论文题目：Role of the gut microbiota in nutrition and health
Published 13 June 2018
- Ana M Valdes, associate professor1 2,
- Jens Walter, CAIP chair for nutrition, microbes, and gastrointestinal health3,
- Eran Segal, professor4,
- Tim D Spector, professor5
Published in The BMJ-British Medical Journal
Google citation: 126
Key messages:
- Gut microbiota influences many areas of human health from innate immunity to appetite and energy metabolism
- Targeting the gut microbiome, with probiotics or dietary fibre, benefits human health and could potentially reduce obesity
- Drugs, food ingredients, antibiotics, and pesticides could all have adverse effects on the gut microbiota
- Microbiota should be considered a key aspect in nutrition; the medical community should adapt their education and public health messages
- Fibre consumption is associated with beneficial effects in several contexts
Outline:
1. Studying the gut microbiota
2. What does the gut microbiota do?
3. The gut microbiota and obesity
4. Microbiota diversity and health
5. Effects of food and drugs on the gut microbiota
6. Manipulating the gut microbiota through diet
6.1 Prebiotic foods and dietary fibre
6.2 Probiotic foods
6.3 Personalised nutrition and future directions
7. Conclusions
Conclusion:
We are entering an era where we can increasingly modify health through food and measure the effects through our microbes or metabolites. Fibre is a key nutrient for a healthy microbiome and has been overlooked while debates have reged about sugar and sugar and fat. The adverse effects on the microbiome of drugs and processed food ingredients can no longer be ignored. Given the current gaps in knowledge, we need clinical practice, ideally through randomised controlled studies that use consistent matrices of prebiotics or probiotics or faecal microbiota transplantation to assess changes in gut microbiota composition and in health outcomes.
- ①肠道菌群影响免疫、能量代谢等人体健康的诸多方面，菌群失调和多样性降低与多种疾病相关；
- ②饮食和营养影响肠道菌群，菌群发酵膳食纤维生成短链脂肪酸，有多种健康益处，三甲胺、吲哚丙酸等菌群代谢产物也对健康产生直接影响；
- ③药物、食品添加剂、抗生素和杀虫剂，均可能对肠道菌群产生不良影响；
- ④膳食纤维及益生元/菌等干预方法靶向肠道菌群，可对特定病症有改善作用，需更多随机对照临床试验进行验证；
- ⑤个性化营养需考虑肠道菌群
几个经常傻傻分不清的概念：
- Microbiome：the collective genomes of the micro-organisms in a particular environment，特定环境中微生物的集体基因组
- microbes，细菌
- metabolites，代谢物，代谢分子
- Microbiota—the community of micro-organisms themselves，微生物群落本身
几个了解肠道菌群必须灰常熟悉的概念：
- Microbiota diversity: A measure of how many different species and, dependent on the diversity indicees, how evenly distributed they are in the community. Lower diversity is considered a marker of dysbiosis (microbial imbalance) in the gut and has been found in autoimmune diseases and obesity and cardiometabolic conditions, as well as in elderly people.
- OTU, Operational taxonomic unit: A definition used to classify groups of closely related organisms. DNA sequences can be clustered according to their similarity to one another, and operational taxonomic units are defined based on the similarity thresh-old (usually 97% similarity) set by the researcher
- Colonocytes, 结肠细胞—epithelial cells of the colon，结肠上皮细胞
- Germ-free animals，无菌动物—animals that have no micro-organisms living in or on them
- Short chain fatty acids, 短链脂肪酸—fatty acids with two to six carbon atoms that are produced by bacterial fermentation of dietary fibres
the microbiome is now best thought of as a virtual organ of the body.
Studying the gut microbiota
The human genome consists of about 23 000 genes, whereas the microbiome encodes over three million genes producing thousands of metabolites, which replace many of the functions of the host, consequently influencing the host’s fitness, phenotype, and health.
Twin studies have shown that, although there is a heritable component to gut microbiota, environmental factors related to diet, drugs, and anthropometric(人体测量的) measures are larger determinants of microbiota composition.
Gut microbes are key to many aspects of human health including immune, metabolic and neurobehavioural traits
The composition of gut microbiota is commonly quantified using DNA based methods, such as next generation sequencing of 16S ribosomal RNA genes or whole genome shotgun sequencing, which also allow inference of microbiota functions.
What does the gut microbiota do?
The gut microbiota provides essential capacities for the fermentation(发酵) of nondigestible substrates like dietary fibres and endogenous intestinal mucus(黏液).
Butyrate(丁酸盐) is the main energy source for human colonocytes(结肠细胞), can induce apoptosis(细胞死亡) of colon cancer cells, and can activate intestinal gluconeogenesis(糖异生), having beneficial effects on glucose and energy homeostasis(体内平衡). Butyrate is essential for epithelial cells(上皮细胞) to consume large amounts of oxygen through β oxidation, generating a state of hypoxia(低氧) that maintains oxygen balance in the gut, preventing gut microbiota dysbiosis. 这个在好像看到过很多次
糖异生又称糖异生作用、糖原发育不良作用，指的是非碳水化合物转变为葡萄糖的过程。
Propionate(丙酸盐) is transferred to the liver, where it regulates gluconeogenesis and satiety(饱腹感) signalling through interaction with the gut fatty acid receptors(肠道脂肪酸受体).
