Enteroendocrine cells comprise about 1% of the epithelial cell population. They are scattered throughout the small intestine (1). The enteroendocrine cell body comprises at least 15 different gut cell types categorized based upon their morphology, specific regional distribution, and peptide hormone expression. The first reports dealing with enteroendocrine cells reach back to the 19th century when Heidenhain and Kulschitzky speculated about distinct intestinal cells appearing with a remarkable staining behavior (2–4). Heidenhain predicted in 1888 that “even an only limited clue about the processes in the gut mucosa deserves many more years of studies” (author’s translation) (3). In fact, only 130 years later, facing an impressive diversity of enteroendocrine cells, researchers became capable of employing transcriptomic and peptidomimetic profiling techniques, revealing a complexity rarely expected by the earlier reports (5,6).
The products of gut endocrine cells now receive high attention by the scientific community. This is because certain gut peptides are targets for the development of drugs for the treatment of important diseases such as diabetes and obesity (7), nonalcoholic fatty liver disease (8), and cardiovascular complications of diabetes (9).
New techniques have completely revolutionized transcriptome analysis and profiling in physiology and human disease (5). Thus, the quantification of gene expression levels and allele-specific expression is possible in single experiments. The identification of novel genes, splice isoforms, and fusion transcripts is at hand. These approaches help indentify novel disease markers and precise molecular targets for new therapeutic strategies on the background of advanced data integration.
In this issue of Diabetes, Roberts et al. (6) present an interesting and timely piece of work dealing with the comparison of human and murine enteroendocrine cells utilizing these new state-of-the-art technologies. They focus on certain gut peptides, such as the proglucagon-derived glucagon-like peptide 1 (GLP-1), recently highly acclaimed as candidates for new therapies of diabetes and other metabolic diseases (7). Although they did not go beyond a grossly descriptive level while reporting their findings, the authors present the notion of longitudinal gradients of a range of enteroendocrine cell–borne peptides, hinting at function and including detailed data of their sequences and posttranslational modifications. Breaking down the complex and detailed findings of the present article into simple take-home messages, it is worthwhile to summarize the following.
The introduction of advanced techniques for transcriptomic and peptidomic profiling allows sophisticated studies in diffuse or scattered endocrine cell systems such as enteroendocrine cell populations.
Evolution has left strong similarities between human and mouse enteroendocrine cell transcriptomes, pointing to biological significance and qualifying mouse models for the search for drug targets in humans.
Among the identified exact peptide sequences produced in both human and mouse mucosa, the detection of multiple processed and preprocessed products of the proglucagon gene residing in L cells is of considerable interest (see below).
This scientific approach is ready to be employed in clinical studies, especially those on bariatric surgery and the impact of the gut microbiota on gut endocrine cell function.
Clearly, several mechanisms act in concert normalizing carbohydrate metabolism after bariatric surgery. Roberts et al. (6) discuss aspects of intestinal endocrine cell regulation after weight loss surgery. As they correctly indicate, their present study is underpowered to address the impact of body weight or diet on endocrine cells. Still, such studies are valued for their approaches. Gut peptides are studied to explain the efficiency of bariatric surgery and, in addition, its unwanted side effects (10). Clearly, it is of great interest to shed more light on the chances of gut hormone secretion after the use of GLP-1–based injection therapies (such as downregulation of proglucagon gene expression) and, in addition, after different types of bariatric surgery. Such changes are suggested to impact appetite regulation and insulin secretion, thereby possibly contributing to metabolic control. GLP-1 and peptide YY (PYY) are targets in the present article and have been earlier addressed by others as important mediators of beneficial effects (7–9).
Generally, the impact of food, i.e., defined diets, on the gut cell population is clearly of interest in this context. Diets are offered to patients for weight reduction. They may prompt as yet undefined effects on enteroendocrine cells in addition to the consequences of a simple reduction of food calories.
Further, recent studies deal with a putative and probably important relationship between the microbiome in the gut and states of health and disease, such as for obesity and type 2 diabetes. It seems that clinical microbiome studies lead to advanced concepts of personalized medicine, finally changing therapeutic strategies of diabetes therapies (11). One wonders how the microbiome impacts the intestinal endocrine cells, e.g., those producing the members of the secretin family such as GLP-1, GIP, or PYY, all candidates for new therapeutic strategies.
L cells are highly responsive to nutrients and microbiota-derived metabolites that stimulate hormone secretion (12). In fact, recent data from studies employing gene expression profiles reveal that the microbiota exert major, rapid, and tissue-specific regulation of the L-cell transcriptome (13). This finding was combined with sophisticated morphologic studies utilizing electron microscopy, allowing a corroboration of key findings. This implies that the approach by Roberts et al. presented here would benefit from controls based upon independent techniques, e.g., electron microscopy, or studies using material from specific knockouts.
Going forward, it will be necessary to define approaches, going beyond the descriptive level, of transcriptional and peptidomic profiling that delineate their functional significance. One can expect and hope that findings by Roberts et al. and future research will pave the way for a better understanding of the significance of the human enteroendocrine system in metabolic diseases and its potential for drug discovery programs. Finally, we need clear-cut data and concepts to accompany sophisticated and highly complex techniques.
See accompanying article, p. 1062.
Duality of Interest. No potential conflicts of interest relevant to this article were reported.