ATP‐binding cassette (ABC) transporters constitute a large group of plasma membrane proteins in mammals. In humans, ABC superfamily includes 48 members encoded by seven families of genes from ABCA to ABCG. Over the last two decades, ABC proteins have attracted considerable attention in pharmacological research as a result of the crucial role of some of them in the lack of response to chemotherapy and, hence, poor prognosis of many cancer patients. For instance, those suffering from liver or gastrointestinal tumours, which are particularly refractory to available pharmacological treatment.¹

Since the initial description of P‐glycoprotein (gene symbol ABCB1), also known as MDR1 because of its major role in multidrug resistance (MDR) phenotype of cancer cells, the involvement of this ATP‐dependent export pump in physiological barriers is largely understood. MDR1 functions are partly shared by a member of the ABCG family, the breast cancer resistance protein (BCRP, gene symbol ABCG2) and several ABCC family members, also involved in anticancer drug resistance, which justifies why these pumps are named multidrug resistance‐associated proteins (MRP).

The present editorial relates to the manuscript entitled "Intraluminal nutrients acutely strengthen rat intestinal MRP2 barrier function by a glucagon‐like peptide‐2‐mediated mechanism" published in Acta Physiologica by Prof. Mottino's group.² In that study, based on a previous proof‐of‐concept article by the same group, in which they demonstrated the short‐term regulation of intestinal MRP2,³ the authors further investigated the impact of nutrients administered intraluminally in the rat distal jejunum on the function of MRP2 (gene symbol ABCC2) at the intestinal level. Moreover, they explored the underlying mechanisms accounting for the control of the observed changes. Their results allow them to conclude that glucagon‐like peptide‐2 (GLP‐2) is involved in the response consisting of an enhanced insertion of MRP2 at the brush border membrane (BBM) of intestinal epithelial cells, a process mediated, at least in part, by cAMP‐dependent protein kinase (PKA) signalling pathway.

The study by Tocchetti et al² is a typical example of an experimental approach with elegant design to elucidate a physiological question by combining in vitro models with well‐performed classical in vivo experiments. A valuable discovery of that study is the connection between the presence of nutrients in the intestinal lumen, such as oleic acid, and the response of the epithelial cells by tuning the efficacy of the intestinal barrier through the expression of MRP2. The study paves the way to further investigations to complete the whole picture of intestinal transportome by determining changes in the expression of a broader panel of transporters involved in the intestinal barrier, including not only ABC pumps but also uptake carriers members of the SLC (Solute Carriers) superfamily of proteins.

In this respect, some years ago, Cheeseman already demonstrated the existence of acute effects of GLP‐2 on the translocation of glucose transporters in the intestinal epithelium.⁴ He reported enhanced sodium‐dependent glucose uptake in rat jejunum BBM vesicles short (30 minutes) after intravenous administration of GLP‐2. These findings were associated with an enhanced insertion of the sodium‐dependent glucose transporter 1 (SGLT‐1, gene symbol SLC5A1) in the apical plasma membrane. Based on their results obtained using wortmannin, Cheeseman suggested a role of phosphoinositide 3‐kinase (PI3K)‐dependent pathway in the activation of SGLT‐1 targeting to the apical membrane of epithelial cells in response to GLP‐2 administration. As discussed by Tocchetti et al in this issue,² it would be highly interesting to unravel whether other SLC transporters at the surface of the intestine are similarly regulated, improving nutrient absorption during the course of a meal.

Regarding ABC pumps, although with different distribution along the intestine, several members of this superfamily of transporters are expressed at the plasma membrane of enterocytes, also playing a role in the intestinal barrier.⁵ Thus, whereas MDR1, MRP4 and BCRP are located at the apical side, hence, facing the intestinal lumen, MRP1, MRP3 and MRP5 are expressed at the opposite basolateral pole of these epithelial cells. In the highlighted study, Tocchetti et al only explore the regulation of MRP2 by nutrients and cannot ascertain whether other members of the ABC family are affected in a similar fashion. However, they had previously provided evidence for GLP‐2 being able to prevent down‐regulation of intestinal expression and activity of MRP2 and MDR1 in a model of endotoxemic rats.⁶

