The enteroendocrine axis and its effect on gastrointestinal function, nutrition, and inflammation

Abstract

Purpose of review

Gastrointestinal (GI) dysfunction limits enteral nutrition (EN) delivery in critical illness and contributes to systemic inflammation. The enteroendocrine (EE) axis plays an integral role in this interface between nutrition, inflammation, and GI function in critical illness. In this review, we present an overview of the EE system with a focus on its role in GI inflammation and function.

Recent findings

Enteroendocrine cells have been primarily described in their role in macronutrient digestion and absorption. Recent research has expanded on the diverse functions of EE cells including their ability to sense microbial peptides and metabolites and regulate immune function and inflammation. Therefore, EE cells may be both affected by and contribute to many pathophysiologic states and interventions of critical illness such as dysbiosis, inflammation, and alternative EN strategies. In this review, we present an overview of EE cells including their growing role in nonnutrient functions and integrate this understanding into relevant aspects of critical illness with a focus on EN.

Summary

The EE system is key in maintaining GI homeostasis in critical illness, and how it is impacted and contributes to outcomes in the setting of dysbiosis, inflammation and different feeding strategies in critical illness should be considered.

INTRODUCTION

The gastrointestinal (GI) tract is one of the key organ systems that is affected during critical illness and has been deemed the “motor” of multiorgan dysfunction [1]. Therefore, maintaining homeostasis is important for GI function and modulation of the inflammatory response in critical illness. Gastrointestinal homeostasis is regulated by a complex network that extends from the local epithelial barrier surface to the central nervous system (CNS) [2]. Integral to this network is the enteroendocrine (EE) system, which links intraluminal signaling with local and systemic effector pathways. Alterations in the EE system as a result of critical illness can impact epithelial barrier health, motility, nutrient absorption, and inflammatory signaling. Nutrition delivery variables such as prolonged fasting, specialized enteral formulas, and modes of enteral nutrition (EN) delivery, such as gastric vs. postpyloric EN or intermittent vs. continuous, all potentially affect and are impacted by EE physiology as well. In this review, we present an overview of the EE system. We have described the basic science and clinical implications of EE system alterations during critical illness in the context of nutrition and inflammation.

BASIC OF THE ENTEROENDOCRINE CELL

Enteroendocrine cells account for 1% of all epithelial cells in the GI tract and are the most active hormone-producing and secretory cell type [3]. They are derived from intestinal stem cells located within the crypts of Lieberkuhn, and their differentiation and proliferation are tightly regulated by numerous transcriptional factors resulting in these cells being isolated and scattered widely throughout the GI tract [4,5■,6].

Fully differentiated EE cells are described as open or closed. (Fig. 1) Open-type EE cells possess a distinctive bottleneck shape facing the intestinal lumen and are directly influenced by cues from the lumen. Closed-type EE cells do not foster microvilli and are located close to the basal membrane of the epithelium, where they are activated indirectly by neurologic and immune signaling [3]. Upon activation via G protein-coupled receptors (GPCRs) and Toll-like receptors (TLRs), EE cells release synthesized peptides and hormones in an exocytic manner. On the basilar end, EE cells are near nerve endings and capillaries, allowing their secretory products to act locally or in extra-intestinal targets. Enteroendocrine cells also possess cytoplasmic processes known as neuropods that extend into the lamina propria and form synapses with nerves in the mucosa, forming a direct connection to the enteric nervous system (ENS) and the CNS via receptors in the spinal cord [7,8]. This connection allows for bidirectional signaling thereby providing positive and negative feedback loops that regulate the gut-brain axis and modulate functions such as satiety and glucose homeostasis.

FIGURE 1.

Schematic of the enteroendocrine cell in the epithelial barrier and its relationship to intraluminal cues and downstream immune and neurologic signaling. EE, enteroendocrine.

