Ethanolic extract from Lepidium virginicum L. ameliorates DNBS-induced colitis in rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Lepidium virginicum L. (Brassicaceae) is a plant widely used in traditional Mexican medicine as an expectorant, diuretic, and as a remedy to treat diarrhea and dysentery, infection-derived gastroenteritis. However, there is no scientific study that validates its clinical use as an anti-inflammatory in the intestine. AIM OF THE STUDY: This study aimed to investigate the anti-inflammatory properties of the ethanolic extract of Lepidium virginicum L. (ELv) in an animal model of inflammatory bowel disease (IBD)-like colitis. MATERIALS AND METHODS: The 2,4-dinitrobenzene sulfonic acid (DNBS) animal model of IBD was used. Colitis was induced by intrarectal instillation of 200 mg/kg of DNBS dissolved vehicle, 50% ethanol. Control rats only received the vehicle. Six hours posterior to DNBS administration, ELv (3, 30, or 100 mg/kg) was administered daily by gavage or intraperitoneal injection. The onset and course of the inflammatory response were monitored by assessing weight loss, stool consistency, and fecal blood. Colonic damage was evaluated by colon weight/length ratio, histopathology, colonic myeloperoxidase (MPO) activity, and gene expression of proinflammatory cytokines, including tumor necrosis factor-alpha (TNF-α), interleukin-1beta (IL-1ß), chemokine C-X-C motif ligand 1 (CXCL-1), and interleukin-6 (IL-6). RESULTS: Rats treated with DNBS displayed significant weight loss, diarrhea, fecal blood, colon shortening, a significant increase in immune cell infiltration and MPO activity, as well as increased proinflammatory cytokine expression. Intraperitoneal administration of ELv significantly reduced colon inflammation, whereas oral treatment proved to be ineffective. In fact, intraperitoneal ELv significantly attenuated the clinical manifestations of colitis, immune cell infiltration, MPO activity, and pro-inflammatory (CXCL-1, TNF-α, and IL-1ß) gene expression in a dose-dependent manner. CONCLUSION: Traditional medicine has employed ELv as a remedy for common infection-derived gastrointestinal symptoms; however, we hereby present the first published study validating its anti-inflammatory properties in the mitigation of DNBS-induced colitis.

The functional role of sulforaphane in intestinal inflammation: a review.

Intestinal inflammation represented by inflammatory bowel disease (IBD) has become a global epidemic disease and the number of patients with IBD continues to increase. This digestive tract disease not only affects the absorption of food components by destroying the intestinal epithelial structure, but also can induce diseases in remote organs via the gut-organ axis, seriously harming human health. Nowadays, increasing attention is being paid to the nutritional and medicinal value of food components with increasing awareness among the general public regarding health. As an important member of the isothiocyanates, sulforaphane (SFN) is abundant in cruciferous plants and is famous for its excellent anti-cancer effects. With the development of clinical research, more physiological activities of SFN, such as antidepressant, hypoglycemic and anti-inflammatory activities, have been discovered, supporting the fact that SFN and SFN-rich sources have great potential to be dietary supplements that are beneficial to health. This review summarizes the characteristics of intestinal inflammation, the anti-inflammatory mechanism of SFN and its various protective effects on intestinal inflammation, and the possible future applications of SFN for promoting intestinal health have also been discussed.

Effects of Jian Pi Qing Chang Hua Shi decoction on mucosal injuries in a 2,4,6-trinitrobenzene sulphonic acid-induced inflammatory bowel disease rat model.

