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Can we understand how the gut microbiota is established?
▸ Seedorf H, Griffin NW, Ridaura VK, et al. Bacteria from diverse habitats colonise and compete in the mouse gut. Cell 2014;159:253–66.
How microbes establish themselves within our GI tract and how our interactions with other humans, animals and our environment impacts on this colonisation remains unknown. Understanding how microbes establish themselves could provide strong clues as to how our gut microbiota shapes our health, and potentially could identify how well-defined species consortia (microbiota-directed therapeutics) could be beneficial. In this study, bacteria from several foreign environments were used to colonise germ-free mice, and their ability to metabolise dietary and host carbohydrates and bile acids were measured. The findings demonstrate that the mouse intestinal tract, while highly selective, shows unanticipated patterns of ecological succession. Nonetheless, cohousing the various colonised mice revealed that most bacterial phylotypes, including those from the human gut, were not capable of effectively colonising a gut harbouring an autochthonous microbiota. These studies illustrate how patterns of colonisation succession cannot be predicted purely on habitat associations. Using a trio cohousing approach they demonstrated that human gut microbes could colonise germ-free mice more rapidly than mouse-derived taxa. The success of colonisation could be correlated with functional features of the community and host. The present study assessed bacteria from extremely broad environmental niches including human skin and tongue, zebra fish, termite gut, soil and estuarine microbial mats; providing confidence that the approach could be generalised to address the current issues relating to the use of microbiota-derived therapeutics. Assessing the patterns of colonisation/succession of these products is vital to allow us to identify which organisms are beneficial or detrimental to re-gaining health. This study provides a useful framework for studies that require consideration of the microbial potential of planned biological interventions.
Stromal Indian Hedgehog signalling is required for adenoma formation in mice
▸ Büller NV, Rosekrans SL, Metcalfe C, et al. Stromal Indian hedgehog signaling is required for adenoma formation in mice. Gastroenterology 2014:pii:S0016-5085(14)01202-5. Published Online First: 9 Oct 2014. doi:10.1053/j.gastro.2014.10.006
Indian hedgehog (IHH) is a known antagonist of Wnt-mediated proliferation and differentiation in the mammalian intestine. The loss of IHH in the intestine leads to an inflammatory state due to an altered stromal cell compartment. Mutations in IHH can play an important, even causal, role in cancer development in certain tissue types. Little is known about its role in colon cancer. IHH is downregulated in familial adenomatous polyposis and sporadic adenomas, both of which rely on APC perturbation for dysplasia development. This study investigates the effect of IHH signalling in the murine intestine and assesses its role in intestinal tumorigenesis. Loss of IHH induces a state of unregulated crypt cell proliferation and increased crypt fission and inflammation. To investigate if this led to adenoma development the authors performed a long-term (up to 12 months) conditional loss of IHH. This led to a hyperplastic state but no dysplasia. To determine the role of IHH signalling in adenomas, Gli1-CreERT2 mice (these express an inducible Cre controlled by regulatory elements of the hedgehog target Gli1, crossed with a LacZ-ZSgreen promoter) allowed visualisation of cells that respond to IHH. Inducing Cre recombination resulted in a stromal-specific staining pattern, specifically within myofibroblasts and smooth muscle cells. Similar results were obtained with Ptch, the hedgehog receptor. An additional cross to Min mice (which develop spontaneous adenomas) revealed similar Gli staining in the stroma of adenomas. When IHH was conditionally knocked out in another Apc-mediated model of adenomas, the number of adenomas was significantly reduced, however the size and morphology of those that did develop was similar to those in mice with functional IHH. However, loss of IHH resulted in a loss of adenoma myofibroblasts and stromal cells. This demonstrates that IHH is required for adenoma development but perhaps is not involved in their growth and maintenance. They also showed that this IHH-mediated adenoma development is a result of COX2 expression. This is an interesting study that clearly demonstrates a stromal role (mediated by epithelial paracrine effects) for adenoma development. The role of stroma in tumorigenesis has been previously proposed but evidence exists for inhibitory and stimulatory effects of tumour growth. This paper is an important contribution to this story.