ENTEROENDOCRINE CELLS IN DIGESTION AND MOTILITY

The first described function of EE cells was that of regulating nutrient digestion and absorption. This includes the process of food trituration, digestion, absorption, and motility. In a standard meal ingested by mouth, solid foods are broken down within the distal stomach, known as trituration. This requires gastric accommodation, rhythmic contractions of the antrum, and the release of gastric juices. Food digestion and absorption take place in the small intestine, where the composition of the food content is accounted for to regulate the transfer of gastric contents into the small intestine. This ensures adequate time and exposure for the passage of a digested meal to be absorbed. The “ileal break” is an example of this feedback loop, whereby peptide-YY (PYY) and glucagon-like peptide 1 (GLP-1) delay small intestinal transit to optimize nutrient digestion and absorption and promote the sense of satiety important for energy homeostasis [9,10]. However, when this coordination between the stomach and small intestine fails, the transfer of food may be too fast resulting in poor absorption, glucose dysregulation, and diarrhea, also known as dumping syndrome, or if the transfer of food is too slow this results in emesis, feeding intolerance, and abdominal distension. Similar symptoms occur during treatment with GLP-1 receptor agonists and after bariatric surgery, which increases circulating GLP-1 levels.

Table 1 reviews the classic description of EE cells, their hormones, and their primary functions. However, it is important to note that although EE cells have been classically described as releasing only one hormone, studies have shown that EE cells can release multiple hormones at once and different types of hormones depending on signaling, in addition to participating in nonnutrition related functions [11].

Table 1.

Classical description of enteroendocrine cells^a

EE cell subtypes	Hormones secreted	Location	Main functions
EC	5-HT	Stomach, SI, colon	Stimulates motility and secretion
D	Somatstatin	Stomach, SI	Slows stomach emptying and gastrointestinal motility
G	Gastrin	Stomach, duodenum	Stimulates gastric acid secretion
I	5-HT, CCK	Proximal SI	Slow stomach emptying and increase pyloric tone
K	5-HT, GIP	Proximal SI	Stimulate insulin release
L	5-HT, GLP-1, GLP-2, PYY, oxyntomodulin	Ileum, colon	Stimulate insulin release and cell proliferation, controls gastrointestinal motility and contributes to the ‘ileal break’
M	Motolin	SI, colon, rectum	Stimulates stomach emptying
N	Neurotensin	SI	Regulates smooth muscle contraction
S	Secretin	Stomach, SI	Slow stomach emptying and intestinal motility
X/A	Ghrelin	Stomach	Stimulates stomach emptying

5-HT, 5-hydroxytryptamine; CCK, cholecystokinin; EE, enteroendocrine; GIP, gastric inhibitory peptide; GLP-1, glucagon-like peptide 1; GLP-2, glucagon-like peptide 2; PYY, peptide YY; SI, small intestine.

^aStudies have demonstrated that enteroendocrine cells are capable of secreting more than one hormone and different hormones than classically described depending on environmental cues and transcriptional factors. This table presents the classic descriptions of enteroendocrine cell location, hormone/peptide release and effect on the gastrointestinal tract.

ENTEROENDOCRINE CELLS AND THE MICROBIOME AND IMMUNE REGULATION

Enteroendocrine cells play a role in regulating immune function and inflammation directly and indirectly through their relationship to the microbiome. Enteroendocrine cells express receptors that can sense microbial metabolites and peptides. Short-chain fatty acids (SCFAs), a microbial metabolite, act on GPCRs on EE cells leading to the release of PYY, which has been associated with colonic motility in experimental models [12–14]. Dietary studies have also demonstrated an association between an increase in PYY and GLP-1 in patients exposed to a high-fiber diet which can modify the composition of microbial metabolites [15]. Exposure of EE cells to LPS, a microbial peptide, identified TLR-dependent CCK and cytokine release, and in a mouse model, intestinal and systemic LPS exposure resulted in the release of GLP-1 [16,17]. Microbiome composition itself has also been associated with levels of chromogranin A (CgA) released by enterochromaffin (EC) cells in population and disease-specific studies and may play a role in intestinal inflammation [18–20].

Enteroendocrine cells also reside near immune cells, and these immune cells, including macrophages, neutrophils, and even adaptive immune cells, express receptors for EE cell hormones [21–24]. As an example, in a mouse model, 5-HT triggered the release of cytokines such as IL-6 from peritoneal macrophages [24–26]. Conversely, the depletion of 5-HT inhibited T-cell activation by macrophages [23]. In addition, hormone levels have been correlated with inflammation. In a cohort of critically ill children, levels of PYY and ghrelin were positively associated with tumor necrosis factor (TNF)-α and C-reactive protein, respectively [27■]. Enteroendocrine hormones also regulate inflammation and immune cell activation indirectly. GLP-2, for example, has been shown to modulate cytokine release via neuronal activation and therefore GLP-2 agonists have been considered as novel therapies for intestinal inflammation [28–30].

