The human gut microbiome is a complex ecosystem of commensal microorganisms that help to shape host development and health. Host diet directly influences not only the composition, but also the function of the microbiome. In turn, the microbiome impacts the health of the host through production of metabolites from ingested food. Studies of this host-microbe relationship have recently enhanced our understanding of disease development and pathogenesis, and are now being targeted to combat disease symptoms and promote health. For example, dietary shifts to a high-fat, high-sugar “Western diet” drives microbiome dysbiosis in several disease models, which correlates with disease severity. Reintroduction of fiber, increased antioxidants, or decreases in fat and sugar intake helps to restore microbial balance to a healthier composition and often improves disease parameters. Analyses of microbiome-produced metabolites emphasize that understanding how diet shifts the function of the microbiome may be of critical importance for therapeutic targeting of the host-microbe relationship to promote health. In this mini-review, we discuss what is known about the three-way relationship between diet, the microbiome, and disease utilizing animal models, as well as the findings from human clinical trials of dietary therapeutics. Impact statement The studies reviewed in this article combine diet in the context of disease progression or treatment with analysis of the microbiome. First, we present findings on how diet manipulation impacts the microbiome and disease pathogenesis in a broad variety of rodent models of disease. Then, we describe results from clinical trials that are using diet therapies to attempt to shift the microbiome and treat disease symptoms. Finally, we discuss what these studies have taught us about the influence of the microbiome of disease and health states and highlight the evidence suggesting that dietary modulation of the microbiome is an emerging therapeutic option for a variety of different diseases.
In addition to their classical roles as bacterial sensors, NOD1 and NOD2 have been implicated as mediators of metabolic disease. Increased expression of NOD1 and/or NOD2 has been reported in a range of human metabolic diseases, including obesity, diabetes, non-alcoholic fatty liver disease, and metabolic syndrome. Although NOD1 and NOD2 share intracellular signaling pathway components, they are differentially upregulated on a cellular level and have opposing impacts on metabolic disease development in mouse models. These NOD-like receptors may directly mediate signaling downstream of cell stressors, such as endoplasmic reticulum stress and calcium influx, or in response to metabolic signals, such as fatty acids and glucose. Other studies suggest that stimulation of NOD1 or NOD2 by their bacterial ligands can result in inflammation, altered insulin responses, increased reactive oxygen signaling, and mitochondrial dysfunction. The activating stimuli for NOD1 and NOD2 in the context of metabolic disease are controversial and may be a combination of both metabolic and circulating bacterial ligands. In this review, we will summarize the current knowledge of how NOD1 and NOD2 may mediate metabolism in health and disease, as well as highlight areas of future investigation.
Food additives are common components of processed foods consumed in a Western diet. In inflammatory bowel disease patients, some diets that exclude food additives improved clinical disease parameters, suggesting a link between food additives and disease pathogenesis. Food additives also enhanced disease severity in mouse colitis models through incompletely described mechanisms. This study examined the mechanisms by which the food additive maltodextrin (MDX) alters the development of colitis in a murine model. Interleukin-10 knockout (IL10KO) mice were fed diets supplemented with MDX or carboxymethyl cellulose (CMC) to determine their impact on colitis onset and severity; microbiome composition, function, and location; colonic immune cell infiltrates; and mucus layer integrity. Primary IL10KO colonic epithelial monolayers were used to dissect the impact of MDX directly on epithelial differentiation and mucus production. MDX or CMC consumption increased the incidence and severity of colitis, as well as decreased microbiome diversity, altered microbial composition, and decreased fecal acetic acid levels. The number of mucus producing cells were decreased in food additive fed mice and resulted in increased microbial proximity to the intestinal epithelium. Additionally, MDX supplementation resulted in crypt hyperplasia and expansion of the HopX+ injury renewal stem cell niche. In primary intestinal epithelial-derived monolayers devoid of microbes and immune cells, MDX exposure decreased goblet cell number and mucus production in association with downregulated expression of the transcription factor Klf4, a marker of terminally differentiated goblet cells. These results suggest MDX disrupts the balance of epithelial cell differentiation and proliferation to contribute to disease pathogenesis through direct and indirect actions on the intestinal epithelial barrier.
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