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The Wnt-β-catenin signaling pathway is active in the stem cell region of intestinal crypts during postnatal growth of the small intestine. This functions to construct and maintain an intestinal stem cell niche in the base of crypts and to protect stem cells from apoptosis. The aim of this study was to identify which Wnt agonists are present to mediate this activity.

OBJECTIVE To evaluate use of a telemetric gastrointestinal (GI) pill to continuously monitor GI temperature in horses at rest and during exercise and to compare time profiles of GI temperature and rectal temperature. ANIMALS 8 Standardbred horses. PROCEDURES Accuracy and precision of the GI pill and a rectal probe were determined in vitro by comparing temperature measurements with values obtained by a certified resistance temperature detector (RTD) in water baths at various temperatures (37°, 39°, and 41°C). Subsequently, both GI and rectal temperature were recorded in vivo in 8 horses over 3 consecutive days. The GI temperature was recorded continuously, and rectal temperature was recorded for 3.5 hours daily. Comparisons were made between GI temperature and rectal temperature for horses at rest, during exercise, and after exercise. RESULTS Water bath evaluation revealed good agreement between the rectal probe and RTD. However, the GI pill systematically underestimated temperature by 0.14°C. In vivo, GI temperature data were captured with minimal difficulties. Most data loss occurred during the first 16 hours, after which the mean ± SD data loss was 8.6 ± 3.7%. The GI temperature was consistently and significantly higher than rectal temperature with an overall mean temperature difference across time of 0.27°C (range, 0.22° to 0.32°C). Mean measurement cessation point for the GI pill was 5.1 ± 1.0 days after administration. CONCLUSIONS AND CLINICAL RELEVANCE This study revealed that the telemetric GI pill was a reliable and practical method for real-time monitoring of GI temperature in horses.

Naturally, fermented milk has become an essential commodity in rural areas in some developing countries, especially in Africa and Asia. A variety of local products appear depending on local knowledge, including the type of milk, containers, and techniques. Although the microbial composition of each product varies, lactic acid bacteria commonly dominate the range of naturally fermented milk products. Research into functional benefits for human health about the role of their microflora is rapidly expanding. The role of lactic acid bacteria as probiotics for either prevention or treatment of human diseases has been a driving force in the exploration of new potential probiotics from naturally fermented milk. Inflammatory intestinal diseases are one of the digestive problems caused by dysbiosis. Therefore, the contribution of probiotics to improve the balance and diversity of intestinal microbiota has become a main concern. The main focus of this review was to summarize a variety of naturally fermented milk products by highlighting the production process and indigenous microflora involved. The determination of probiotics that are highly involved in the fermentation of milk may have health benefits for treating inflammatory intestinal diseases, especially inflammatory bowel disease and intestinal mucositis Refereed/Peer-reviewed

Background: Current treatments for the inflammatory bowel diseases, encompassing Crohn's disease and ulcerative colitis, are variably effective. Emu oil, extracted from emu fat, predominantly comprises fatty acids, with purported claims of anti-inflammatory properties. Aim: We evaluated emu oil for its potential to ameliorate dextran sulphate sodium (DSS)-induced colitis in rats. Conclusions: Emu oil improved tissue damage associated with colitis, suggesting its potential as a unique formulation to augment conventional treatment approaches for IBD. Methods: Male Sprague-Dawley Rats were allocated to treatment groups (n = 8). Groups 1 and 2 consumed water and were gavaged (1 ml) daily with water (group 1) or emu oil (group 2) from days 0 to 10. Groups 3-6 ingested 2% DSS in the drinking water from days 5 to 10 and were gavaged from days 0 to 10 with water (group 3), 0.5 ml emu oil (group 4) or 1 ml emu oil (group 5). Group 6 received 1 ml emu oil after commencing DSS treatment (days 6-10). Disease activity index, metabolic parameters, 13C-sucrose breath test, and histological colonic damage severity and crypt depth were assessed. Results: Emu oil in DSS-treated rats reduced colonic damage severity compared to DSS-controls (up to threefold; P < 0.001). In DSS-treated rats, crypts in the proximal colon were lengthened by 0.5 ml emu oil (373 ± 18 μm), compared with DSS-controls (302 ± 8 μm); whilst in the distal colon (DSS control: 271 ± 17 μm), crypt depth was greater following 0.5 ml emu oil (352 ± 22 μm) and 1 ml emu oil (341 ± 9 μm) and also when emu oil was administered post-DSS commencement (Group 6: 409 ± 16 μm; P < 0.05). Emu oil did not significantly affect other parameters of colonic architecture. Refereed/Peer-reviewed