Targeting MDM2 in pancreatic cancer
▸ Wang W, Qin JJ, Voruganti S, et al. Identification of a new class of MDM2 inhibitor that inhibits growth of orthotopic pancreatic tumors in mice. Gastroenterology 2014;147:893–902.
The prognosis for patients with pancreatic cancer remains poor with lack of effective, potentially curative therapies. MDM2 acts as an oncogene via negative regulation of the tumour suppressor p53, and also p53 independent mechanisms. MDM2 is overexpressed in pancreatic cancer and linked to poor prognostic indicators, such as metastases and drug resistance. Therefore, this is a potentially novel therapeutic target. Current MDM2 inhibitors block interaction between p53 and MDM2. These therefore rely on the presence of wild type p53 and in reality most tumours express a mutated form. The exploration for alternative chemicals showing MDM2 inhibition by high throughput virtual screening identified 34 with strong binding capacity to MDM2. In vitro assessment of anticarcinogenic properties revealed one strong candidate, SP141; this was cytotoxic to several pancreatic cancer cell lines at low dose with limited effect on normal cells, suggesting selectivity and low toxicity. The underlying mechanism was p53 independent, and involved growth cycle arrest, increase in apoptosis, and also a novel mechanism of increased autoubiquitination and proteasomal degradation. This compound was then tested in vivo in xenograft and orthotopic murine pancreatic tumour models (with human pancreatic cancer cells injected subcutaneously in the flank, and directly into the pancreas with subsequent monitoring by Bioluminescence imaging, respectively). In the xenograft model, tumour growth was reduced by 75% compared with control by day 18. In the orthotopic model, there was almost complete tumour regression by 3 weeks with no apparent toxicity. This paper is an elegant example of successful drug discovery and has unearthed a potentially transforming therapeutic for pancreatic cancer.
Gut selective inhibition of leucocyte trafficking as a treatment for Crohn's disease
▸ Sands BE, Feagan BG, Rutgeerts P, et al. Effects of vedolizumab induction therapy for patients with Crohn's disease in whom tumor necrosis factor antagonist treatment had failed. Gastroenterology 2014;147:618–27.
New ‘gut-specific’ biological therapies could improve options available to treat IBD. Vedolizumab, a humanised monoclonal antibody that modulates lymphocyte trafficking by selectively blocking binding of the α4β7 integrin to its tissue receptor MAdCAM-1, has recently secured US Food and Drug Administration approval for use in adults with moderate to severe UC and Crohn’s disease (CD) when one or more standard therapies (corticosteroids, immunomodulators or TNF blocker medications) have not resulted in an adequate response. Its gut-specific mechanism is thought to minimise the risk of progressive multifocal leucoencephalopathy (PML), a potentially devastating side effect which significantly curtailed the clinical use of the less selective α4 integrin blocker natalizumab. This phase 3, double-blind, placebo-controlled trial reports the safety and efficacy of vedolizumab induction treatment in over 300 patients with CD in whom previous TNF antagonist therapy had failed. Participants were randomly allocated to placebo or 300 mg vedolizumab intravenously at weeks 0, 2 and 6. The primary end point was clinical remission (Crohn's disease activity index (CDAI) <150) at week 6 of treatment, but results showed that vedolizumab was not superior to placebo for inducing remission at this time point. However when assessing secondary and prespecified outcomes at week 10 a statistically significant number of patients treated with vedolizumab compared with patients treated with placebo were in clinical remission (26.6% vs 12.1%; p=0.001). This study did not assess long-term efficacy, however short- term outcomes in terms of inducing remission appear modest in this particular patient group. Previously published data in patients with CD also demonstrated a seemingly modest effect in terms of rapid induction of remission but more impressive results in rates of clinical remission when maintenance therapy was continued for 12 months. The authors speculate that gradual onset of efficacy may be an attribute of drugs that influence the inflammatory response by modulation of lymphocyte trafficking. The safety profile of vedolizumab was similar to that of placebo. To date no PML cases have been reported in the integrated vedolizumab safety database but concerns about the potential for developing PML will not be fully allayed until more comprehensive long-term follow-up data is amassed.
No new indication for oral 5ASAs!