The actual physiological relevance of the mechanism described by Tocchetti et al is not fully elucidated, but the authors reasonably suggested that acutely regulating intestinal activity of MRP2, and perhaps other ABC pumps, in response to food intake might be important in protecting the organism against the absorption of dietary toxicants also contained in the meal. Indeed, GLP‐2 secretion depends on the specific nutrient composition of the diet,⁷ and several ABC transporters can transport a wide range of hydrophobic compounds, including lipids and lipid derivatives.⁸

Another possibility is that toxic compounds could be produced by bacterial metabolism from food components. It should be kept in mind that the gut microbiota connects diet to the metabolism by producing small molecules via diverse metabolic pathways, some of which can be maintained in the intestinal lumen through the activity of export pumps located at the BBM. The role of this defensive barrier could be critical under pathological conditions, such as inflammatory bowel disease (IBD), where microbiota dysbiosis, which is a frequent feature accompanying these pathological conditions, can contribute to the generation of more toxic metabolites.⁹

This is of particular clinical relevance regarding fatty acids, such as oleic acid, which has been identified by Tocchetti et al as a strong stimulator of GLP‐2 release³ because fatty acids¹⁰ and their metabolites¹¹ are known to induce inflammation and superficial lysis of the colon epithelium. This is followed by an increase in colonic mitotic activity and the number of cells engaged in DNA synthesis in compensatory regeneration, which explains, in part, the promotional effect of dietary fat in colon carcinogenesis.

In addition to physiological and pathological implications of intestinal ABC proteins regulation by food components, the impact of enhanced export activity on the net absorption of orally administered drugs (that are a substrate of these pumps) may lead to reduce their pharmacological efficacy. This may be considered for identifying diet incompatibilities during treatment with such drugs.¹²

Finally, another appealing aspect of the study by Tocchetti et al is the hypothesis proposed by the authors regarding the involvement of neuronal elements in the control loop, which still remains to be fully explored.

Thus, the summarized contribution to our understanding of intestinal physiology derived from this study is that nutritional signals may trigger a neuroendocrine flow of information/orders aimed at adapting the intestinal mucosa phenotype to a dynamically changing metabolomic environment, which likely includes gut microbiota interactions among the determining elements.

ATP结合盒（ABC）转运蛋白在哺乳动物中构成了一大部分的质膜蛋白。在人类中，ABC超家族包括48个成员，这些成员由从ABCA到ABCG的七个基因家族编码。在过去的二十年中，由于ABC蛋白中的某些在对化学疗法无响应的过程中起着至关重要的作用，因此许多癌症患者的预后较差，因而在药理学研究中引起了极大的关注。例如，那些患有肝或胃肠道肿瘤的患者，对于现有的药物治疗而言尤其难治。^1个

自从对P糖蛋白（基因符号ABCB1）的最初描述（由于其在癌细胞的多药耐药性（MDR）表型中起主要作用）而又被称为MDR1以来，人们对这种依赖于ATP的输出泵在生理屏障中的参与已广为了解。MDR1功能部分由ABCG 家族成员，乳腺癌抗性蛋白（BCRP，基因符号 ABCG2）和几个 ABCC 家族成员共享 ，它们也参与了抗癌药耐药性，这证明了为什么将这些泵称为多药耐药相关蛋白（MRP）。

本社论涉及由莫蒂诺教授在《生理学报》上发表的题为“腔内营养通过胰高血糖素样肽2介导的机制急性增强大鼠肠道MRP2屏障功能”的手稿。² 在该研究的基础上，基于同一组以前的概念验证文章，他们证明了肠道MRP2的短期调节，[ ^3] 作者进一步研究了腔内施用空肠远端营养对大鼠空肠营养的影响。 MRP2的功能（基因符号 ABCC2）。此外，他们探索了控制观察到的变化的潜在机制。他们的结果使他们得出结论，胰高血糖素样肽2（GLP-2）参与了这种反应，其中包括MRP2在肠上皮细胞刷状缘膜（BBM）上的增强插入，这一过程至少在细胞内介导。部分通过cAMP依赖性蛋白激酶（PKA）信号传导途径。