Acetate(乙酸盐)—the most abundant SCFA,短链脂肪酸 and an essential metabolite for the growth of other bacteria—reaches the peripheral tissues where it is used in cholesterol(胆固醇) metabolism and lipogenesis(脂肪生成), and may play a role in central appetite regulation.
Butyrate and propionate, but not acetate, seem to control gut hormones and reduce appetite and food intake in mice.
Other specific products of the gut microbiota have been implicated directly in human health outcomes.
The gut microbiota and obesity
The gut microbiota seems to play a role in the development and progression of obesity. Most studies of overweight and obese people show a dysbiosis characterised by a lower diversity.
Gut microbiota dysbiosis probably promotes diet induced obesity and metabolic complications by a variety of mechanisms including immune dysregulation, altered energy regulation, altered gut hormone regulation, and proinflammatory mechanisms. 肠道菌群失调可能通过多种机制（包括免疫失调，能量调节改变，肠激素调节和促炎机制）促进饮食诱发的肥胖和代谢并发症。
Microbiota diversity and health
这一块应该要重点理解
Lower bacterial diversity has been reproducibly observed in people with inflammatory bowel disease, psoriatic arthritis, type 1 diabetes, atopic eczema, coeliac disease, obesity, type 2 diabetes, and arterial stiffness, than in healthy controls. 与健康对照组相比，在炎症性肠病，银屑病关节炎，1型糖尿病，特应性湿疹，乳糜泻，肥胖，2型糖尿病和动脉僵硬的人群中，都观察到菌群多样性较低。
In Crohn’s disease smokers have even lower gut microbiome diversity.
所以只评估了一个指标，菌群多样性吗？
Consequently, diversity seems to be a generally good indicator of a “healthy gut.” 不太确定的语气~ 事情肯定没有这么简单。。。
But recent interventional studies indicate that major increases in dietary fibre can temporarily reduce diversity, as the microbes that digest fibre become specifically enriched, leading to a change in composition and, through competitive interactions, reduced diversity. 最近的很多饮食干预的研究表明，增加膳食纤维的摄入会暂时导致多样性的降低。而膳食纤维是已经被证明健康的饮食习惯，所以多样性来衡量健康，不严谨……那应该可以仔细分析膳食纤维的摄入导致了哪些菌群发生变化，从而导致了多样性的降低？
The functional role of the gut microbiome in humans has been shown using faecal microbiota transplantation.
Effects of food and drugs on the gut microbiota
Specific foods and dietary patterns can all influence the abundance of different types of bacteria in the gut, which in turn can affect health.
some animal studies have shown that these sugar substitutes may have negative effects on the gut microbiota.
Food additives(食品添加剂), such as emulsifiers(乳化剂), which are ubiquitous(普遍存在的) in processed foods, have also been shown to affect the gut microbiota in animals.
Other areas of concern include the side effects of popular restrictive diets on gut health. 比如说素食主义
A study of 15 vegans and 16 ominvores found striking differences in serum metabolites generated by the gut microbes but very modest differences in gut bacterial communities. 素食者和杂食者之间的肠道菌群差异不大，代谢产物差异显著。为什么呢？我还以为差别会很大呢，可能是因为观察时间太短我感觉？
A controlled feeding experiment of 10 human omnivores randomised to receive either a high fat and low fibre diet or a low fat and high fibre for 10 days found very modest effects on gut microbiome composition and no difference in short chain fatty acid production. 低脂高纤维的饮食长期来看应该要更健康才对，而肠道菌群也应该更健康才对？所以这个实验是因为干预时间太短么？
Together these data support a greater role for diet influencing the bacterial derived metabolome than just the short term bacterial community.
Table 1 | Examples of foods, nutrients, and dietary patterns that influence human health linked to their effect on the gut microbiota 总结了不少饮食干预的study
Animal and in vitro studies indicate that gluten-free(无麸质) bread reduces the microbiota dysbiosis seen in people with gluten sensitivity or coeliac(乳糜泻) disease.
One study showed that 21 healthy people had substantially different gut microbiota profiles after four weeks on a gluten-free diet. Most people showed a lower abundance of several key beneficial microbe species. 不同的人对相同的食物，肠道菌群的反应也会不一样。因为这类研究结果，大家都推荐吃杂粮吧。
Low FODMAP diets lead to profound changes in the microbiota and metabolome, the duration and clinical relevance of which are as yet unknown.
In addition to diet, medication is a key modulator of the gut microbiota composition.