CONTEXT: Jian Pi Qing Chang Hua Shi decoction (JPQCHSD) has been considered as an effective remedy for the treatment of inflammatory bowel disease (IBD) in Chinese traditional medicine. OBJECTIVE: We evaluated the efficacy of JPQCHSD on 2-4-6-trinitrobenzene sulphonic acid (TNBS)-induced IBD rats and the responsible mechanisms. MATERIALS AND METHODS: Except the rats of the control group (50% ethanol), Sprague-Dawley rats (180 ± 20 g) induced by TNBS (150 mg/kg in 50% ethanol), received water extract of JPQCHSD daily at 0, 9.5, 19, or 38 g/kg for 12 days. The rats were sacrificed, and their colons were removed to evaluate the disease activity index. Malondialdehyde (MDA), superoxide dismutase (SOD), myeloperoxidase (MPO), immunoglobulin A (IgA), tumour necrosis factor (TNF)-α, interleukin (IL)-1ß, IL-6, and nuclear factor-κB were evaluated. RESULTS: JPQCHSD extract significantly reduced the disease activity index of TNBS-induced colitis with a median effective dose (ED50) of 26.93 g/kg. MPO and MDA were significantly reduced in the 19 and 38 g/kg groups (ED50 values 37.38 and 53.2 g/kg, respectively). The ED50 values for the increased SOD and IgA were 48.98 and 56.3 g/kg. ED50 values for inhibition of TNF-α, IL-1ß, and IL-6 were 32.66, 75.72, and 162.06 g/kg, respectively. DISCUSSION: JPQCHSD promoted mucosal healing in IBD rats via its anti-inflammation, immune regulation, and antioxidation properties. CONCLUSIONS: JPQCHSD has healing function on IBD. Further clinical trials are needed to demonstrate its efficacy and tolerance to IBD.

Dietary Bioactive Peptide Alanyl-Glutamine Attenuates Dextran Sodium Sulfate-Induced Colitis by Modulating Gut Microbiota.

Inflammatory bowel disease (IBD) is a chronic intestinal disorder threatening human health. Di-peptide alanyl-glutamine (Ala-Gln) has various beneficial effects on gut health. However, its role and functional mechanism in treating IBD are still not clear. Therefore, the protective effects of Ala-Gln and glutamine (Gln) on dextran sulfate sodium- (DSS-) induced colitic mice were investigated in this study. The results showed that oral supplementation of Ala-Gln or Gln significantly attenuated the colitis symptoms in mice, including body weight loss, colon length, disease activity index, histological scores, and tissue apoptosis. The concentrations of interleukin- (IL-) 1ß, IL-6, tumor necrosis factor-α, and myeloperoxidase were significantly decreased, while the concentrations of immunoglobulins (IgA, IgG, and IgM) and superoxide dismutase were significantly increased by Ala-Gln or Gln supplementation. The expression of occludin and peptide transporter 1 (PepT1) was significantly increased by Ala-Gln or Gln. Interestingly, Ala-Gln had better beneficial effects than Gln in alleviating colitis. In addition, 16S rDNA sequencing showed that the DSS-induced shifts of the microbiome (community diversity, evenness, richness, and composition) in the mouse colon were restored by Gln and Ala-Gln, including Lactobacillus, Bacteroides_acidifaciens, Bacteroidales, Firmicutes, Clostridia, Helicobacter, and Bacteroides. Correspondingly, the functions of the microflora metabolism pathways were also rescued by Ala-Gln, including fatty acid metabolism, membrane transporters, infectious diseases, and immune system. In conclusion, the results revealed that Ala-Gln can prevent colitis through PepT1, enhancing the intestinal barrier and modulating gut microbiota and microflora metabolites.

Depletion of CD56+CD3+ invariant natural killer T cells prevents allergen-induced inflammation in humanized mice.

BACKGROUND: CD56-expressing natural killer (NK) cells as well as invariant NK T (iNKT) cells have been shown to either promote or inhibit allergic immune responses. OBJECTIVE: The aim of the present study was to investigate the impact of these cells in a recently developed humanized mouse model of allergen-induced IgE-dependent gut and lung inflammation. METHODS: Nonobese diabetic-severe combined immunodeficiency γ-chain knockout mice were injected intraperitoneally with human PBMCs or CD56-depleted (CD56neg) PBMCs from highly sensitized donors with birch or grass pollen allergy together with the respective allergen or with NaCl as a control. Three weeks later, the mice were challenged with the allergen rectally and gut inflammation was monitored by video miniendoscopy and by histology. Furthermore, airway inflammation was measured after an additional intranasal allergen challenge. RESULTS: Allergen-specific human IgE in mouse sera, detectable only after coinjection of the respective allergen, was reduced in mice being injected with CD56neg PBMCs compared with in mice receiving nondepleted PBMCs. Consequently, allergen-induced IgE-dependent colitis, airway hyperreactivity, and mucus-producing goblet cells were significantly inhibited in these mice. Interestingly, reconstitution of CD56neg PBMCs with nondepleted CD56+ cells and with CD56+CD3+ iNKT cells restored gut as well as lung inflammation, whereas addition of CD3-depleted CD56+ cells did not. CONCLUSION: These results demonstrate that allergen-specific gut and lung inflammation in PBMC-engrafted humanized mice is promoted by CD56+CD3+ iNKT cells, which opens new possibilities of therapeutic intervention in allergic diseases.

