Leptin modifies the prosecretory and prokinetic effects of the inflammatory cytokine interleukin‐6 on colonic function in Sprague–Dawley rats

Abstract

To be submitted to: Experimental Physiology. Running title:Crosstalk between leptin and IL-6 in IBS.Keywords: colonic contractility, enteric neurons, colonic secretion, leptin, interleukin-6. Subject area: GI and epithelial physiology Number of words (excluding references and figure legends): 6,113Number of references: 40 New Findings:• What is the central question of this study?Does crosstalk exist between leptin and interleukin-6 in colonic enteric neurons and is this a contributory factor in gastrointestinal dysfunction associated with irritable bowel syndrome (IBS)?• What is the main finding and its importance?Leptin ameliorates the pro-secretory and pro-kinetic effects of the pro-inflammatory cytokine, interleukin-6 on rat colons. Leptin also suppresses the neurostimulatory effects of IBS plasma, which has elevated levels of interleukin-6, on enteric neurons. This may indicate a regulatory role for leptin in immune-mediated bowel dysfunction. Abstract:In addition to its role in regulating energy homeostasis, the adipokine, leptin modifies gastrointestinal (GI) function. Indeed, leptin-resistant obese humans and leptin-deficient obese mice exhibit altered GI motility. In the functional GI disorder, irritable bowel syndrome (IBS), circulating leptin levels are reported to differ from healthy controls. Additionally, IBS patients display altered cytokine profiles, including elevated circulating levels of the pro-inflammatory cytokine, interleukin (IL)-6, which bears structural homology and similarities in intracellular signalling to leptin. This study aims to investigate interactions between leptin and IL-6 in colonic neurons and their possible contribution to IBS pathophysiology. The functional effects of leptin and IL-6 on colonic contractility and absorpto-secretory function were assessed in organ baths and Ussing chambers in Sprague Dawley rat colons. Calcium imaging and immunohistochemical techniques were employed to investigate the neural regulation of GI function by these signalling molecules. Our findings provide a neuromodulatory role for leptin in submucosal neurons, where it inhibited the stimulatory effects of IL-6. Functionally, this translated to suppression of IL-6 evoked potentiation of veratridine-induced secretory currents. Leptin also attenuated IL-6-induced colonic contractions, although it had little direct effect on myenteric neurons. Calcium responses evoked by IBS plasma in both myenteric and submucosal neurons were also suppressed by leptin, possibly through interactions with IL-6, which is elevated in IBS plasma.As leptin has the capacity to ameliorate the neurostimulatory effects of soluble mediators in IBS plasma and modulated IL-6-evoked changes in bowel function, leptin may have a role in immune-mediated bowel dysfunction in IBS patients.

GHSR‐1 agonist sensitizes rat colonic intrinsic and extrinsic neurons to exendin‐4: A role in the manifestation of postprandial gastrointestinal symptoms in irritable bowel syndrome?

“…GLP‐1 may also contribute to the neurostimulatory actions of IBS plasma in both neuronal plexi of both rat strains as the GLP‐1R antagonist resulted in a decrease in the amplitude of response. However, it is likely that GLP‐1 is just one contributory factor in the altered modulation of enteric neurons, as we have previously noted the importance of immune factors and circulatory hormones in this effect . In our cohort, we found that fasting GLP‐1 was lower in IBS‐D with no change in IBS‐C patients, which contrasts with a report that indicated plasma GLP‐1 was decreased in IBS‐C patient samples …”

“…However, research demonstrating that feeding status tunes the sensitivity of myenteric neurons to orexigenic or anorexigenic molecules, 2,48 and our finding that However, it is likely that GLP-1 is just one contributory factor in the altered modulation of enteric neurons, as we have previously noted the importance of immune factors and circulatory hormones in this effect. 38,39,49 In our cohort, we found that fasting GLP-1 was lower in IBS-D with no change in IBS-C patients, which contrasts with a report that indicated plasma GLP-1 was decreased in IBS-C patient samples. 50 Others have examined the functional effects of GLP-1 on mucosal secretory physiology and postulated that activation of submucosal GLP-1Rs leads to a decrease in neurally evoked chloride secretion, a pathway mediated through suppression of neural acetylcholine.…”

Divergent effects of exendin‐4 and interleukin‐6 on rat colonic secretory and contractile activity are associated with changes in regional vagal afferent signaling

“…To investigate further, the role of neuronal control in colonic secretion, veratridine, a lipid‐soluble steroidal alkaloid which results in neuronal depolarization was applied to evoke a secretory current. Both Ex‐4 30 and IL‐6 35 independently enhanced veratridine‐evoked secretory currents; however, despite the modulatory effect of IL‐6 being larger than that of Ex‐4, no additional increase was observed when both reagents were applied together. This could be due to different sub‐populations of submucosal neurons being activated by either IL‐6 or Ex‐4.…”

“…9 Finally, to determine whether functional changes in contractile activity This latest study supports a growing body of data that has revealed complicated interactions between cytokines and hormones in the gut. 9,11,26,35 Moreover,severalphysiologicalsystemsareinvolved in the diverse effects of endocrine and immune factors on gut function,whichislikelytobeakeyfactorunderlyingtheheterogeneity of symptoms relating to the pathophysiology of functional bowel disorders.CirculatinglevelsofIL-6andGLP-1differbetweenhealthy individuals and IBS patients 3,6,26 implicating these immune and endocrine factors in disruption of bowel function. Endogenous GLP-1 is thought to protect against harmful stimuli, 30,58 probably through anti-inflammatoryeffects.…”

The brain needs interleukin-6 (IL-6) to maintain a “healthy” energy balance. Focus on “IL-6 ameliorates defective leptin sensitivity in DIO ventromedial hypothalamic nucleus neurons”

“…If so, any approach may require a strong site specificity because reports about antagonistic actions of leptin and IL-6 can be found in the literature. One example is with respect to colonic function (5), where IL-6 seems to have negative effects in irritable bowel disease, which can be partly counteracted by leptin. Furthermore, the role of IL-6 with respect to liver metabolism may be beneficial or negative, depending on the exact conditions, concentrations, and duration of exposure.…”