Inflammatory bowel disease (IBD) is a chronic, debilitating disease associated with severe damage to the intestinal mucosa. Glucagon-like peptide-2 (GLP-2) is a potent and specific gastrointestinal growth factor that is demonstrating therapeutic potential for the prevention or treatment of an expanding number of intestinal diseases, including short bowel syndrome (SBS), small bowel enteritis and IBD. The biological activity of GLP-2 is limited due to proteolytic inactivation by the protease dipeptidyl peptidase (DP)IV. Inhibitors of DPIV activity may represent a novel strategy to prolong the growth promoting actions of GLP-2. This review outlines evidence for the clinical application of GLP-2, its degradation resistant analogue, Teduglutide, and novel DPIV inhibitors in efficacy studies utilizing pre-clinical models of intestinal damage, in particular IBD. Refereed/Peer-reviewed

Beneficial bacteria (probiotics) and probiotic-derived factors have the potential to ameliorate disorders of the intestine. The aim of this study was to compare live Streptococcus thermophilus TH-4 (TH-4), dead TH-4 and TH-4 supernatant in rats treated with 5-Fluorouracil. Rats were randomly allocated to five treatment groups (n = 8–10): Saline + Water; 5-FU + Skim Milk; 5-FU+ Live TH-4; 5-FU + Supernatant TH-4; and 5-FU + Dead TH-4.5-FU (150 mg.kg-1) was administered by a single intraperitoneal injection on day zero; animals were killed on day four. Treatments were administered daily from days -2 to +3 via oro-gastric gavage. Metabolic parameters were measured daily. Blood was obtained by cardiac puncture, and intestinal tissues removed for quantitative and qualitative histological assessment, including: villus height and area; crypt depth and area, mitotic count and crypt fission;biochemical determination of sucrase and myeloperoxidase (MPO)activity; and disease severity scoring. One-way ANOVA statistical analyses were conducted for the majority of outcome measures. Live TH-4 significantly reduced disease severity score by 13% (p 0.05) in the occurrence of bacteraemia were evident across all groups. Live TH-4 partially normalized mitotic count and histological severity score in 5-FU treated rats. The inhibitory effect of live TH-4 and TH-4 Supernatant on crypt fission suggests therapeutic utility in the prevention of disorders characterized by increased crypt fission,such as colorectal carcinoma.

The dextran sulfate sodium (DSS) colitis model has been utilized to screen for novel therapeutics for ulcerative colitis. Evidence suggests the small intestine may also be affected by DSS. We characterized the effects of DSS on the small intestine and assessed the potential for Lactobacillus fermentum BR11 to modify or normalize DSS-induced changes. Rats were allocated to three groups, Water + Vehicle, DSS + Vehicle, and DSS + L. fermentum BR11. BR11 was administered twice daily for 14 days. DSS (2%) was provided from days 7 to 14. Small-intestinal tissue was analyzed for sucrase activity, histology, and crypt cell proliferation. Increased ileum crypt depth and cell proliferation was observed in DSS-treated rats compared to controls (P < 0.05). BR11 normalized these parameters. While DSS predominantly induces colonic damage, minor morphological alterations were also detected in the distal small intestine. L. fermentum BR11 normalized these features. Refereed/Peer-reviewed

Radiation and chemotherapy are commonly used to treat a variety of neoplasms. However, their indiscriminate mechanism of action, targeting cancer cells, in concert with all rapidly diving cells within the body, can lead to debilitating side-effects. Intestinal mucositis refers to the cell loss and subsequent damage to the gastrointestinal tract following chemotherapy or abdominal radiotherapy. Refereed/Peer-reviewed

