論文題目：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腸道菌羣影響免疫、能量代謝等人體健康的諸多方面，菌羣失調和多樣性降低與多種疾病相關；
- ②飲食和營養影響腸道菌羣，菌羣發酵膳食纖維生成短鏈脂肪酸，有多種健康益處，三甲胺、吲哚丙酸等菌羣代謝產物也對健康產生直接影響；
- ③藥物、食品添加劑、抗生素和殺蟲劑，均可能對腸道菌羣產生不良影響；
- ④膳食纖維及益生元/菌等干預方法靶向腸道菌羣，可對特定病症有改善作用，需更多隨機對照臨牀試驗進行驗證；
- ⑤個性化營養需考慮腸道菌羣
幾個經常傻傻分不清的概念：
- Microbiome：the collective genomes of the micro-organisms in a particular environment，特定環境中微生物的集體基因組
- microbes，細菌
- metabolites，代謝物，代謝分子
- Microbiota—the community of micro-organisms themselves，微生物羣落本身
幾個瞭解腸道菌羣必須灰常熟悉的概念：
- 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, 結腸細胞—epithelial cells of the colon，結腸上皮細胞
- Germ-free animals，無菌動物—animals that have no micro-organisms living in or on them
- Short chain fatty acids, 短鏈脂肪酸—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(人體測量的) 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(發酵) of nondigestible substrates like dietary fibres and endogenous intestinal mucus(黏液).
Butyrate(丁酸鹽) is the main energy source for human colonocytes(結腸細胞), can induce apoptosis(細胞死亡) of colon cancer cells, and can activate intestinal gluconeogenesis(糖異生), having beneficial effects on glucose and energy homeostasis(體內平衡). Butyrate is essential for epithelial cells(上皮細胞) 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. 這個在好像看到過很多次
糖異生又稱糖異生作用、糖原發育不良作用，指的是非碳水化合物轉變爲葡萄糖的過程。
Propionate(丙酸鹽) is transferred to the liver, where it regulates gluconeogenesis and satiety(飽腹感) signalling through interaction with the gut fatty acid receptors(腸道脂肪酸受體).
Acetate(乙酸鹽)—the most abundant SCFA,短鏈脂肪酸 and an essential metabolite for the growth of other bacteria—reaches the peripheral tissues where it is used in cholesterol(膽固醇) 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. 腸道菌羣失調可能通過多種機制（包括免疫失調，能量調節改變，腸激素調節和促炎機制）促進飲食誘發的肥胖和代謝併發症。
Microbiota diversity and health
這一塊應該要重點理解
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. 與健康對照組相比，在炎症性腸病，銀屑病關節炎，1型糖尿病，特應性溼疹，乳糜瀉，肥胖，2型糖尿病和動脈僵硬的人羣中，都觀察到菌羣多樣性較低。
In Crohn’s disease smokers have even lower gut microbiome diversity.
所以只評估了一個指標，菌羣多樣性嗎？
Consequently, diversity seems to be a generally good indicator of a “healthy gut.” 不太確定的語氣~ 事情肯定沒有這麼簡單。。。
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. 最近的很多飲食干預的研究表明，增加膳食纖維的攝入會暫時導致多樣性的降低。而膳食纖維是已經被證明健康的飲食習慣，所以多樣性來衡量健康，不嚴謹……那應該可以仔細分析膳食纖維的攝入導致了哪些菌羣發生變化，從而導致了多樣性的降低？
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(食品添加劑), such as emulsifiers(乳化劑), 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. 比如說素食主義
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. 素食者和雜食者之間的腸道菌羣差異不大，代謝產物差異顯著。爲什麼呢？我還以爲差別會很大呢，可能是因爲觀察時間太短我感覺？
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. 低脂高纖維的飲食長期來看應該要更健康纔對，而腸道菌羣也應該更健康纔對？所以這個實驗是因爲干預時間太短麼？
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 總結了不少飲食干預的study
Animal and in vitro studies indicate that gluten-free(無麩質) bread reduces the microbiota dysbiosis seen in people with gluten sensitivity or coeliac(乳糜瀉) 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. 不同的人對相同的食物，腸道菌羣的反應也會不一樣。因爲這類研究結果，大家都推薦吃雜糧吧。
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. 抗生素干預結果是否與人類菌羣狀態有關聯？
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劑更好嗎？我們是不是應該當作保健品來吃？經常吃？
- Can low dose antibiotics in food affect human health? 是不是短期內影響，長期看來人體能自動恢復？
- 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
這一節講很多飲食干預，重點關注哦
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. 腸道菌羣對飲食的反應，短時間內就能發生。之前低脂高纖維和高脂低纖維的食物干預實驗沒有這個發現，因爲這個短時間發生屬於極端干預實驗
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 益生元食品和膳食纖維
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.
-
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
-
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,雙歧桿菌 and Lactobacillus, 乳酸桿菌 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. 對313項試驗和46至826名參與者的分析表明，補充益生菌對預防腹瀉，壞死性小腸結腸炎，急性上呼吸道感染，囊性纖維化患兒的肺病惡化和溼疹有有益的作用。
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. 他們沒有進一步分析的原因？
Table 2 Summary of systematic reviews analysing the role of probiotics on clinical outcomes
感覺這個表格總結的所有trail都需要去看看有木有數據吧，313個啊啊啊啊
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.