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EXPERTQ&A

The Gut Microbiome in

Karen Beer, PA-C, MSPAS, RD, LD, CDE

he surfaces of the human body ex- is unclear whether these bacterial imbal- Karen Beer practices at the posed to the environment are colo- ances cause or result from disease. Oregon Medical T nized by microbes—the majority of Group in Eugene. which reside in the intestinal tract. Collec- ROLE IN TYPE 2 DIABETES The author tively, the microbial cells that live in and The microbiome of patients with type 2 dia- reports no financial on us (, eukaryotes, viruses, fungi, betes (T2DM) is characterized by reduced relationships and archaea) make up our microbiota, and levels of and Clostridia and an relevant to this their genetic material constitutes our mi- increased ratio of :Firmicutes article. crobiome. There are at least 100 times more (this ratio correlates with plasma glu- genes in the human microbiome than in the cose concentration).4,5 Interestingly, al- human genome.1,2 though T2DM and obesity are closely With the help of recent technologic ad- related, available data indicate that gut vances in genetic sequencing, we’re be- microbiome changes are not always iden- ginning to understand more about this tical between these two patient popula- vast biological habitat. We know that the tions. In some studies, the microbiome microbiota plays a role in vitamin produc- of obese individuals involves a decreased tion, energy harvest and storage, and fer- Bacteroidetes:Firmicutes ratio, in contrast mentation and absorption of undigested to the increase seen with T2DM—which carbohydrates. It also has bidirectional in- raises the question of whether the same or fluence on the central nervous system and different factors cause these two entities.1,5-7 neuropsychologic health and is involved in continued on next page >> the maturation and development of the im- mune system. A healthy biome is characterized by bac- terial diversity and richness. is mostly comprised of Firmicutes (64%), Bacteroidetes (23%), Proteobacteria (8%), and Actinobacteria (3%).2 The distribution of these bacteria is largely determined by diet; individuals who follow a diet high in animal fat have a -dominant pattern, whereas those who follow a carbo- hydrate-rich diet tend toward a - dominant pattern.1-3 Lack of bacterial diversity and over- growth of pathobacteria results in dysbiosis, an imbalance in the gut’s microbial com- position. Alterations in the proportions of bacteria are thought to result in metabolic disease. As such, dysbiosis is correlated with obesity and diabetes, as well as other diseases (eg, inflammatory bowel disease, multiple sclerosis, Crohn disease, and rheu- matoid arthritis).1-3 At this time, however, it Credit: Shutterstock/Anatomy Insider clinicianreviews.com FEBRUARY 2018 • Clinician Reviews 13 EXPERTQ&A

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Patients with T2DM also have decreased can have profound and irreversible ­effects amounts of butyrate-producing bacteria on intestinal microbial diversity and com- in their microbiomes. Butyrate, acetate, position. For example, short-term use of oral and propionate are short-chain fatty acids vancomycin was found to impair peripheral (­SCFAs) fermented in the large intestine insulin sensitivity in males with metabolic by bacteria from dietary fiber. These SCFAs syndrome associated with ­altered gut mi- play an important role in energy metabo- crobiota, while amoxicillin did not.6 lism and are critical for modulating immune responses and tumorigenesis in the gut. PREBIOTICS AND PROBIOTICS Butyrate, in particular, provides energy for Prebiotics are indigestible carbohydrates colonic epithelial cells. By feeding colonic that improve host health by stimulating cells, butyrate helps to maintain intestinal the growth and activity of colonic bacteria. integrity and prevent translocation—a pro- Most prebiotics are oligosaccharides, which cess that moves gram-negative intestinal can travel through the upper GI system un- bacteria across the lumen of the gut, caus- digested. When they reach the colon, they ing endotoxemia. Endotoxemia triggers a are fermented to produce SCFAs that stim- low-grade inflammatory response, and low- ulate the growth of microbes that reside grade inflammation is thought to underlie there. Prebiotics come from a wide variety T2DM.2,5,6 of food sources, including asparagus, bar- Therapeutic interventions—such as ley, garlic, onions, and wheat bran.2,3 Pick- dietary modifications, prebiotics, probi- led and fermented foods (eg, kimchi, sau- otics, antibiotics, metformin, fecal trans- erkraut, yogurt, miso) are good sources of plantation, and bariatric surgery—can both prebiotics and probiotics.2 effectively alter the composition of gut Bifidobacteria and lactobacilli are the bacteria. It has been proposed that these most commonly used strains in foods and interventions could be harnessed to pre- supplements containing probiotics. These vent and treat T2DM in the future.2 So, live microorganisms bring about specific what might these interventions have (or changes in the composition and activity of not have) to offer? gut microbiota: they secrete antimicrobial substances, compete with pathogenic bac- ANTIBIOTICS teria, strengthen the intestinal barrier, and Antibiotics are useful for eradicating patho- modulate the immune system.2,3,6 Research genic bacteria, but they can also destroy on human and animal models suggests that beneficial intestinal commensals in the administering probiotics may help manage process. Therefore, concern about the wide- diabetes.2 spread use of antibiotics in humans and livestock has increased. Subtherapeutic use DIETARY MODULATION of antibiotics, which has been common in Dietary changes have been shown to mod- farm animals throughout the past 50 years ify the bacterial metabolic activity of the to increase growth and food production, human gut. In one study, obese adults with has been shown to affect metabolic path- T2DM were placed on either a fat- or car- ways—particularly with respect to SCFAs— bohydrate-restricted diet, and it was found in mouse studies.6 that their levels of Bacteroidetes increased Recent data on humans have linked an- and Firmicutes decreased.7 tibiotic treatment in early infancy to long- In another study, patients with T2DM ad- term effects on microbial diversity and hered to one of two calorie-controlled diets: childhood overweight. Similarly, long-term a high-fiber macrobiotic diet or a Mediter- use of IV vancomycin in adults has been ranean-style (control) diet. The macrobiotic linked to an increased obesity risk. But it’s diet was high in complex carbohydrates, not just long-term exposure that poses a legumes, fermented products, sea salt, and threat; even short courses of oral antibiotics green tea and was free of animal protein,

