膳食纤维调节肠道细菌可缓解Ⅱ型糖尿病

Gut bacteria selectively promoted by dietary fibers alleviate type 2 diabetes

Science（2018）

doi: 10.1126/science.aao5774

膳食纤维可经肠道菌群发酵生成短链脂肪酸（SCFA），对人体健康有重要作用。此前研究表明，SCFA生产不足与Ⅱ型糖尿病等诸多疾病都有关系。今天Science上线了由上海交通大学赵立平、彭永德和张晨虹共同主导的重要研究，证实高膳食纤维营养干预辅助阿卡波糖治疗，可快速有效地改善Ⅱ型糖尿病。通过分析患者肠道菌群的变化，还鉴定出一组与临床治疗效果显著相关的SCFA产生菌。以这些关键细菌为靶点，或可用于个性化营养方案来防治Ⅱ型糖尿病。

论文摘要

The gutmicrobiota is a complex microbial ecosystem, and maintaining a mutualisticrelationship with it is critical for human health (1). A notable example ofsuch a re- lationship is the production of short-chain fatty acids (SCFAs)through bacterial fermen- tation of carbohydrates: The human host diet providesnondigestible carbohydrates to sup- port bacterial growth, and in return, thebacteria generate SCFAs that provide an energy substrate to colonocytes,mitigate inflammation, and regu- late satiety, etc. (2, 3). Deficiency in SCFAproduc- tion has been associated with diseases, including type 2 diabetesmellitus (T2DM) (4–7). In clin- ical trials, increased intake of nondigestiblebut fermentable carbohydrates (dietary fibers) alle- viated the diseasephenotypes of T2DM but was associated with vastly different treatment re-sponses (8–10). Hundreds of gut bacterial species across many taxa share thegenes for ferment- ing carbohydrates into SCFAs (11). Strains of the sameSCFA-producing species also show differ- ent responses to increasedavailability of dietary fibers (12, 13). To improve the clinical efficacy of dietaryfiber interventions, it is critical to un- derstand how members of the gutecosystem respond as individual strains as well as how they interact with oneanother as functional groups when exposed to increased carbohydrates as a newenvironmental resource. In this study, we used exposure to a large amount ofdiverse fibers from dietary sources to perturb the gut ecosys- tem. We thenapplied a strain-level, microbiome- wide association approach to characterizethe dynamics of the gut microbiota and its impact on glucose homeostasis inpatients with T2DM. This strategy has led to the identification of a specificgroup of SCFA producers that alleviate T2DM by increasing SCFA production. Thisin- creased SCFA production restores a mutualistic relationship with the humanhost and diminishes producers of metabolically detrimental compounds.

We randomized patients with clinically diag- nosedT2DM to receive either the usual care [pa- tient education and dietaryrecommendations based on the 2013 Chinese Diabetes Society guidelines for T2DM(14)] as the control group (U group; n = 16 patients) or a high-fiber dietcomposed of whole grains, traditional Chinese medicinal foods, and prebiotics(the WTP diet; see materials and methods and table S1 in the supplementarymaterials) as the treatment group (W group; n = 27 patients) in an open-label,parallel- group study designated the GUT2D study (fig. S1). Both groupsreceived acarbose (an amylase inhibi- tor) as the standardized medication.Acarbose trans- forms part of the starch in the diet into a “fiber” by educingits digestion and making it more available as fermentable carbohydrate in thecolon (15). By design, the W group had a significantly higher intake of dietaryfibers with diverse structures than the U group, but the daily energy andmacro- nutrient intakes were similar across groups (table S2). The level ofhemoglobin A1c (HbA1c), our primary outcome measure, decreased significantlyfrom baseline in a time-dependent manner in both groups; from day 28 onward,however, there was a greater reduction in the W group (Fig. 1A). The proportionof participants who achieved adequate glycemic control (HbA1c < 7%) at theend of the intervention was also significantly higher in the W group (89%versus 50% in the U group) (Fig. 1B). There was a temporal difference infasting blood glucose levels—only the W group achieved a sig- nificantreduction by day 28, although at the end of the intervention there was nodifference between groups (Fig. 1C)—and a similar trend was observed forpostprandial glucose (Fig. 1D). The W group also showed greater reduction inbody weight and better blood lipid profiles than the U group (table S3). Ourclinical data indicate that increased availability of nondigestible butfermentable car- bohydrates is sufficient to induce clinically relevantmetabolic improvements in patients with T2DM, as demonstrated by the responseto increasing un- digested starch with acarbose in the U group. We observedmore significant and faster improvement in clinical outcomes in the W groupwhen more diverse carbohydrates were provided as added fibers in the diet.

实验综述

① Ⅱ型糖尿病患者随机分成两组，均用阿卡波糖治疗，U组（16例）为常规治疗组，W组（27例）接受同等热量的高膳食纤维营养干预；

② 相比U组，W组的糖化血红蛋白等指标改善得更快更好，该临床效果可经粪菌移植在小鼠中重现；

③ 治疗过程中患者肠道菌群结构改变，高膳食纤维富集了由15株乙酸和丁酸产生菌组成的功能群，抑制了吲哚和硫化氢产生菌；

④ 这组菌尤其增加丁酸生成，促进GLP-1和PYY分泌改善血糖，其丰度和多样性与临床治疗效果显著相关。

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