Tocchetti等人[ ^2]的研究 是将体外模型与性能良好的经典体内试验相结合，从而阐明生理问题的一种优雅设计的实验方法的典型示例。该研究的一个重要发现是肠内腔中营养物质（例如油酸）的存在与通过调节MRP2的表达调节肠屏障的功效而引起的上皮细胞反应之间的联系。该研究通过确定参与肠屏障的更广泛转运蛋白表达的变化，为进一步研究肠道转运蛋白的整体铺平了道路，不仅包括ABC泵而且还包括SLC的摄取载体成员（Solute Carriers） ）蛋白质超家族。

在这方面，几年前，Cheeseman已经证明了GLP-2对葡萄糖转运蛋白在肠上皮细胞转运中的急性作用。⁴他报告说，静脉注射GLP-2后短时间（30分钟）大鼠空肠BBM囊泡中钠依赖性葡萄糖的摄取增强。这些发现与钠依赖性葡萄糖转运蛋白1（SGLT-1，基因符号SLC5A1）在心尖质膜中的插入增强有关 。根据他们使用渥曼青霉素获得的结果，Cheeseman提出了磷酸肌醇3激酶（PI3K）依赖性途径在响应于GLP-2给药的靶向上皮细胞顶膜的SGLT-1活化中的作用。正如Tocchetti等人在本期中所讨论的，²揭开肠道表面的其他SLC转运蛋白是否受到类似调节，从而改善进餐过程中的营养吸收将是非常有趣的。

关于ABC泵，尽管沿肠道分布不同，但该转运蛋白超家族的几个成员在肠细胞的质膜表达，在肠屏障中也起作用。⁵ 因此，尽管MDR1，MRP4和BCRP位于顶端，因此，面对肠腔，MRP1，MRP3和MRP5在这些上皮细胞的相对基底外侧极表达。在突出的研究中，Tocchetti等人仅探讨了营养物质对MRP2的调节作用，而无法确定ABC家族的其他成员是否也以类似的方式受到影响。但是，他们先前提供的证据表明，GLP-2能够防止内毒素血症大鼠模型中肠道表达的下调以及MRP2和MDR1的活性。⁶

Tocchetti等人描述的机制的实际生理相关性尚未完全阐明，但作者合理地建议，响应食物摄入而对MRP2以及其他ABC泵的肠道活性进行急性调节可能对保护生物体免受微生物侵害至关重要。膳食中还含有膳食中有毒物质的吸收。确实，GLP-2的分泌取决于饮食中特定的营养成分^7， 并且几种ABC转运蛋白可以转运多种疏水化合物，包括脂质和脂质衍生物。⁸

另一种可能性是有毒化合物可能是由食品成分中的细菌代谢产生的。应当记住，肠道微生物群通过多种代谢途径产生小分子，从而将饮食与代谢联系起来，其中一些可以通过位于BBM处的出口泵的活动而维持在肠腔中。在诸如炎症性肠病（IBD）等病理条件下，这种防御性屏障的作用可能至关重要。在这种疾病中，伴随这些病理条件发生的常见特征是微生物群失调，可促进毒性更大的代谢产物的产生。⁹

这与脂肪酸（例如油酸）具有特殊的临床相关性，Tocchetti等已将其鉴定为GLP-2释放的强烈刺激剂^3，因为已知脂肪酸¹⁰及其代谢物¹¹会引起炎症和表皮溶解。结肠上皮。其次是结肠有丝分裂活性的增加和代偿性再生中参与DNA合成的细胞数量的增加，这部分解释了饮食脂肪在结肠癌发生中的促进作用。

除了食物成分对肠道ABC蛋白的生理和病理影响外，出口活动增强对口服给药药物（这些泵的底物）的净吸收的影响还可能导致其药理作用降低。可以考虑用这种方法来确定在用此类药物治疗期间饮食不相容的情况。¹²

最后，Tocchetti等人的研究的另一个吸引人的方面是作者提出的关于神经元参与控制回路的假说，该假说尚待充分探讨。

因此，从本研究中得出的对我们对肠道生理的理解的总结性贡献在于，营养信号可能会触发信息/顺序的神经内分泌流，旨在使肠道粘膜表型适应动态变化的代谢环境，这可能包括肠道微生物群之间的相互作用。确定要素。