14 Clinician Reviews • FEBRUARY 2018 clinicianreviews.com EXPERTQ&A

fat, and added sugar. Both diets were ef- dramatic changes to the gut microbiota were fective at improving dysbiosis—ecosystem seen at three months following surgery. diversity increased, and health-promoting BMI was reduced by 15% to 32%, C-reactive SCFA producers were replenished. Howev- protein decreased in five of six patients, and er, the macrobiotic diet was more effective T2DM was alleviated in all. Postoperatively, than the control diet at reducing fasting and there was a striking shift towards higher postprandial glucose, A1C, serum choles- amounts of Proteobacteria and lower rela- terol, insulin resistance, BMI, and waist and tive amounts of Firmicutes and Bacteroides hip circumferences; and only the macrobi- in the gut phyla. Postoperative increases in otic diet counteracted the inflammation- certain bacteria were more profound than producing bacterial groups.8 the amount in lean controls, suggesting these changes are related to alterations in METFORMIN the gut, not lower body weight.4,6 Metformin has therapeutic effects on mi- crobial composition and SCFA synthesis. CONCLUSION In a microbiome comparison study, pa- We are just beginning to understand the mi- tients with T2DM treated with metformin crobiome and its relationship to health and had more butyrate-producing bacteria than disease. For patients with T2DM, a variety of their untreated counterparts. The trend to- interventions may be used to return the gut ward increased seen in the microbiota to health. Dietary interventions, context of T2DM was reduced or reversed prebiotics and probiotics, fecal microbial by metformin treatment. Researchers were transplant, and bariatric surgery can influ- able to tell which patients were (and were ence gut microbial composition, with the not) treated based on their gut microbiome goal of preventing and/or treating disease. taxonomic signature.9 In the future, gut microbial signatures may serve as early diagnostic markers. CR FECAL MICROBIOTA TRANSPLANT Fecal microbiota transplant, also known as stool transplant or bacteriotherapy, is the REFERENCES process of transferring fecal bacteria from a 1. Clemente JC, Ursell LK, Parfrey LW, Knight R. The impact of the gut microbiota on human health: an integrative healthy individual into a recipient. It is used view. Cell. 2012;148(6):1258-1270. in the treatment of recurrent Clostridium 2. Barengolts E. Gut microbiota, prebiotics, probiotics and synbiotics in management of obesity and prediabetes: difficile colitis to replenish beneficial bac- review of randomized controlled trials. Endod Prac. teria in the digestive tract following use of 2016;22(10):1224-1234. 3. Fujimura KE, Slusher NA, Cabana MD, Lynch SV. Role of wide-spectrum antibiotics. In a double- the gut microbiota in defining human health. Expert Rev blind randomized controlled trial, insulin- Anti Infect Ther. 2010;8(4):435-454. resistant men received either autologous 4. Graessler J, Qin Y, Zhong H, et al. Metagenomic sequencing of the human gut microbiome before and (reinfusion of one’s collected feces) or al- after bariatric surgery in obese patients with type 2 dia- logenic (feces from a lean donor) infusions. betes: correlation with inflammatory and metabolic parameters. Pharmacogenomics J. 2013;13(6):514-522. Allogenic transplantation resulted in sig- 5. Larsen N, Vogensen F, van den Berg F, et al. Gut micro- nificantly increased intestinal microbial biota in human adults with type 2 diabetes differs from diversity and increased levels of butyrate- non-diabetic adults. PloS One. 2010;5(2):e9085. 6. Hartsra AV, Bouter KEC, Backhed F, Nieuwdorp M. producing , accompanied by signifi- Insights into the role of the microbiome in obesity and cantly improved peripheral muscle sensi- type 2 diabetes. Diabetes Care. 2015;38(1):159-165. 1,6 7. Ley RE, Turnbaugh PJ, Klein S, Gordon JI. Microbial tivity to insulin. ecology: human gut microbes associated with obesity. Nature. 2006;444:1022-1023. BARIATRIC SURGERY 8. Candela M, Biagi E, Soverini M, et al. Modulation of gut microbiota dysbioses in type 2 diabetic patients by mac- Bariatric surgery, specifically Roux-en-Y robiotic Ma-Pi 2 diet. Br J Nutr. 2016;116(1):80-93. gastric bypass (RYGBP), is a powerful tool 9. Forslund K, Hildebrand F, Nielsen T, et al. Disentangling type 2 diabetes and metformin treatment signatures in used to treat obesity. In six patients (five of the human gut microbiota. Nature. 2015;528(7581): whom had diabetes) treated with RYGBP, 262-266.

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