Aims. The authors investigated the effects of TH-4 in a rat model of mucositis induced by the anthracycline chemotherapy drug, doxorubicin. Background. Mucositis is a debilitating intestinal side effect of chemotherapeutic regimens. Probiotics have been considered a possible preventative treatment for mucositis. Streptococcus thermophilus TH-4 (TH-4), a newly identified probiotic, has been shown to partially alleviate mucositis induced by administration of the antimetabolite chemotherapy drug, methotrexate in rats; likely mediated through a mechanism of folate production. However, its effects against other classes of chemotherapy drug have yet to be determined. Conclusions. The minimal amelioration of doxorubicin-induced mucositis by TH-4 further supports folate production as a likely mechanism of TH-4 action against methotrexate-induced mucositis. Further studies into TH-4 are required to confirm its applicability to other conventional chemotherapy regimens. Methods. Gastrointestinal damage was induced in female Dark Agouti rats (148.3 ± 1.5 g) by intraperitoneal injection of doxorubicin (20 mg/kg). Animals recieved a daily oral gavage of TH-4 at 109 cfu/ml or skim milk (vehicle) from days 0 to 8. At day 6, rats were injected with either saline or doxorubicin. At kill, small intestinal tissues were collected for determination of sucrase and myeloperoxidase (MPO) activities and histological assessment. Results. Body weight was significantly decreased by doxorubicin compared with normal controls (p < 0.05). Histological parameters, such as crypt depth and villus height, were also significantly decreased by doxorubicin. TH-4 partially prevented the loss of body weight induced by doxorubicin (2.3% compared with 4%), but provided no further therapeutic benefit. Refereed/Peer-reviewed

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Background: Short-chain fatty acids (SCFA) are undergoing increased scrutiny as chemotherapeutics for colon cancer, although a comprehensive understanding of their mode of action is lacking. We investigated candidate SCFA for their capability to modulate apoptosis, cell cycle, intracellular redox state and glucose metabolism in the Caco-2 human colon cancer cell line. Methods: Caco-2 cells were incubated with butyrate, propionate or a combination of these SCFA (1:1) and assessed by flow cytometry, enzyme activity analysis or by isotope ratio mass spectrometry. Results: Butyrate and the SCFA combination induced apoptosis and G2-M arrest to a greater extent than propionate alone (p < 0.05). SCFA treatment led to time-dependent alterations to the oxidative pentose pathway, reductions in glutathione availability and increases in levels of reactive oxygen species (p < 0.05) compared with untreated controls. The rate of D-glucose metabolism was increased by all SCFA, although to the greatest extent by butyrate (p < 0.05). Conclusions: These results suggest that butyrate, or the combination of both SCFA, induced rapid and extensive apoptosis and G2-M arrest associated with changes to redox state and D-glucose metabolism. These results support the potential for butyrate and propionate to act as adjuncts to conventional chemotherapy regimens for colon cancer.

Cancer chemotherapy can cause osteopenia or osteoporosis, and yet the underlying mechanisms remain unclear, and currently, no preventative treatments are available. This study investigated damaging effects of 5-fluorouracil (5-FU) on histological, cellular, and molecular changes in the tibial metaphysis and potential protective benefits of emu oil (EO), which is known to possess a potent anti-inflammatory property. Female dark agouti rats were gavaged orally with EO or water (1 ml·day−1·rat−1) for 1 wk before a single ip injection of 5-FU (150 mg/kg) or saline (Sal) was given. The treatment groups were H2O + Sal, H2O + 5-FU, EO + 5-FU, and EO + Sal. Oral gavage was given throughout the whole period up to 1 day before euthanasia ( days 3, 4, and 5 post-5-FU). Histological analysis showed that H2O + 5-FU significantly reduced heights of primary spongiosa on days 3 and 5 and trabecular bone volume of secondary spongiosa on days 3 and 4. It reduced density of osteoblasts slightly and caused an increase in the density of osteoclasts on trabecular bone surface on day 4. EO supplementation prevented reduction of osteoblasts and induction of osteoclasts and bone loss caused by 5-FU. Gene expression studies confirmed an inhibitory effect of EO on osteoclasts since it suppressed 5-FU-induced expression of proinflammatory and osteoclastogenic cytokine TNFα, osteoclast marker receptor activator of nuclear factor-κB, and osteoclast-associated receptor. Therefore, this study demonstrated that EO can counter 5-FU chemotherapy-induced inflammation in bone, preserve osteoblasts, suppress osteoclast formation, and potentially be useful in preventing 5-FU chemotherapy-induced bone loss.