Dysbiosis and immune dysregulation are prevalent in critical illness, and therefore it is likely that EE cells are affected by and contribute to these phenomena [31–35]. In critically ill children, reduced diversity of the microbiome and lower levels of SCFAs in the stool were identified in comparison to healthy controls [33]. Low SCFA levels can be secondary not only to changes in the microbial composition but also to dietary changes. When EN is initiated in critical illness, fiber-containing formulas and supplements have been avoided due to concerns for the risk of bowel ischemia, though more recent studies suggest they are safe to administer [36,37]. Similarly, the use of probiotics is discouraged, particularly in highly inflamed patients given reports of central-line associated bloodstream infections with probiotic bacterial strains such as Lactobacillus [38]. However, microbiome modulation can play a role in GI and EE status. In a cross-over study, premature infants who received oral care with mother’s milk had higher levels of motilin, secretin, and CCK as compared to controls [39]. These studies emphasize the complex and interdependent relationship between the EE system, nutrition composition, the microbiome, and the immune system. More research is needed to understand this relationship in critical care where potentially modifiable approaches to nutrition can be considered and lead to the development of novel therapeutic targets.

ENTEROENDOCRINE CELLS AND CLINICAL IMPLICATIONS IN CRITICAL ILLNESS

Motility and enteral nutrition tolerance

Most studies examining the EE axis in critically ill patients have focused on the association between hormone levels and delayed gastric emptying and EN intolerance (Table 2). Cholecystokinin, PYY, and amylin are the most widely studied hormones. Cholecystokinin and PYY have been associated with delayed gastric emptying and EN intolerance and have been found to be elevated during both fasting and feeding in critically ill adults as compared to healthy controls [40–42]. However, in critically ill children, low levels of PYY were associated with delayed gastric emptying, and in neonates, low levels of PYY have been associated with delayed EN advancement [43,44]. Amylin has been found to be elevated in critically ill pediatric and neonatal patients with either delayed gastric emptying or EN intolerance [43,45,46]. Gastrointestinal hormones have also been studied in the context of GI recovery in critical illness. In critically ill adults, PYY concentrations have been shown to take up to 3 weeks to return to baseline levels [47]. In a heterogenous cohort of critically ill children receiving EN, a decrease in CCK and an increase in glucagon were found as EN delivery increased over the first 5 days of intensive care unit (ICU) admission was reported [48■■]. Collectively, these findings demonstrate a relationship between the EE system and GI function in critical illness and the complexity of this relationship given the varied results across age groups and conditions.

Table 2.

Adult and pediatric studies that have examined gastrointestinal hormones in critical illness