Long-Term Iron Deficiency and Dietary Iron Excess Exacerbate Acute Dextran Sodium Sulphate-Induced Colitis and Are Associated with Significant Dysbiosis.

BACKGROUND: Oral iron supplementation causes gastrointestinal side effects. Short-term alterations in dietary iron exacerbate inflammation and alter the gut microbiota, in murine models of colitis. Patients typically take supplements for months. We investigated the impact of long-term changes in dietary iron on colitis and the microbiome in mice. METHODS: We fed mice chow containing differing levels of iron, reflecting deficient (100 ppm), normal (200 ppm), and supplemented (400 ppm) intake for up to 9 weeks, both in absence and presence of dextran sodium sulphate (DSS)-induced chronic colitis. We also induced acute colitis in mice taking these diets for 8 weeks. Impact was assessed (i) clinically and histologically, and (ii) by sequencing the V4 region of 16S rRNA. RESULTS: In mice with long-term changes, the iron-deficient diet was associated with greater weight loss and histological inflammation in the acute colitis model. Chronic colitis was not influenced by altering dietary iron however there was a change in the microbiome in DSS-treated mice consuming 100 ppm and 400 ppm iron diets, and control mice consuming the 400 ppm iron diet. Proteobacteria levels increased significantly, and Bacteroidetes levels decreased, in the 400 ppm iron DSS group at day-63 compared to baseline. CONCLUSIONS: Long-term dietary iron alterations affect gut microbiota signatures but do not exacerbate chronic colitis, however acute colitis is exacerbated by such dietary changes. More work is needed to understand the impact of iron supplementation on IBD. The change in the microbiome, in patients with colitis, may arise from the increased luminal iron and not simply from colitis.

Euterpe oleracea Mart. (Açaí) attenuates experimental colitis in rats: involvement of TLR4/COX-2/NF-ĸB.

Euterpe oleracea Mart., commonly known as açaí, has been demonstrated to exhibit significantly antioxidant and inflammatory activities in experimental models. These effects of the hydroalcoholic extract from the açaí seed (ASE) were investigated in TNBS-induced (2,4,6-trinitrobenzenesulfonic acid) acute colitis model in rats. Wistar rats (180-220 g) were orally pretreated with saline (0.3 mL), ASE (10, 30 and 100 mg/kg) and dexamethasone (control group, 1 mg/kg) once daily for 3 days starting before TNBS instillation. On day 3 after TNBS, the animals were euthanized, the portion of distal colon was collected and washed with 0.9% saline for macroscopy and histological evaluation, glutathione (GSH) and malonyldialdehyde (MDA) levels, myeloperoxidase (MPO) and catalase (CAT) activity, nitrate and nitrite (NO3/NO2) concentration, pro-inflammatory cytokines levels and intestinal barrier integrity. We also evaluated Toll-like Receptor 4/cyclooxygenase-2/nuclear factor kappa B expression as a possible mechanism related to the ASE effects. Treatment with ASE 100 mg/kg decreased significantly macroscopic and microscopic damage induced by TNBS. In addition, MPO activity, TNF-α (tumor necrosis factor-alpha) and IL-1ß (interleukin 1) levels were reduced in rats with colitis. ASE 100 mg/kg restored GSH and MDA levels, CAT activity, NO3/NO2 concentration and improved the intestinal barrier integrity in the TNBS group. ASE 100 mg/kg significantly reduced TNBS-induced expression of the TLR4, COX-2 and NF-κB p65. ASE 100 mg/kg improved macroscopy and histological parameters, inflammation, intestinal barrier integrity and nitric and oxidative stress through the TLR-4/COX-2/NF-κB pathway.