Background: Inflammatory bowel disease (IBD) is a chronic inflammatory disorder of the gastrointestinal tract associated with altered composition of the gut microbiota. Lactobacillus reuteri BR11 (BR11) has recently been reported to reduce the severity of experimental IBD because of its probiotic properties possibly attributed to a mechanism of thiol production via its unique cysteine/cystine-transport system. Aim: We compared BR11 and a BR11 mutant deficient in the cystine-uptake system (PNG201), for their capacity to reduce the severity of experimental colitis. Methods: Male Sprague-Dawley rats (n = 8 per group) were gavaged (1 ml/day) with skim milk, BR11 or PNG201 (1 × 10 9 CFU/ml) for 12 days. Rats consumed either water or 2% dextran sulfate sodium in drinking water from days 6 to 12 to induce colitis. Metabolism data, disease activity index, intestinal mucin profile, and histological analyses were assessed and compared by ANOVA. Results Assessed histologically, DSS administration resulted in significant colonic deterioration, including loss of crypt area and increased damage severity. BR11 administration only partially alleviated the DSS effects, with a minor improvement in crypt area (P0.05) against the DSS control for any of the end-points. However, the mutant strain induced significantly greater (P

The dextran sulfate sodium (DSS) model of colitis has been commonly utilized in mice to assess novel treatments for ulcerative colitis. Recent studies have indicated that morphological and biochemical changes extend to the small intestine (SI). This study aimed to characterize histological and biochemical changes in the SI during DSS colitis in wild-type (WT) and DPIV knock-out (DPIV−/−) mice treated with saline or the DPIV inhibitors, Ile-Pyrr-(2-CN)*TFA or Ile-Thia. Groups (n = 10) of DPIV−/− and WT mice were orally gavaged twice daily with saline, Ile-Pyrr-(2-CN)*TFA or Ile-Thia. Mice consumed 2% DSS in drinking water for 6 days to induce colitis. Small intestinal tissue was assessed for histological changes, sucrase, and DPIV activity and neutrophil infiltration. Jejunal villus length was increased in all groups after 6 days DSS consumption (P

Certain live bacteria have demonstrated preliminary indications of efficacy for the treatment of chemotherapy-induced intestinal mucositis. However, probiotic derived supernatants (SN) have yet to be investigated in the mucositis setting. We evaluated SN from Escherichia coli Nissle 1917 (EcN) and Lactobacillus fermentum BR11 (BR11) for their capacity to decrease 5-Fluorouracil (5-FU)-induced damage in vivo. Female Dark Agouti rats were gavaged with 1 mL of either SN or vehicle daily (days 0-8) and intraperitoneally injected with 5-FU (150 mg/kg) on day 5 to induce mucositis. On day 9, animals were culled and intestinal tissues collected. Significantly lower histological damage scores were apparent in the jejunum of 5-FU treated rats receiving SN compared to 5-FU controls. Myeloperoxidase levels in the jejunum of 5-FU treated rats were increased in vehicle and BR11 SN treatments compared to untreated controls, whereas no significant increase was observed after EcN SN treatment. 5-FU treatment significantly reduced villus height and crypt depth in the jejunum compared to normal controls; however no significant reduction in these parameters was observed in 5-FU treated rats receiving either SN. We conclude that bacterial SN, especially EcN, partially protect the intestine from 5-FU mucositis. Further studies are required to define specific mechanisms by which SN exert their beneficial effects. Refereed/Peer-reviewed

Introduction: Pre-clinical studies have indicated that palifermin may be an effective treatment modality for intestinal mucositis, a debilitating complication of cancer chemotherapy. We determined whether palifermin was protective in rats with experimentally induced intestinal mucositis and the applicability of the sucrose breath test (SBT) to monitor palifermin for its efficacy as an anti-mucositis agent. Conclusion: The SBT can monitor the ability of palifermin to modify the functional capacity of the small intestine in rats with intestinal mucositis. Further studies are indicated to investigate the prophylactic potential of palifermin against intestinal mucositis. Methods: Dark agouti rats (n = 10) were subcutaneously injected with palifermin or vehicle for 3 d after which they were injected with 5-fluorouracil (5-FU) and sacrificed after 72 h. The in vivo SBT and in vitro sucrase assay were used to evaluate small intestinal function and damage. Intestinal disease severity was determined by histological assessment of villus height and crypt depth. Results: SBT values and sucrase activity were reduced in all 5-FU-treated groups compared with untreated controls (p < 0.05). At 72 h post 5-FU, sucrase activity was higher in rats treated with palifermin compared with 5-FU controls (p < 0.05). Jejunal and ileal villus heights were lower in all 5-FU groups compared with saline controls. Refereed/Peer-reviewed