Authors	Study population	Gastrointestinal function assessment	Biomarker studied	Outcome
Adult studies
Nguyen et al. [40]	19 ICU patients/24 controls	Feed tolerance by GRV and emesis	CCK, PYY	PYY and CCK levels were increased in feed-intolerant patients during fasting and feeding
Nguyen et al. [41]	31 ICU patients/28 healthy controls	Feed tolerance	CCK	CCK levels were increased in fasting and feeding plasma, and in association with feed intolerance.
Nguyen et al. [42]	28 ICU patients	Feed tolerance by GRV	CCK, PYY, Glucose	No differences in plasma CCK and PYY levels during fasting and feeding
Nematy et al. [47]	16 ICU patients/36 controls	Changes in appetite	Ghrelin, PYY	Ghrelin levels were lower in critically ill than controls and normalized the last 3 weeks of hospital stay
Deane et al. [68]	25 ICU patients	Gastric emptying	Glucose, insulin glucagon	Exogenous GLP-1 worsened gastric emptying in critically ill patients with normal gastric emptying but not those with slow gastric emptying. GLP-1 lowered feeding glucose, but was not associated with insulin or glucagon
Crona et al. [71]	20 ICU patients with feed intolerance and 10 without	Gastric emptying and feed tolerance by GRV	Ghrelin, CCK, Motilin	Ghrelin levels were increased in feed-intolerant patients, Feed intolerance correlated with delayed GE
Summers et al. [72]	26 ICU patients/23 controls	Gastric emptying	Amylin, GLP-1, Glucose	GLP-1 levels were increased in feed-intolerant patients
Santacruz et al. [73]	30 ICU patients/10 controls	Feed intolerance by GRV	PYY, ghrelin	Ghrelin levels were decreased in critically ill than in controls, No difference by feed intolerance
Pediatric studies
Martinez et al. [46]	14 PICU patients	Time to deliver 50% of EN prescribed energy goal	CCK, GLP-1, PYY, GIP, Glucagon, Ghrelin and Amylin	Increased GLP-1, glucagon, and amylin levels correlated with greater time to reach 50% EN goal. Decreased PYY and Ghrelin levels correlated with slow gastric emptying
Shanahan et al. [47]	64 NICU patients	Time to reach full EN goal	Amylin, GIP, GLP1 GLP-2, Ghrelin, Insulin, Leptin, PYY	PYY and GIP levels were decreased in feed-intolerant patients
Mayer et al. [49]	23 PICU patients	Gastric emptying and feed tolerance by GRV	Amylin	Amylin levels were increased in feed-intolerant patients, Feed intolerance correlated with delayed GE.
Kairamkonda et al. [50]	70 NICU patients	Feed tolerance by GRV; Time to goal EN	Amylin	Amylin levels were increased in feed-intolerant patients
Veldscholte et al. [51]	172 PICU patients	Achieving EN goal	CCK, glucagon	CCK and glucagon levels changes over time but did not correlate to achieving EN goal
Zahar et al. [61]	42 PICU patients	No GI assessment, correlated with inflammation	Ghrelin, PYY	Ghrelin level was influenced by admission nutrition status of the children and age. PYY was influenced by macronutrient intake and age. C-reactive protein was positively associated with ghrelin levels and tumor necrosis factor alpha with PYY levels
Hanekamp et al. [74]	24 ICU patients on ECMO	Receiving PN vs. changing from PN to EN	Gastrin, CCK, PYY	Concentrations of hormones were significantly increased in ECMO patients receiving EN compared with ECMO patients who received PN.
Sharman-Koendjbiharie et al. [75]	8 NICU patients with NEC and ileostomy/11 controls	Feed intolerance by volume of feed provided	Gastrin, CCK, PYY	CCK levels were increased and PYY levels were decreased when feeding volume was decreased
Zaher et al. [76]	42 PICU patients	Energy expenditure and inflammation	GLP-1	GLP-1 levels were increased in relation to cytokines and energy expenditure

AAT, acetaminophen absorption test; CCK, cholecystokinin; ECMO, extracorporeal membrane oxygenation; EN, enteral nutrition; GE, gastric emptying; GI, gastrointestinal; GIP, gastric inhibitory polypeptide; GLP-1, glucagon-like peptide 1; GLP-2, glucagon-like peptide 2; GRV, gastric residual volume; ICU, intensive care unit; NEC, necrotizing enterocolitis; NICU, neonatal intensive care unit; PICU, pediatric intensive care unit; PN, parenteral nutrition; PYY, peptide-YY.

Alternative feeding strategies

Enteral nutrition is preferred over parenteral nutrition in critical illness when EN is not contraindicated [36,49]. There are multiple strategies for delivering EN and their consideration is particularly interesting in the context of each strategy’s potential relationship to GI physiology in critical illness.

Few studies have examined the pathophysiologic effects of postpyloric nutrition over gastric nutrition in the critically ill population. In critically ill patients, postpyloric nutrition has been associated with longer and more mixed (forward and backward) antro-duodenal waves and gastric nutrition with less antegrade and shorter antro-duodenal waves [50,51]. These findings suggest that altered antro-duodenal motility is secondary to critical illness and not nutrition delivery strategy. However, clinical findings from randomized controlled trials (RCTs) suggest a difference in GI function between gastric and postpyloric nutrition. Meta-analyses have shown a trend towards lower aspiration events in patients fed via the postpyloric route and greater EN delivery with a Cochrane review reporting postpyloric fed patients received on average 7.8 times higher EN targets than gastric-fed patients [52,53]. Studies in pediatric patients are limited. Two pediatric RCTs have shown no difference in the frequency of aspiration events and one reported delivery of 17% more of the EN target in postpyloric fed patients over gastric fed patients [54,55]. A propensity-score matched analysis showed postpyloric fed critically ill children received >30% more EN on the first 3 days of EN delivery than gastric-fed patients and similar duration of mechanical ventilation between the two cohorts [56]. These differences in tolerance with postpyloric EN in adults and children, and with incidence of aspiration in adults, may be linked to altered GI physiology and signaling between these two routes of EN delivery. Bypassing of the stomach has been shown to have significant EE effects in other conditions such as the Roux-en-y surgery for weight loss, where significant short-term and long-term changes in PYY and ghrelin levels have been shown [57].