Select animal models of colitis and their value in predicting clinical efficacy of biological therapies in ulcerative colitis.

Introduction: Advancing new therapies from discovery to development usually requires proof-of-concept in animal models to justify the costs of continuing the program. While animal models are useful for understanding the mechanism of action (MOA) of a target, limitations of many published colitis models restrict their value to predict clinical efficacy.Areas covered: The authors focused their literature search on published studies of chronic animal models used to evaluate the pre-clinical efficacy of therapeutic molecules subsequently evaluated in clinical trials for UC. The UC therapies evaluated were anti-α4ß7, anti-IL13, anti-IL12p40, and anti-IL23p19. The models of chronic colitis evaluating these molecules were: mdra1a-/-, chronic dextran sulfate sodium (DSS), chronic 2,4,6-trinitrobenzene sulfonic acid (TNBS), and the T cell transfer model.Expert opinion: While some models provide insight into target MOA in UC, none is consistently superior in predicting efficacy. Evaluation of multiple models, with varying mechanisms of colitis induction, is needed to understand potential drug efficacy. Additional models of greater complexity, reflecting the disease chronicity/heterogeneity seen in humans, are needed. Although helpful in prioritizing targets, animal models alone will likely not improve outcomes of UC clinical trials. Transformational changes to clinical efficacy will likely only occur when precision medicine approaches are employed.

Beneficial effect of Bidens pilosa L. (Asteraceae) in a rat model of colitis.

Background Bidens pilosa (BP) possessed anti-inflammatory, antioxidant, and immunomodulatory activities. Its beneficial effects on intestinal inflammation and oxidative stress in 2,4,6 trinitrobenzene sulfonic acid (TNBS) induced colitis in Wistar rats was evaluated. Methods Thirty female Wistar rats weighing 180-200 g were distributed into six groups (n = 5): non-colitic, untreated colitic and colitic rats treated graded doses of methanol extract of BP (50-400 mg/kg). Colitis was induced in rats by intracolonic instillation of 0.2 mL of 40 mg/mL TNBS. BP was administered two days pre-colitis induction and treatments continued until seven days post-colitis induction. A day after the last treatment, rats were euthanized, colon removed aseptically and response to treatment assessed. Phytochemical composition of BP was determined using the GC-MS. Results BP significantly reduced macroscopic colonic damage score, weight/length ratio, colonic lipid peroxidation level, leukocytes infiltration, and TNF-α level in comparison to untreated colitic rats (p ≤ 0.008). Similarly, treatment with 200 and 400 mg/kg BP prevented depletion of colonic glutathione level than other treatment groups (p ≤ 0.0002). Histological findings revealed that treatment with 400 mg/kg BP significantly preserved the mucosal epithelial layer. It also prevented ulceration and sloughing of the mucosal layers and reduced infiltration of inflammatory cells compared to other treatment groups. Among the 16 compounds identified were oleic acid (6.2%) and n-hexadecanoic acid (2.0%) with antioxidant anti-inflammatory activities. Conclusions The beneficial effects of BP in rat colitis might be related to the reduction of leucocytes infiltration, inhibition of oxidative stress and pro-inflammatory cytokines.

Sacral nerve stimulation ameliorates colonic barrier functions in a rodent model of colitis.