Although chemotherapy remains the current best practice for the treatment of neoplasia, the severity of its associated side-effects continues to impact detrimentally on the quality of life. Mucositis can affect both the oral cavity and intestine, and represents one of the most common side-effects of chemotherapy. It is characterized by ulceration, inflammation, diarrhoea, and intense abdominal pain. Despite extensive research there remains no definitive therapy for mucositis. This may be due to the multiple factors which contribute to its pathogenesis, including up-regulation of pro-inflammatory cytokines, increased apoptosis of epithelial cells, alteration of the gastrointestinal microbiota, and damage to the epithelium. Although employed increasingly in other gastrointestinal disorders, probiotics are yet to be comprehensively investigated in the treatment or prevention of chemotherapy-induced mucositis. Probiotic-based therapies have been shown to exert beneficial effects, including modulation of the microbiota and inhibition of pro-inflammatory cytokines. This review outlines the current evidence supporting the use of probiotics in intestinal mucositis, and suggests further research directions for the future. Refereed/Peer-reviewed

Mucositis resulting from cancer chemotherapy is a serious disorder of the alimentary tract. Emu oil has demonstrated anti-inflammatory properties in animal models of arthritis and wound healing; however, its effects on the intestine remain unknown. We investigated emu oil for its potential to decrease the severity of mucositis in a rat model. Female Dark Agouti rats (110–150 g) were orogastrically gavaged with emu oil (0·5 or 1 ml) or water (1 ml) for 5 d before intraperitoneal injection of 5-fluorouracil (5-FU, 150 mg/kg) or saline (control), and this was continued up to the day of sacrifice (48, 72 and 96 h post 5-FU administration). Histological (villus height, crypt depth (CD) and disease severity score) and biochemical (myeloperoxidase (MPO) activity) parameters were determined in intestinal tissues collected at sacrifice. Sucrase activity in vivo was quantified by the sucrose breath test. Activated neutrophil activity (MPO) in the ileum was significantly decreased by emu oil (0·5 ml, 451 (sem 168) U/g and 1 ml, 503 (sem 213) U/g) compared with 5-FU-treated controls (1724 (sem 431) U/g) 96 h post 5-FU administration. There were also significant increases in CD (152 (sem 8) μm) in the ileum of rats that receivied 1 ml emu oil at 96 h compared with 5-FU-treated controls (CD (106 (sem 12) μm)). Emu oil did not affect sucrase activity. Emu oil decreased acute ileal inflammation, and improved mucosal architecture in the intestine during recovery from chemotherapy in rats. Further studies investigating the potential benefits of emu oil as a nutritional supplement for the treatment of intestinal disorders are indicated.

Mucositis is a common side-effect of high-dose chemotherapy regimens. Grape seed extract (GSE) represents a rich source of proanthocyanidins with the potential to decrease oxidative damage and inflammation within the gastrointestinal tract. We evaluated GSE for its capacity to decrease the severity of chemotherapy- induced mucositis in vitro and in vivo. In vitro: GSE was administered to IEC-6 intestinal epithelial cells prior to damage induced by 5-Fiuorouracil (5-FU). Cell viability was determined by neutral red assay. In vivo: Female Dark Agouti rats (130-180 g) were gavaged with 1 ml GSE (400 mg/kg) daily (day 3-11) and received 5-FU (150 mg/kg) by intraperitoneal (i.p.) injection on day nine to induce mucositis. Rats were sacrificed at day 12 and intestinal tissues collected for myeloperoxidase and sucrase activity assays and histological analyses. Statistical analysis was performed by one-way AN OVA. GSE prevented the decrease in IEC-6 cell viability induced by 5-FU (p < 0.01). Compared with 5-FU controls, GSE significantly reduced myeloperoxidase activity by 86% and 27% in the proximal jejunum (p < 0.001) and distal ileum (p < 0.05) respectively; decreased qualitative histological scores of damage (p < 0.05) in the proximal jejunum; increased villus height in the proximal jejunum (17%; p < 0.05) and distal ileum (50%; p < 0.01), and attenuated the 5-FU-induced reduction of mucosal thickness by 16% in the jejunum (p < 0.05) and 45% in the ileum (p < 0.01). GSE partially protected IEC-6 cells from 5-FU-induced cytotoxicity and ameliorated intestinal damage induced by 5-FU in rats. GSE may represent a promising prophylactic adjunct to conventional chemotherapy for preventing intestinal mucositis. Refereed/Peer-reviewed

