >200 outbred mice. In each experiment, consumption of a high-fat, high-sugar diet reproducibly altered the gut microbiota despite differences in host genotype. The gut microbiota exhibited a linear dose response to dietary perturbations, taking an average of 3.5 days for each diet-responsive bacterial group to reach a new steady state. Repeated dietary shifts demonstrated that most changes to the gut microbiota are reversible, while also uncovering bacteria whose abundance depends on prior consumption. These results emphasize the dominant role that diet plays in shaping interindividual variations in host-associated microbial communities.

Our associated microbial communities play a critical role in human health and predisposition to disease, but the degree to which they also shape therapeutic interventions is not well understood. Here, we integrate results from classic and current studies of the direct and indirect impacts of the gut microbiome on the metabolism of therapeutic drugs and diet-derived bioactive compounds. We pay particular attention to microbial influences on host responses to xenobiotics, adding to the growing consensus that treatment outcomes reflect our intimate partnership with the microbial world, and providing an initial framework from which to consider a more comprehensive view of pharmacology and nutrition.

Long-term dietary intake influences the structure and activity of the trillions of microorganisms residing in the human gut, but it remains unclear how rapidly and reproducibly the human gut microbiome responds to short-term macronutrient change. Here we show that the short-term consumption of diets composed entirely of animal or plant products alters microbial community structure and overwhelms inter-individual differences in microbial gene expression. The animal-based diet increased the abundance of bile-tolerant microorganisms (Alistipes, Bilophila and Bacteroides) and decreased the levels of Firmicutes that metabolize dietary plant polysaccharides (Roseburia, Eubacterium rectale and Ruminococcus bromii). Microbial activity mirrored differences between herbivorous and carnivorous mammals, reflecting trade-offs between carbohydrate and protein fermentation. Foodborne microbes from both diets transiently colonized the gut, including bacteria, fungi and even viruses. Finally, increases in the abundance and activity of Bilophila wadsworthia on the animal-based diet support a link between dietary fat, bile acids and the outgrowth of microorganisms capable of triggering inflammatory bowel disease. In concert, these results demonstrate that the gut microbiome can rapidly respond to altered diet, potentially facilitating the diversity of human dietary lifestyles.

The mammalian gut microbiota influences both sides of the energy balance equation, salvaging energy from undigested nutrients and directing the host to accumulate adipose tissue. Semova et al. (2012) use zebrafish to demonstrate that the gut microbiota also promotes dietary lipid absorption, emphasizing the many host-microbial interactions contributing to adiposity.

The gut microbiota is a diverse and dynamic ecological community that is increasingly recognized to play important roles in host metabolic, immunological, and behavioral functioning. As such, identifying new routes for manipulating the microbiota may provide valuable additional methods for improving host health. Dietary manipulations and prebiotic supplementation are active targets of research for altering the microbiota, but to date, this work has disproportionately focused on carbohydrates. However, many other resources can limit or shape microbial growth. Here, we provide a brief overview of the resource landscape in the mammalian gut and review relevant literature documenting associations between noncarbohydrate nutrients and the composition of the gut microbiota. To spur future work and accelerate translational applications, we propose that researchers take new approaches for studying the effects of diet on gut microbial communities, including more-careful consideration of media for in vitro experiments, measurement of absolute as well as relative abundances, concerted efforts to articulate how physiology may differ between humans and the animal models used in translational studies, and leveraging natural variation for additional insights. Finally, we close with a discussion of how to determine when or where to employ these potential dietary levers for manipulating the microbiota. [ABSTRACT FROM AUTHOR]

ABSTRACT Starch, protein, and lipid are three major sources of calories in the human diet. The unique and universal human practice of cooking has been demonstrated to increase the energy gained from foods rich in starch or protein. Yet no studies have tested whether cooking has equivalent effects on the energy gained from lipid-rich foods. Using mice as a model, we addressed this question by examining the impact of cooking on the energy gained from peanuts, a lipid-rich oilseed, and compared this impact against that of nonthermal processing (blending). We found that cooking consistently increased the energy gained per calorie, whereas blending had no detectable energetic benefits. Assessment of fecal fat excretion showed increases in lipid digestibility when peanuts were cooked, and examination of diet microstructure revealed concomitant alterations to the integrity of cell walls and the oleosin layer of proteins that otherwise shield lipids from digestive lipases. Both effects were consistent with the greater energy gain observed with cooking. Our findings highlight the importance of cooking in increasing dietary energy returns for humans, both past and present. Am J Phys Anthropol 156:11-18, 2015 © 2014 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Calorie restriction (CR) extends lifespan and retards age-related chronic diseases in most species. There is growing evidence that the gut microbiota has a pivotal role in host health and age-related pathological conditions. Yet, it is still unclear how CR and the gut microbiota are related to healthy aging. Here, we report findings from a small longitudinal study of male C57BL/6 mice maintained on either ad libitum or mild (15%) CR diets from 21 months of age and tracked until natural death. We demonstrate that CR results in a significantly reduced rate of increase in the frailty index (FI), a well-established indicator of aging. We observed significant alterations in diversity, as well as compositional patterns of the mouse gut microbiota during the aging process. Interrogating the FI-related microbial features using machine learning techniques, we show that gut microbial signatures from 21-month-old mice can predict the healthy aging of 30-month-old mice with reasonable accuracy. This study deepens our understanding of the links between CR, gut microbiota, and frailty in the aging process of mice. [ABSTRACT FROM AUTHOR]