BACKGROUND: The mucosal barrier damage is recognized as one of the key factors in the pathogenesis of colitis. While sacral nerve stimulation (SNS) was reported to have therapeutic potential for colitis, its mechanisms of actions on colonic permeability remained largely unknown. METHODS: In this study, colitis was induced by intrarectal administration of TNBS in rats. Five days later, they were treated with SNS or sham-SNS for 10 days. The effects of SNS on colonic permeability were assessed by measuring the expression of tight-junction proteins involved in regulating permeability and the FITC-dextran test. The mechanism of actions of SNS was investigated by studying the function of the enteric nervous system (ENS) cells and analyzing the autonomic nervous system. KEY RESULTS: SNS decreased the disease activity index, microscopic and macroscopic scores, myeloperoxidase activity, and pro-inflammatory cytokines (TNF-α, IL-6). SNS increased the expression of Zonula Occludens-1, Occludin, Claudin-1, and Junctional adhesion molecule-A in the colon tissue. The FITC-dextran test showed that the colonic permeability was lower with SCS than sham-SNS. SNS increased ChAT, pancreatic polypeptide, and GDNF and reduced norepinephrine NGF, sub-P, and mast cell overactivation in the colon tissue. Concurrently, SNS increased acetylcholine in colon tissues and elevated vagal efferent activity. CONCLUSIONS & INFERENCES: SNS ameliorates colonic inflammation and enhances colonic barrier function with the proposed mechanisms involving the increase in parasympathetic activity and modulation of the activity of the ENS and immune system, including mast cells.

Barbaloin Attenuates Mucosal Damage in Experimental Models of Rat Colitis by Regulating Inflammation and the AMPK Signaling Pathway.

BACKGROUND Barbaloin is one of the main medicinal ingredients of aloe vera, which displays various anti-inflammatory and anti-apoptosis properties in several inflammatory and fibrotic diseases. Our study evaluated its efficacy against dextran sulfate sodium (DSS)-induced colitis in rats. MATERIAL AND METHODS Ulcerative colitis (UC) rat models were established in vivo, and after barbaloin treatment, body weight and inflammation index were measured. Additionally, the signaling mechanism by which barbaloin protects against UC was investigated using LPS-infected Caco-2 cells. RESULTS Barbaloin could significantly reverse UC-induced weight loss and colon injury. Further, it could effectively increase the mRNA expression of IL-4 and IL-10 in colon tissues, while decreasing the expression of IFN-γ, IL-6, IL-1ß, and TNF-alpha. Furthermore, it significantly enhanced UC-inhibited atresia band 1 (ZO-1), occludin, and E-cadherin, and was also found to activate the AMPK signaling pathway. Additionally, si-RAN-induced knockdown, and overexpression assay showed that barbaloin could inhibit the UC-enhanced MLCK signaling pathway by activating the AMPK signaling pathway. CONCLUSIONS Barbaloin can effectively inhibit inflammation and reverse epithelial barrier function to protect against UC, possibly via activation of the AMPK signaling pathway.

Analgesic effect of resveratrol on colitis-induced visceral pain via inhibition of TRAF6/NF-κB signaling pathway in the spinal cord.

Visceral pain is a complex and common symptom of inflammatory bowel disease (IBD) patients. Developing novel efficient therapeutics is still a common interest for clinicians. Increasing evidence have shown that tumor necrosis factor (TNF) receptor associated factor 6 (TRAF6) contributes to the pathological pain state in some pain models. Resveratrol (RSV) has showed promising potential for the treatment of neuropathic pain and inflammatory pain. However, whether RSV has analgesic effect on visceral pain and the underlying mechanisms remain unclear. In this study, we established the colitis model through intrarectal administration of 2,4,6-trinitrobenzene sulfonic acid (TNBS), and found that TNBS induced colonic inflammation and visceral hypersensitivity. Meanwhile, astroglial marker glial fibrillary acidic protein (GFAP), TRAF6, phosphorylation of NF-κB (pNF-κB), tumor necrosis factor-α (TNF-α) and interleukin-1ß (IL-1ß) levels were increased in L6-S1 spinal cord after TNBS enema. Then, intrathecal injection of TRAF6 siRNA attenuated visceral pain, blocked the upregulation of pNF-κB, TNF-α and IL-1ß levels in the spinal cord in TNBS mice. Furthermore, spinal administration of NF-κB inhibitor, BAY11-7082 reversed the pain behavior and suppressed spinal TNF-α and IL-1ß expression in TNBS mice. Finally, repeated intrathecal injection of RSV reversed TNBS-induced visceral pain hypersensitivity in a dose-dependent manner. Meanwhile, TNBS-induced enhancement of spinal GFAP, TRAF6, pNF-κB, TNF-α and IL-1ß were reduced by the same treatment of RSV. In conclusion, our results suggest that RSV exerts the effects of antinociception on colitis-induced visceral hyperalgesia through inhibition of spinal TRAF6/NF-κB signaling pathway and the production of inflammatory mediators in the spinal cord, suggesting a new application of RSV for the treatment of visceral pain.