There is an acute need for the development of effective therapies for mucositis, a debilitating side effect of cancer chemotherapy. Iberogast® is a herbal extract reported to possess anti-inflammatory properties. We investigated Iberogast® for its potential to reduce the severity of 5-Fluorouracil (FU)-induced mucositis in rats. Rats were allocated to three treatment groups(n = 8) and gavaged daily with a 10% solution of Iberogast® or water from day 0 to day 8. Rats were injected intraperitoneally with 5-FU (150 mg/kg) or saline on day 6, and killed after 72 h.In vivo and in vitro sucrase activity was assessed by 13C-sucrose breath test (SBT) and sucrase assay respectively. Intestinal disease severity was determined by histological assessment of villus height and crypt depth. Significant increases in villus height (277± 9 μm) and crypt depth (67 ± 3 μm) were observed in 5-FU +Iberogast®-treated rats compared with 5-FU + Water (224 ± 13μm and 48 ± 2 μm respectively; p < 0.05). Sucrase activity was significantly reduced in all 5-FU groups compared to control.Significant reductions in SBT and sucrase activity were observed in all 5-FU groups compared with Saline + Water controls(p < 0.05). We conclude that although Iberogast® partially improved the histopathological features of 5-FU induced mucositis, it conferred no significant protection as indicated by the assessed endpoints. Refereed/Peer-reviewed

Mucositis is a common and debilitating side effect of chemotherapy that manifests due to the inability of chemotherapy agents to discriminate between normal and neoplastic cells. This results in ulcerating lesions lining the gastrointestinal tract. Moreover, the development of efficacious treatments for small intestinal mucositis has been hindered as the pathobiology of mucositis is still not fully understood. The small intestine is an extensive organ which is largely inaccessible by conventional means. Non-invasive biomarkers such as small intestinal permeability, H2 breath tests, serum citrulline tests and the 13C-sucrose breath test (SBT) have emerged as potential markers of small intestinal function. The SBT is emerging as the more appropriate biomarker to assess chemotherapy-induced mucositis in cancer patients and animal models, where it measures the decrease in sucrase activity associated with villus blunting and crypt disruption. The SBT has been successfully applied to detect mucositis induced by different classes of chemotherapy agents and has been used successfully to monitor small intestinal function with a range of candidate anti-mucositis treatments. We propose the SBT a superior biomarker of small intestinal function that could be successfully applied in clinical practice for monitoring the development of mucositis in cancer patients undergoing chemotherapy. Refereed/Peer-reviewed

Mucopolysaccharidosis type IIIA (MPS IIIA) is a lysosomal storage disorder caused by a deficiency in sulphamidase (NS), a lysosomal enzyme required for the degradation of heparan sulphate glycosaminoglycans (gags). The MPS IIIA mouse is a naturally occurring model that accurately reflects the human pathology and disease course. It displays primarily central nervous system pathology accompanied by widespread accumulation of gag in somatic tissues. MPS IIIA mice exhibit greater bodyweight gain than normal littermates and attain a higher mature bodyweight. In this study, gastrointestinal morphology and function was characterised in the IIIA mouse. Stomach and duodenum weight increased in MPS IIIA mice and duodenum length also increased. An increased submucosal thickness was observed in MPS IIIA intestine compared to normal mice and lysosomal storage of gag was observed in this region. Storage was also observed in the lamina propria of the villus tip. All other morphometric measurements including villus height and crypt depth fell within the normal range. The gastric emptying half-life of solid and liquid meals decreased with age in normal mice whereas the T½ of solid meals did not alter with age in MPS IIA mice such that they were elevated above normal by 38 weeks of age. Sucrase activity was higher than normal in MPS IIIA at all ages tested. These abnormalities in GI structure and function observed in MPS IIIA may contribute to weight gain in this disorder. Refereed/Peer-reviewed

