Receptors for Short Chain Fatty Acids in the control of bacterial infection and gut immunity

人类的肠道中通常含有几乎难以想象的细菌。在健康方面，它们扮演着许多关键角色，并产生大量自身新陈代谢的副产品，对我们身体的细胞和组织产生积极的影响。然而，在某些环境中，入侵细菌大量繁殖，这可能导致健康不佳，从轻微的胃部不适症状到严重得多的、危及生命的情况，如败血症。肠道有一个监测系统，可以检测这种入侵细菌的存在，这种与肠道相关的淋巴组织的一个主要成分是所谓的“帕伊尔氏斑”。它们含有广泛的免疫细胞，参与这些最初的过程，然后协调身体的反应，使这些细菌失效并摧毁它们。这两组免疫细胞被称为树突状细胞和3型先天性淋巴(IL3)细胞。多年来，我们一直在研究由短链脂肪酸激活的细胞表面受体，如醋酸，许多肠道细菌的代谢活动会产生大量的短链脂肪酸。这些受体被称为游离脂肪酸受体2和游离脂肪酸受体3，是被称为G蛋白偶联受体的跨膜蛋白大家族的成员，这些受体是许多成功使用的药物的靶标，我们一直在许多情况下探索，包括糖尿病和其他代谢疾病，激活或阻断其中一个或另一个短链脂肪酸受体是否可能是治疗疾病的有效手段。在这些研究中，我们开发了许多新的化学配体，它们要么模仿短链脂肪酸的作用，要么阻断它们的作用。结果表明，树突状细胞和3型固有淋巴(IL3)细胞都表达非常高数量的游离脂肪酸受体2，而肠道中的其他细胞表达游离脂肪酸受体3。这意味着游离脂肪酸受体2，也可能是游离脂肪酸受体3，可能在检测侵袭性细菌和促进肠道和全身免疫反应中发挥重要作用。许多研究支持这一观点，但其他研究则自相矛盾。最初的研究旨在了解基本的生物过程，以及它们是否有可能成为治疗人类疾病的靶点，这些研究通常在小鼠身上进行。这反映出，作为哺乳动物，它们拥有许多与人类相同的生理功能和控制机制。然而，也有许多不同之处，在游离脂肪酸受体2的情况下，我们和制药公司都开发了潜在的类似药物的分子来阻断这种受体，这些分子对人类形式的受体非常有效，但在老鼠形式的受体中不起作用。由于我们需要充分了解在小鼠体内激活或阻断该受体的可能影响，然后才能考虑对人类进行研究，因此我们对小鼠进行了改造，使其表达人类形式的受体，而不是小鼠形式的受体。我们还对这些转基因小鼠的受体进行了其他基因修改，以使我们能够清楚地看到表达人类受体的细胞。我们计划使用这些小鼠和我们开发的各种类药物化合物来评估激活修饰的受体，或者实际上是在这些小鼠中没有变化的游离脂肪酸受体3，是否有效地对抗包括沙门氏菌在内的入侵细菌定植肠道和潜在疾病的能力。我们还将使用其他遗传策略来评估仅在树突状细胞或类型3型先天淋巴(IL3)细胞中激活游离脂肪酸受体2是否能够并足以对抗感染。如果激活游离脂肪酸受体可以提供一种可用于人类研究的治疗策略，这些实验将产生清晰的理解。

The human intestine routinely contains an almost unimaginable number of bacteria. In health they perform many key roles and generate a vast number of by-products of their own metabolism that positively affect the cells and tissue of our own body. However, in certain settings invasive bacteria multiply extensively and this can result in ill-health that can range from mild symptoms of an 'upset stomach' to much more serious and life-threatening conditions such as sepsis. The gut has a surveillance system that detects the presence of such invasive bacteria, and a major element of this Gut-Associated Lymphoid Tissue is the so called 'Payer's patches'. These contain a wide range of immune cells involved in both these initial processes and then co-ordinating the response of the body to disable and destroy such bacteria. Two sets of these immune cells are called 'dendritic' cells and 'type 3 innate lymphoid (IL3)' cells. For many years we have been studying cell surface receptors that are activated by short chain fatty acids, such as acetic acid, that are generated in large amounts by the metabolic activity of many of the gut bacteria. These receptors, called Free Fatty Acid Receptor 2 and Free Fatty Acid Receptor 3 are members of a large family of transmembrane proteins called G protein-coupled receptors that are the targets of many successfully used medicines, and we have been exploring in many settings, including diabetes and other metabolic disorders, if activating or blocking one or other of these receptors for short chain fatty acids might be a useful means to treat disease. Within these studies we have developed a number of novel chemical ligands that either mimic the effects of the short chain fatty acids or block their actions. It turns out that both 'dendritic' cells and 'type 3 innate lymphoid (IL3)' cells express very high amounts of Free Fatty Acid Receptor 2 and other cells in the gut express Free Fatty Acid Receptor 3. This implies that Free Fatty Acid Receptor 2, and possibly also Free Fatty Acid Receptor 3, are likely to play important roles in the detection of invasive bacteria and promote both gut and overall whole body immune responses. A number of studies have supported this idea but other studies are contradictory. Initial studies that are designed to understand basic biological processes and whether they can potentially be targeted to treat human disease are often performed in mice. This reflects that as mammals they share many of the same physiological functions and mechanisms of control as humans. However, there are also many differences, and in the case of Free Fatty Acid Receptor 2, potential drug-like like molecules that both we and pharmaceutical companies have developed to block this receptor are very effective at the human form of the receptor but do not work at the mouse form. As we need to fully understand the possible effects of activating or blocking this receptor in mouse before studies in human can be considered we have engineered mice so that they express the human form of the receptor in place of the mouse version. We have also made other genetic modifications to the receptor in these modified mice to allow us to 'see' clearly the cells in which the human receptor is expressed. We plan to use these mice and the variety of drug-like compounds we have developed to assess if activating the modified receptor, or indeed Free Fatty Acid Receptor 3 which is unchanged in these mice, is effective in combatting the ability of invasive bacteria including Salmonella to colonise the gut and potential cause disease. We will also use other genetic strategies to assess if activating Free Fatty Acid Receptor 2 only in dendritic' cells or 'type 3 innate lymphoid (IL3)' cells is able and sufficient to combat infection. These experiments will generate clear understanding if activating free fatty acid receptors can suggest a therapeutic strategy that can be taken forward to human studies.