Autonomically mediated anti-inflammatory effects of electrical stimulation at acupoints in a rodent model of colonic inflammation.

BACKGROUND: Acupuncture has been widely accepted for treatments of many diseases. This study was performed to determine effects and mechanisms of electroacupuncture (EA) by chronically implanted electrodes at acupoint ST36 on colonic inflammation induced by TNBS in rats. METHODS: After intrarectal administration of TNBS, the rats were treated with sham-EA, EA1/EA2 (two sets of parameters) for 3 weeks. Disease activity index (DAI), macroscopic and microscopic lesions, plasma levels of TNF-α, IL-1ß and IL-6 were observed as evaluation of inflammatory responses. The autonomic function was assessed by analysis of the heart rate variability. RESULTS: (a) Vagal activity was significantly increased with both acute and chronic EA1/EA2; (b) DAI was significantly decreased with both chronic EA1 and EA2, and EA2 was more potent than EA1 (P < 0.05); (c) The macroscopic score was 6.4 ± 0.6 with sham-EA and reduced to 4.9 ± 0.1 with EA1 (P < 0.05) and 4.0 ± 0.2 with EA2 (all P < 0.05). The histological score was 4.05 ± 0.58 with sham-EA and remained unchanged (3.71 ± 0.28) with EA1 (P > 0.05) but reduced to 3.0 ± 0.3 with EA2 (P < 0.01); (d) The plasma levels of TNF-α, IL-1ß and IL-6 were significantly decreased with EA2. CONCLUSIONS: Electrical stimulation at ST36 improves colonic inflammation in TNBS-treated rats by inhibiting pro-inflammatory cytokines via the autonomic mechanism.

An Emergency Department Presentation of Severe Colitis After a Home Hydrogen Peroxide Enema.

BACKGROUND: Health information found on open access Internet platforms is often unscrutinized, unreliable, and can lead to considerable morbidity for patients and their presentation to the emergency department. Currently, home treatments for constipation and other gastrointestinal ailments featuring the use of hydrogen peroxide (H2O2) enemas are readily available. CASE REPORT: We present a case of a 48-year-old female with a history of fibroids who presented to the emergency department with acute abdominal pain after self-administering a 3% H2O2 enema, which she learned about on the Internet as a treatment for constipation. She subsequently developed a severe colitis with evidence of pneumatosis and focal perforation. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Although toxicity from oral ingestions of H2O2 is well described in the literature, there are few reports of the sequelae related to rectal administration. Due to its significant morbidity and the public health concerns related to this mechanism of toxicity, emergency physicians are at the frontlines for diagnosing and properly managing these patients. This case report reviews the patient's presentation, findings, and management.

Electroacupuncture Alleviated Referral Hindpaw Hyperalgesia via Suppressing Spinal Long-Term Potentiation (LTP) in TNBS-Induced Colitis Rats.