Dipeptidyl peptidase (DPP)-4 is a member of the S9b serine protease family, which also includes DPP8 and DPP9. DPP4 cleaves a number of regulatory factors, including chemokines and growth factors. DPP4 inhibitors have recently emerged as an effective treatment option for type 2 diabetes. Early in vitro studies demonstrated that DPP4 inhibitors inhibit T-cell proliferation and cytokine production, leading to their investigation in numerous pre-clinical models of inflammatory diseases, including arthritis, multiple sclerosis and inflammatory bowel disease. Recent data suggest that the early DPP4- specific inhibitors might also bind DPP8 and DPP9, thus exerting their effects through non-specific binding. This review highlights recent insights into the applicability of DPP inhibitors as novel pharmacological agents for inflammatory disease. Refereed/Peer-reviewed

Although probiotics are beginning to enter mainstream medicine for disorders of the colon, their effects on the small bowel remain largely unexplored. We investigated the recently identified probiotic, Lactobacillus fermentum (L. fermentum) BR11 (BR11) and the prebiotic, fructo-oligosaccharide (FOS), both individually and in synbiotic combination, for their potential to alleviate intestinal mucositis. From Days 0-9, rats consumed skim milk (SM; saline + SM), low dose (LD-BR11; 1 x 10(6)cfu/ml), high dose (HD-BR11; 1 x 10(9)cfu/ml), LD-FOS (3%), HD-FOS (6%), or synbiotic (HD-BR11/FOS). On Day 7, rats were injected with 5-fluorouracil (5-FU; 150 mg/kg). All rats were sacrificed on Day 10. Intestinal tissues were collected for quantitative histology, sucrase, and myeloperoxidase (MPO) determinations. 5-FU decreased sucrase activity, villus height, crypt depth, and crypt cell proliferation compared to controls. Compared to 5-FU + SM, histological damage severity scores were increased for all treatments, although all were effective at reducing jejunal inflammation, indicated by reduced MPO activity (P < 0.05). The combination of BR11 and FOS did not provide additional protection. Moreover, HD-FOS and the synbiotic actually increased clinical mucositis severity (P < 0.05). We conclude that L. fermentum BR11 has the potential to reduce inflammation of the upper small intestine. However, its combination with FOS does not appear to confer any further therapeutic benefit for the alleviation of mucositis.

Background: Intestinal mucositis is a common and debilitating side-effect of chemotherapy, associated with severe small intestinal inflammation. Marine oils, such as Lyprinol™, a lipid extract derived from New Zealand Green-lipped Mussels, rich in long-chain omega-3 polyunsaturated fatty acids (n-3 PUFA), have demonstrated therapeutic potential for the treatment of inflammatory conditions. We assessed the effects of Lyprinol™ on the severity of 5-fluorouracil (5-FU)-induced mucositis in female DarkAgouti rats. Conclusion: Lyprinol™ treatment in rats with 5-FU-induced mucositis only minimally decreased indicators of intestinal integrity.Further studies of marine oils high in omega-3 PUFA contentare warranted for the potential prophylactic treatment of intestinal mucositis. Methods: Rats were allocated to six groups (n = 8/group);Saline+vehicle, 5-FU+vehicle, 5-FU+high-dose Lyprinol™ (5-FU+HDL), 5-FU+low-dose Lyprinol™ (5-FU+LDL), 5-FU+olive oil (5-FU+OO), and 5-FU+fish oil (5-FU+FO). Treatments were administered via oro-gastric gavage from days 0-7. Mucositis was induced on day 5 by 5-FU injection (150mg/kg i.p.). 13C-sucrose breath tests (SBT) were conducted on days 0, 5 and 8 to assess small intestinal function. Rats were sacrificed on day 8 and small intestinal tissues collected for histological and biochemical analysis. Results: Small intestinal weight was significantly greater in rats treated with 5-FU+HDL, 5-FU+LDL and 5-FU+FO compared to 5-FU-treated controls (p < 0.05). My eloperoxidase activity in the proximal and mid small intestine were significantly lower in5-FU+OO-treated rats compared to 5-FU+vehicle-treatedcontrols (p < 0.05). Histological damage severity was elevated in5-FU+vehicle, 5-FU+OO and 5-FU+FO-treated rats compared to saline-treated controls, but not in rats treated with 5-FU+HDL or 5-FU+LDL. SBT results and biochemically-assessed sucrase activity were lower in all 5-FU-treated rats compared to saline treated controls. 5-FU+HDL treated animals had significantly longer crypts and increased proliferation in the mid small intestine compared to 5-FU+vehicle rats (p < 0.05).