But humans have very variable responses to antibiotics, and intervention studies have not shown consistent metabolic consequences. 抗生素干预结果是否与人类菌群状态有关联？
Insufficient clinical evidence exists to draw clear conclusions or recommendations for these or other dietary preferences based on gut microbiota.
But future studies of food additives, drugs, and the safety and efficacy of dietary modifications must take into account these advances and their effect on the gut microbiota.
Box 2 summarises our current knowledge on the interactions between gut microbiota, nutrition, and human health.
What we know
- Probiotic supplementation has several beneficial effects on human health
- The microbes in our gut influence and human energy metabolism
- Diet and medication have a strong influence on gut microbiota composition
- Microbiota composition influences reponse to chemotherapy and immunotherapy
- Microbiome composition defines glucose repsonse to foods and can be used to personalise diet
- Dietary fibre intake influences gut microbiota composition and is related to better health
What we don't know
- Are natural probiotics in food better than probiotic supplements? Show we take them preventively? 食物中的天然益生菌比益生菌添加剂更好吗？我们是不是应该当作保健品来吃？经常吃？
- Can low dose antibiotics in food affect human health? 是不是短期内影响，长期看来人体能自动恢复？
- What is the effect of pesticides in food on the gut microbiome? Is organic food better for the gut microbiota?
- Should all new drugs and food chemicals be tested on the gut microbiota?
Manipulating the gut microbiota through diet
这一节讲很多饮食干预，重点关注哦
Changes to the gut microbiota can occur within days of changing diet; remarkable differences were found after African Americans and rural Africans switched diets for only two weeks. 肠道菌群对饮食的反应，短时间内就能发生。之前低脂高纤维和高脂低纤维的食物干预实验没有这个发现，因为这个短时间发生属于极端干预实验
But healthy microbiota are resilient to temporal changes by dietary interventions, meaning that homeostatic reactions restore the original community composition, as recently shown in the case of bread.
Prebiotic foods and dietary fibre 益生元食品和膳食纤维
Some non-digestible carbohydrates have been referred to as “prebiotics,” which are defined as food components or ingredients that are not digestible by the human body but specifically or selectively nourish beneficial colonic micro-organisms.
some scientists prefer the term “microbiota accessible carbohydrates,” which are essentially equivalent to fermentable dietary fibre in that they become available as growth substrates for gut microbes that possess the necessary enzymatic capacity to use them.
Box 3 What are prebiotics and probiotics?
Dietary amounts of protein, saturated and unsaturated fats, carbohydrates, and dietary fibre influence the abundance of different types of bacteria in the gut. The microbiota can also be modified by adding live micro-organisms to food or by periods of fasting.
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Probiotics are live bacteria and yeasts that, when administrated in a viable form and in adequate amounts, are beneficial to human health. They are usually added to yoghurts or taken as food supplements.
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Prebiotics are defined as a substrate that is selectively used by host micro-organisms conferring a health benefit. Although all compounds considered prebiotics are microbiota accessible carbohydrates or fermentable dietary fibre, the reverse is not true. The prebiotic concept is an area of current debate70
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Synbiotics contain a mixture of prebiotics and probiotics
These changes only last as long as the carbohydrate is consumed, and they are highly individual, which provides a basis for personalised approaches.
these findings, together with the role of butyrate in preventing oxygen induced gut microbiota dysbiosis, provide a strong rational to enrich dietary fibre consumption to maintain intact mucosal barrier function in the gut.
Considerable observational evidence shows that fibre intake is beneficial for human health.
Probiotics are live micro-organisms that, when administered in adequate amounts, confer a health benefit on the host). Probiotics (mostly Bifidobacterium,双歧杆菌 and Lactobacillus, 乳酸杆菌 species) can be included in a variety of products, including foods, dietary supplements, or drugs.
The therapeutic effect of probiotic supplementation has been studied in a broad range of diseases.
a total of 22 systematic reviews
The analysis of 313 trials and 46 826 participants showed substantial evidence for beneficial effects of probiotic supplementation in preventing diarrhoea, necrotising enterocolitis, acute upper respiratory tract infections, pulmonary exacerbations in children with cystic fibrosis, and eczema in children. 对313项试验和46至826名参与者的分析表明，补充益生菌对预防腹泻，坏死性小肠结肠炎，急性上呼吸道感染，囊性纤维化患儿的肺病恶化和湿疹有有益的作用。
the studies were not homogeneous and were not necessarily matched for type or dose of probiotic supplementation nor length of intervention, which limits precise recommendations. 他们没有进一步分析的原因？
Table 2 Summary of systematic reviews analysing the role of probiotics on clinical outcomes
感觉这个表格总结的所有trail都需要去看看有木有数据吧，313个啊啊啊啊
Given the variation in the gut microbiota between people, the optimal diet of a person may need to be tailored to their gut microbiota.
Much more research is needed to establish whether these kinds of personalised approaches are feasible, sustainable, and have a positive effect on clinical outcomes.
