Microbial Ecology in States of Health and Disease Workshop Summary (2014) / Chapter Skim
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A3 Pathways in microbe-induced obesity--Laura M. Cox and Martin J. Blaser
A3 Pathways in microbe-induced obesity--Laura M. Cox and Martin J. Blaser
Pages 131-152
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Microbiota disruption during early development can result in syndromes of metabolic dysfunction. We focus on the pathways involved in these interactions, particularly related to energy extraction and the role of inflammation in the metabolic phenotypes.
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The microbes that colonize humans substantially outnumber human cells (Savage, 1977) , and the collective unique microbial genes outnumber human genes by a factor of more than 100 (Arumugam et al., 2011; Human Microbiome Project Consortium, 2012; Qin et al., 2010)
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In the liver, acetate is a substrate for cholesterol synthesis and lipogenesis. Locally, butyrate increases the epithelial tight junctions, blocking the translocation of LPS, a potent inflammatory mediator that increases weight gain, total body and liver adiposity, and insulin resistance.
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The very presence of microbiota influences weight gain and fat storage, as germ-free mice have significantly lower weight and body fat percent, despite eating more calories than conventionalized mice (Bäckhed et al., 2004)
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. Importantly, in this model, competition between the major classes affects host mucus layer, epithelial permeability, and inflammation, which has downstream metabolic consequences.
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That excessive caloric intake in ob/ob mice receiving normal chow and in mice fed ad libitum on a DIO diet selects for an obesogenic microbiota argues that the increased caloric intake, not dietary composition, is the driving force. In the large intestine, complex nutrients that have not been absorbed by the host are fermented to short-chain fatty acids (SCFAs)
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. STAT increased the abundance of microbial genes involved in SCFA production and also increased acetate, butyrate, and propionate concentrations in the intestine.
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c Resistance to DIO also achieved by deleting IL23a and RORγt, elements downstream of the lymphotoxin pathway.
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Mice that underwent gastric bypass extracted significantly less energy from the diet than mice that underwent sham surgery or calorie-restricted mice, which may have been mediated by a combination of gut restructuring and changes in the intestinal microbiota. Germfree mice colonized with microbiota from RYGB mice weighed significantly less than mice colonized with microbiota from sham surgery mice, showing that the RYGB-altered microbiota play an active role in weight loss and metabolic status.
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High-dose antibiotic treatment or deletion of CD14 reduces inflammatory cytokine expression and ameliorates weight gain on HFD, demonstrating the important interaction of microbiota and inflammatory signaling cascades. Prebiotic fibers fermented to SCFA by the intestinal microbiota can block LPS-mediated metabolic consequences by increasing colonic expression of tight junction proteins zona occludens 1 and claudin 3, improving gut barrier function and reducing systemic LPS (Neyrinck et al., 2012)
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. In a separate study, Tlr5−/− mice housed at two different animal facilities did not show an obesity phenotype or increased basal intestinal inflammation (Letran et al., 2011)
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Well-evolved ecosystems often have functional redundancy in which several species can perform the same task. This concept explains how the taxa that constitute the mammalian gut microbiome often are highly diverse and variable from person to person, yet share high-degree functional capacity (Human Microbiome Project Consortium, 2012; Kurokawa et al., 2007; Turnbaugh et al., 2009)
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Since mammals have evolved to provide a portion of their microbes to their offspring, shifts occurring during pregnancy may reflect selection that increases the probability of offspring survival. The greater representation of lactic acid bacteria may be seen as an adaptation to prepare the mother for transfer of these organisms in the birth and perinatal period to her offspring to take maximum advantage of the main energy source for the child, lactose in
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trimester of pregnancy, those receiving the T3 microbiota had increased intestinal cytokines, gained more weight, and were more glucose intolerant than those receiving the T1 microbiota. This result implies that the T3 microbiota induces an alternative metabolic state in its host, associated with greater energy storage.
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Recovery from perturbation requires a full complement of species or of functional groups. In the gut, there appears to be enormous functional redundancy (Human Microbiome Project Consortium, 2012; Turnbaugh et al., 2009)
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In the late winter, essentially all of the energy available to the microbiota is host derived. Hibernation, rather than specific host, diet, or age, is the major determinant of the gut microbial community composition.
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The digestion of mucus and the loss of butyrate resulting from perturbations that affect the microbes requiring dietary energy sources are examples of secondary effects on the interface between the microbiota and the host. These can result in differential signaling to epithelial and immune cells, with both immune and metabolic consequences (Canani et al., 2011)
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. Energy contributions of volatile fatty acids from the gastrointestinal tract in various species.
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. Changes in gut microbiota control metabolic endotoxemia-induced inflammation in high-fat diet-induced obesity and diabetes in mice.
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. Gut microbiota composition and activity in relation to host metabolic phenotype and disease risk.
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. Conserved shifts in the gut microbiota due to gastric bypass reduce host weight and adiposity.
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. Microbial ecology of the gastrointestinal tract.
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