▸ Raskin JB, Kamm MA, Jamal MM, et al. Mesalamine did not prevent recurrent diverticulitis in phase 3 controlled trials. Gastroenterology 2014;147:793–802.
The most common complication of diverticular disease is diverticulitis, which affects the minority of patients with diverticulae. The evidence base to guide therapy after an attack of acute diverticulitis is poor and weak; in particular that for dietary modification is inconclusive and inconsistent. Raskin et al recently published the results of two randomised placebo-controlled clinical trials (PREVENT 1 and 2) investigating whether mesalamine can prevent the recurrence of diverticulitis. Over 1000 patients who had at least one confirmed attack of acute diverticulitis over the preceding 24 months were randomised to receive 1.2 g, 2.4 g or 4.8 g of mesalamine or placebo daily for 104 weeks. Recurrence of diverticulitis (as defined by need for any surgical intervention for diverticular disease or CT evidence of colonic wall thickening or pericolic fat stranding) at week 104 was the primary end point. The data suggested that there was no difference between any dose of mesalamine and placebo. There were no new adverse events noted with patients treated with mesalamine. The authors concluded that mesalamine was ineffective at preventing recurrence of diverticulitis and furthermore highlighted the low rates of surgery (<5%) in the trial cohort overall suggesting that the large majority of patients are indeed managed conservatively following an acute attack. Future studies should be aided by stratifying patients on entry using validated colonoscopic scoring systems for diverticular disease. In the present study, mesalamine was ineffective at preventing the recurrence of diverticulitis in a large randomised clinical trial and is not recommended for this indication.
The purge of hepatic encephalopathy?
▸ Rahimi RS, Singal AG, Cuthbert JA, et al. Lactulose vs polyethylene glycol 3350-electrolyte solution for treatment of overt hepatic encephalopathy: the HELP randomized clinical trial. JAMA Intern Med 2014;174:1727–33.
The treatment of hepatic encephalopathy (HE) has never reached the sophistication of the management of other complications of cirrhosis. The traditional approach of achieving two to three loose bowel motions in a partly obtunded patient with HE by administering lactulose or an enema has stood the test of time! The dramatic effects of this can be vouched and ratified by physicians everywhere. It has been demonstrated that bacteria in the gut play a major role in the aetiopathogenesis of HE. Indeed, poorly absorbed antibiotics like neomycin in the past and rifaximin more recently are efficacious for treatment of HE. Lactulose is believed to acidify the stool and act as a laxative to clear ammonia from the gut. This small randomised trial asked whether the purge is possibly the most important component. Fifty subjects with overt HE were randomised to standard treatment consisting of lactulose, 20–30 g administered orally or by nasogastric tube (three or more doses within 24 h) or 200 g by rectal tube if oral intake was not possible versus 4 L of polyethylene glycol 3350-electrolyte solution (PEG) administered orally or via nasogastric tube, as a single dose over 4 h. The PEG group did not receive any further treatment for the next 24 h after which they were reassessed and allowed lactulose. The primary outcome was improvement of the HE scoring algorithm score by 1 or more at 24 h. A total of 52% of patients in the standard therapy arm had an improvement as opposed to 91% for the PEG arm after 24 h (p<0.01). Patients on PEG had a lower mean HE scoring algorithm score at 24 h (p=0.002). More importantly, the median time for HE resolution was 2 days for standard therapy and 1 day for the PEG group (p=0.01). Despite the small sample size, lack of standardisation of lactulose dosage in the control group and the lack of rifaximin, which has now become a standard of care, there are some important messages to take home. A rapid purge with PEG did result in a rapid response. In the hospital setting it is a reasonably cheap alternative worth considering, especially if it cuts down hospital stay. Any additional effects of the PEG purge in terms of ammonia generation and altered neurotransmission remains to be elucidated.
Dr Georgina Hold, Dr Stuart McDonald, Dr Mairi H McLean, Dr Jonathan MacDonald, Dr Dan Gaya, Dr Ashis Mukhopadhya
Cell, Gastroenterology, Journal of the American Medical Association Internal Medicine.
Provenance and peer review Not commissioned; internally peer reviewed.
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