Another debated strategy for delivering EN is the use of intermittent vs. continuous EN. The intermittent delivery of EN mimics the phasic feeding pattern that is present during health in most people, which should trigger physiologic signaling between the neurologic and EE systems. Furthermore, recent research has identified the importance of intermittent feeding in the context of preserving circadian rhythms in noncritically ill populations, which also contributes to microbiome health and therefore regulation of the immune system [58]. Two systematic reviews on intermittent vs. bolus feeding in critically ill adults reported lower rates of constipation in the intermittently fed patients and longer lengths of ICU stay but no other differences between the two modes of nutrition [59,60]. A systematic review of critically ill children did not make summative conclusions given many differences in design of the few available studies [61]. The largest RCT, 70 patients per study arm, identified that intermittently fed patients achieved their nutrition goal 2 h earlier than continuously fed patients [62]. A recent, international, multicenter-study using prospectively collected data on EN delivery in mechanically ventilated children, did not show a difference between intermittently and continuously fed patients in the time to achieve nutritional goal and the frequency of acquired infections [63■]. Other potential benefits from intermittent feeding associated with the promotion of physiologic EE signaling on the microbiome, immune regulation, and circadian health are possible. Studies integrating physiologic parameters, including GI function testing and hormone levels, and microbiome and immune status, should be considered to understand the potential physiologic influence of alternative feeding strategies and their benefits in critical illness.

Macronutrient composition

Last, the macronutrient composition of formula could have an impact on the EE system and GI physiology. Most studies examining the effect of macronutrients on the EE system have been in noncritically ill cohorts. High-fat diets have been associated with a decrease in colon length and ileal crypt depth, a key regulator in EE cell proliferation [64]. A high-fat diet has also been shown to impair EE cell hormone release, especially in L-cells, which release GLP-1 and PYY [65]. Regarding carbohydrates, a high fiber and starch diet has been associated with an increase in the release of GLP-1 [66,67]. Glucagon-like peptide 1 release secondary to carbohydrate exposure has also been demonstrated to be GI-segment specific, which is relevant to the potential effects of feeding postpyloric vs. gastric [67]. Furthermore, exogenous GLP-1 therapy has been examined in critically ill adults where it was found to delay gastric emptying and improve glycemia [68]. Fewer studies have examined the effect of protein modification on the EE system, however, amino acids are known to be EE cell stimuli and a building block for serotonin production by EC cells [69]. Protein intake has been shown to increase colonic expression of glucagon, PYY, and CCK, regulated by microbial metabolism, but not alter small intestine hormone secretion from EE cells. The increase in colonic gut hormone secretion is most likely due to the undigested proteins in the distal gut, driven by modulated gut microbiota [70].

As research on the optimal route or method for EN, amount of protein, or even caloric density delivered via EN in critical illness is pursued, the effects of these alternative approaches on the EE system should be considered.

CONCLUSION

EE cell-derived hormone secretion is often modulated in ICU patients, in a complex relationship, potentially contributing to alterations in immune and GI functions. Dysbiosis and alternative EN delivery methods during ICU admissions may play a role in regulating hormone secretion and affecting inflammation and GI function. As optimal feeding strategies are studied in the ICU, the changes in the EE system should be considered.

KEY POINTS.

• The enteroendocrine system regulates macronutrient digestion and absorption.

• Recent findings have shown that the enteroendocrine system also interacts with microbial metabolites and peptides, and the immune system.

• Feeding strategies, gastric vs. postpyloric nutrition, or alternative formulas, can impact the enteroendocrine axis and its impact on dysbiosis and inflammation in addition to nutritional outcomes.