Next Generation Probiotics: The Development of Microbial-based Oral Formulations for Microbiome-altering Applications

有数以万亿计的细菌生活在我们的肠道内。这是正常的，因为它们在消化和防御进入我们饮食中的“坏”细菌方面很重要。有趣的是，在一系列疾病(包括炎症性肠病(IBD)、心血管疾病和肥胖症)中，肠道细菌群落的类型发生了变化。我们不知道细菌群落的这些变化是由健康状况不佳造成的，还是导致的。然而，我们确实知道，如果我们重新引入与健康相关的细菌，患者就会受益。为了更好地了解这些结果，目前全球正在进行许多临床试验。最近的发现表明，肠道中需要特定的细菌菌株来治疗疾病。不幸的是，这些细菌菌株往往是敏感的，所以我们不能简单地将它们包括在患者每天可以服用的常规药物或药片中。这是因为，例如，有些人不喜欢暴露在氧气中，有些人不能忍受酸度的变化，有些人只能在潮湿的环境中生长，有些人不能施加任何压力/热量(通常在压片时使用)。因此，目前唯一有效的将细菌重新引入肠道的方法是被称为粪便微生物移植(FMT)的过程。我们从健康人身上取出粪便(其中含有我们需要的细菌)，然后将其移植到患者的结肠中。然而，为了使物质到达结肠而不破坏细菌，我们必须使用结肠镜或鼻胃管。这两种手术都是侵入性的，令人不适，而且成本高昂。因此，这个项目旨在找出如何使用简单的口服药物来移植细菌，患者可以在家里服用。目前，我们能够将持久的细菌(如酸奶等食品中发现的细菌)放入可以口服的药物中，但我们需要小心更敏感的细菌菌株。因此，我们需要创建一个适合这些细菌的新配方目录。这份目录将包括有助于阻止氧气进入的配方，对酸度不同变化做出反应的配方，以及确保细菌只在到达结肠时才释放的配方。从本质上讲，每一种不同的配方都会提供一套不同的环境条件。该目录将使我们能够确定哪种配方为每种不同菌株的细菌提供了最佳条件，使细菌能够安全地移植到结肠。然后，我们需要测试细菌是否能够生长和定植在肠道，并改变那里现有的细菌群落，正如我们在FMT研究中观察到的那样。为了做到这一点，我们将使用人造人类肠道，将配方暴露在所有不同的环境中，通常情况下可能发生在人类身上。这个人工模型的复杂方面将使我们能够模拟特定疾病患者肠道内存在的细菌菌株，然后看看新的配方是否会改变那里现有的细菌群落，以治疗这种疾病。我们将敏感菌株移植到结肠的能力在不久的将来将是至关重要的，我们希望我们的配方目录将不仅有助于了解在该项目范围内要测试的细菌菌株，而且还将有助于了解与不同疾病相关的细菌。

There are trillions of bacteria living within our bowels. This is normal as they are important in digestion and defence from incoming 'bad' bacteria within our diets. Interestingly, in a range of diseases (examples include Inflammatory Bowel Disease (IBD), cardiovascular disease and obesity) the types of bacterial communities that live in the bowel change. We don't know if these changes in bacterial communities result from poor health, or cause it. However, we do know that patients benefit if we re-introduce bacteria associated with wellbeing. Many clinical trials are currently happening globally to better understand these outcomes.Recent findings have shown that specific strains of bacteria are needed in the bowel to remedy disease. Unfortunately, these strains of bacteria tend to be sensitive, so we cannot simply include them in regular medicines or pills that patients can take every day. This is because, for example, some don't like to be exposed to oxygen, some can't tolerate changes in acidity, some only thrive in a wet environment and some can't have any pressure/heat exerted on them (commonly applied when compressing a tablet). Consequently the only currently effective way to reintroduce bacteria to the bowel is a procedure known as Faecal Microbial Transplantation (FMT). We take stool from a healthy person (that contains the bacteria we need) and transplant it into the colon of the patient. However, in order for the material to reach the colon without any destruction to the bacteria, we must use either a colonoscope or a naso-gastric tube. Both procedures are invasive, uncomfortable and costly. So this project is designed to find out how to transplant the bacteria using simple oral-administered medicines that patients could take at home.Currently, we are able to put durable bacteria (such as those found in foods like yoghurts) in medicines that can be taken orally, but we need to be careful with the more sensitive strains of bacteria. As such, we need to create a catalogue of new formulations that suit these bacteria. This catalogue will consist of formulations that are good at keeping oxygen out, formulations that respond to different changes in acidity, and formulations that ensure the bacteria are released only when they reach the colon. In essence, each different formulation will offer a different set of environmental conditions. The catalogue will enable us to identify which formulation offers the best conditions for each different strain of bacteria, to enable the bacteria to be safely transplanted to the colon. We will then need to test whether the bacteria can grow and colonise the bowel, and alter the existing bacterial communities there, as we observe in FMT studies. In order to do this, we will use an artificial human gut, that will expose the formulations to all the different environments that could normally occur in a human. The sophisticated aspect of this artificial model will enable us to mimic the strains of bacteria present within the bowels of patients with a particular disease, and then see if new formulations alter the existing bacterial communities there, to treat the disease.The ability for us to transplant sensitive strains of bacteria to the colon will be of paramount importance in the near future, and we hope that our catalogue of formulations will be useful not only to understand the bacterial strains to be tested within the scope of this project but also to understand bacteria relevant to different diseases.