Although referred pain or hypersensitivity has been repeatedly reported in irritable bowel syndrome (IBS) patients and experimental colitis rodents, little is known about the neural mechanisms. Spinal long-term potentiation (LTP) of nociceptive synaptic transmission plays a critical role in the development of somatic hyperalgesia in chronic pain conditions. Herein, we sought to determine whether spinal LTP contributes to the referral hyperalgesia in colitis rats and particularly whether electroacupuncture (EA) is effective to alleviate somatic hyperalgesia via suppressing spinal LTP. Rats in the colitis group (induced by colonic infusion of 2,4,6-trinitrobenzenesulfonic acid, TNBS), instead of the control and vehicle groups, displayed evident focal inflammatory destruction of the distal colon accompanied not only with the sensitized visceromotor response (VMR) to noxious colorectal distension (CRD) but also with referral hindpaw hyperalgesia indicated by reduced mechanical and thermal withdrawal latencies. EA at Zusanli (ST36) and Shangjuxu (ST37) attenuated the severity of colonic inflammation, as well as the visceral hypersensitivity and referral hindpaw hyperalgesia in colitis rats. Intriguingly, the threshold of C-fiber-evoked field potentials (CFEFP) was significantly reduced and the spinal LTP was exaggerated in the colitis group, both of which were restored by EA treatment. Taken together, visceral hypersensitivity and referral hindpaw hyperalgesia coexist in TNBS-induced colitis rats, which might be attributed to the enhanced LTP of nociceptive synaptic transmission in the spinal dorsal horn. EA at ST36 and ST37 could relieve visceral hypersensitivity and, in particular, attenuate referral hindpaw hyperalgesia by suppressing the enhanced spinal LTP.

Impaired adaptation of energy intake induces severe obesity in aged mice on a high-fat diet.

High-fat diet (HFD) feeding induces inflammation in various tissues, including the nodose ganglion and hypothalamus, resulting in obesity and metabolic disorders. In this study, we investigated the effect of short-term HFD on aged and young mice. Aged mice easily gained weight during short-term HFD feeding, and required many days to adapt their energy intake. One-day HFD in aged mice induced inflammation in the distal colon, but not in the nodose ganglion or hypothalamus. The anorexic effect of glucagon-like peptide-1 (GLP-1) was attenuated in aged mice. Intraperitoneal administration of GLP-1 did not induce expression of genes that regulate feeding in the hypothalamus of aged mice. mRNA expression of the gene encoding the GLP-1 receptor (Glp1r) in the nodose ganglion was significantly lower in aged mice than in young mice. Our findings suggest that adaptation of energy intake regulation was attenuated in aged mice, causing them to become obese in response to short-term HFD feeding.

Interactions Between Diet and the Intestinal Microbiota Alter Intestinal Permeability and Colitis Severity in Mice.

BACKGROUND & AIMS: It is not clear how the complex interactions between diet and the intestinal microbiota affect development of mucosal inflammation or inflammatory bowel disease. We investigated interactions between dietary ingredients, nutrients, and the microbiota in specific pathogen-free (SPF) and germ-free (GF) mice given more than 40 unique diets; we quantified individual and synergistic effects of dietary macronutrients and the microbiota on intestinal health and development of colitis. METHODS: C56BL/6J SPF and GF mice were placed on custom diets containing different concentrations and sources of protein, fat, digestible carbohydrates, and indigestible carbohydrates (fiber). After 1 week, SPF and GF mice were given dextran sulfate sodium (DSS) to induce colitis. Disease severity was determined based on the percent weight change from baseline, and modeled as a function of the concentration of each macronutrient in the diet. In unchallenged mice, we measured intestinal permeability by feeding mice labeled dextran and measuring levels in blood. Feces were collected and microbiota were analyzed by 16S rDNA sequencing. We collected colons from mice and performed transcriptome analyses. RESULTS: Fecal microbiota varied with diet; the concentration of protein and fiber had the strongest effect on colitis development. Among 9 fiber sources tested, psyllium, pectin, and cellulose fiber reduced the severity of colitis in SPF mice, whereas methylcellulose increased severity. Increasing dietary protein increased the density of the fecal microbiota and the severity of colitis in SPF mice, but not in GF mice or mice given antibiotics. Psyllium fiber reduced the severity of colitis through microbiota-dependent and microbiota-independent mechanisms. Combinatorial perturbations to dietary casein protein and psyllium fiber in parallel accounted for most variation in gut microbial density and intestinal permeability in unchallenged mice, as well as the severity of DSS-induced colitis; changes in 1 ingredient could be offset by changes in another. CONCLUSIONS: In an analysis of the effects of different dietary components and the gut microbiota on mice with and without DSS-induced colitis, we found complex mixtures of nutrients affect intestinal permeability, gut microbial density, and development of intestinal inflammation.

Prebiotic Supplementation Following Ileocecal Resection in a Murine Model is Associated With a Loss of Microbial Diversity and Increased Inflammation.

