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      The gut-bone axis: how bacterial metabolites bridge the distance

      Author(s): , , ,
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      Journal: Journal of Clinical Investigation
      Publisher: American Society for Clinical Investigation

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          Abstract

          The gut microbiome is a key regulator of bone health that affects postnatal skeletal development and skeletal involution. Alterations in microbiota composition and host responses to the microbiota contribute to pathological bone loss, while changes in microbiota composition that prevent, or reverse, bone loss may be achieved by nutritional supplements with prebiotics and probiotics. One mechanism whereby microbes influence organs of the body is through the production of metabolites that diffuse from the gut into the systemic circulation. Recently, short-chain fatty acids (SCFAs), which are generated by fermentation of complex carbohydrates, have emerged as key regulatory metabolites produced by the gut microbiota. This Review will focus on the effects of SCFAs on the musculoskeletal system and discuss the mechanisms whereby SCFAs regulate bone cells.

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          The microbiome and butyrate regulate energy metabolism and autophagy in the mammalian colon.

          Dallas R Donohoe, Nikhil Garge, Xinxin Zhang … (2011)
          The microbiome is being characterized by large-scale sequencing efforts, yet it is not known whether it regulates host metabolism in a general versus tissue-specific manner or which bacterial metabolites are important. Here, we demonstrate that microbiota have a strong effect on energy homeostasis in the colon compared to other tissues. This tissue specificity is due to colonocytes utilizing bacterially produced butyrate as their primary energy source. Colonocytes from germfree mice are in an energy-deprived state and exhibit decreased expression of enzymes that catalyze key steps in intermediary metabolism including the TCA cycle. Consequently, there is a marked decrease in NADH/NAD(+), oxidative phosphorylation, and ATP levels, which results in AMPK activation, p27(kip1) phosphorylation, and autophagy. When butyrate is added to germfree colonocytes, it rescues their deficit in mitochondrial respiration and prevents them from undergoing autophagy. The mechanism is due to butyrate acting as an energy source rather than as an HDAC inhibitor. Copyright © 2011 Elsevier Inc. All rights reserved.
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            Energy contributions of volatile fatty acids from the gastrointestinal tract in various species.

            E BERGMAN (1990)
            The VFA, also known as short-chain fatty acids, are produced in the gastrointestinal tract by microbial fermentation of carbohydrates and endogenous substrates, such as mucus. This can be of great advantage to the animal, since no digestive enzymes exist for breaking down cellulose or other complex carbohydrates. The VFA are produced in the largest amounts in herbivorous animal species and especially in the forestomach of ruminants. The VFA, however, also are produced in the lower digestive tract of humans and all animal species, and intestinal fermentation resembles that occurring in the rumen. The principal VFA in either the rumen or large intestine are acetate, propionate, and butyrate and are produced in a ratio varying from approximately 75:15:10 to 40:40:20. Absorption of VFA at their site of production is rapid, and large quantities are metabolized by the ruminal or large intestinal epithelium before reaching the portal blood. Most of the butyrate is converted to ketone bodies or CO2 by the epithelial cells, and nearly all of the remainder is removed by the liver. Propionate is similarly removed by the liver but is largely converted to glucose. Although species differences exist, acetate is used principally by peripheral tissues, especially fat and muscle. Considerable energy is obtained from VFA in herbivorous species, and far more research has been conducted on ruminants than on other species. Significant VFA, however, are now known to be produced in omnivorous species, such as pigs and humans. Current estimates are that VFA contribute approximately 70% to the caloric requirements of ruminants, such as sheep and cattle, approximately 10% for humans, and approximately 20-30% for several other omnivorous or herbivorous animals. The amount of fiber in the diet undoubtedly affects the amount of VFA produced, and thus the contribution of VFA to the energy needs of the body could become considerably greater as the dietary fiber increases. Pigs and some species of monkey most closely resemble humans, and current research should be directed toward examining the fermentation processes and VFA metabolism in those species. In addition to the energetic or nutritional contributions of VFA to the body, the VFA may indirectly influence cholesterol synthesis and even help regulate insulin or glucagon secretion. In addition, VFA production and absorption have a very significant effect on epithelial cell growth, blood flow, and the normal secretory and absorptive functions of the large intestine, cecum, and rumen. The absorption of VFA and sodium, for example, seem to be interdependent, and release of bicarbonate usually occurs during VFA absorption.(ABSTRACT TRUNCATED AT 400 WORDS)
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              Dietary modulation of the human colonic microbiota: updating the concept of prebiotics.

              Glenn R. Gibson, Hollie Probert, Jan Van Loo … (2004)
              Prebiotics are non-digestible (by the host) food ingredients that have a beneficial effect through their selective metabolism in the intestinal tract. Key to this is the specificity of microbial changes. The present paper reviews the concept in terms of three criteria: (a) resistance to gastric acidity, hydrolysis by mammalian enzymes and gastrointestinal absorption; (b) fermentation by intestinal microflora; (c) selective stimulation of the growth and/or activity of intestinal bacteria associated with health and wellbeing. The conclusion is that prebiotics that currently fulfil these three criteria are fructo-oligosaccharides, galacto-oligosaccharides and lactulose, although promise does exist with several other dietary carbohydrates. Given the range of food vehicles that may be fortified by prebiotics, their ability to confer positive microflora changes and the health aspects that may accrue, it is important that robust technologies to assay functionality are used. This would include a molecular-based approach to determine flora changes. The future use of prebiotics may allow species-level changes in the microbiota, an extrapolation into genera other than the bifidobacteria and lactobacilli, and allow preferential use in disease-prone areas of the body.
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                Author and article information

                Journal
                Title: Journal of Clinical Investigation
                Publisher: American Society for Clinical Investigation
                ISSN (Print): 0021-9738
                ISSN (Electronic): 1558-8238
                Publication date Created: August 1 2019
                Publication date Created: August 1 2019
                Publication date Created: August 1 2019
                Publication date (Electronic): July 15 2019
                Publication date (Print): July 15 2019
                Publication date (Print): August 1 2019
                Volume: 129
                Issue: 8
                Pages: 3018-3028
                Article
                DOI: 10.1172/JCI128521
                PMC ID: 6668676
                PubMed ID: 31305265
                SO-VID: 4d0680e0-b429-43a0-9cd8-5c5fbbe33ae1
                Copyright © © 2019
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