Background: Individuals with Crohn's disease frequently require ileocecal resection (ICR), and inflammation often recurs in the neoterminal ileum following surgery. Fructooligosaccharide (FOS) is a fermentable prebiotic that stimulates the growth of bifidobacteria and may promote anti-inflammatory activity. The aim of this study was to determine if supplementation of a postICR diet with FOS in a mouse model would be effective in stimulating the growth of bifidobacteria and reducing systemic and local inflammation. Methods: ICR was performed in IL10-/- mice (129S1/SvlmJ) with colitis. Following surgery, nonICR control and ICR mice were fed a chow diet ± 10% FOS for 28 days. Serum, colon, and terminal ileum (TI) were analyzed for cytokine expression by MesoScale discovery platform. DNA extracted from stool was analyzed using 16s rRNA sequencing and qPCR. Expression of occludin and ZO1 was assessed using qPCR. Short-chain fatty acid (SCFA) concentrations were assessed using gas chromatography. Results: ICR led to increased systemic inflammation (P < 0.05) and a significant decline in fecal microbial diversity (P < 0.05). Mice on the FOS diet had a greater reduction in microbial diversity and also had worsened inflammation as evidenced by increased serum IL-6 (P < 0.05) and colonic IFNγ and TNFα (P < 0.05). Expression of occludin and ZO1 were significantly reduced in FOS-supplemented mice. There was a correlation between loss of diversity and the bifidogenic effectiveness of FOS (r = -0.61, P < 0.05). Conclusions: FOS-supplementation of a postICR diet resulted in a decrease in fecal bacterial diversity, reduction in barrier function, and increased gut inflammation.

Melatonin alters amino acid metabolism and inflammatory responses in colitis mice.

Inflammatory bowel disease is a chronic inflammatory dysfunction of the gastrointestinal tract. This study explored the hypothesis that melatonin has beneficial functions in the mouse model of colitis induced by dextran sodium sulfate (DSS), with a specific focus on the expression of intestinal inflammatory cytokines and the serum levels of amino acids. The results revealed that mice with melatonin supplementation had a reduction in weight loss and disease index induced by DSS treatment. Melatonin stifled the expression of colonic IL-17 in mice with DSS-induced colitis. Melatonin also lowered the serum levels of Asp, Ser, Met, and Leu (p < 0.05), but increased those of Glu and Cys (p < 0.05). Thus, melatonin treatment is promising and may function as a potential adjuvant therapy to alleviate the clinical symptoms of patients with inflammatory bowel disease.

Berberine inhibits colitis-associated tumorigenesis via suppressing inflammatory responses and the consequent EGFR signaling-involved tumor cell growth.

The anti-inflammatory and anti-tumor effects of berberine, a traditional Chinese medicine, were separately discovered in pathological intestinal tissues. However, whether the anti-inflammatory effect of berberine contributes to its anti-tumor effect on colitis-associated colorectal cancer (CACRC) remains unknown. In the present study, we found that berberine effectively inhibited colitis-associated tumorigenesis and colonic epithelium hyperproliferation in dextran sulfate sodium (DSS)-treated ApcMin/+ mice. A mechanistic study identified that these inhibitory effects of berberine occurred through blocking interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) expression in colonic macrophages. An in vitro study on cell lines identified that berberine treatment of Raw 264.7 macrophages resulted in conditioned media with fewer proliferative effects on a cell line with a heterozygous Apc mutation (Immorto-Min colonic epithelium, IMCE). EGFR-ERK signaling act downstream of berberine/pro-inflammatory cytokines axis to regulate CACRC cell proliferation. Furthermore, in vivo administration of IL-6 to DSS-treated ApcMin/+ mice effectively weakened the inhibitory effects of berberine on tumorigenesis and EGFR-ERK signaling in colon tissues. Altogether, the results of our studies have revealed that berberine inhibits the development of CACRC by interfering with inflammatory response-driven EGFR signaling in tumor cell growth. The findings of this study support the possibility that berberine and other anti-inflammatory drugs may be beneficial in the treatment of CACRC.