Colorectal Cancer: Of Mice and Microbiota

A recent study (SH Wong et al. Gastroenterol 2017; 153: 1621-33) highlights the potential role of the microbiota and colorectal cancer (CRC).

In this study, the stool from either patients with CRC or control patients was gavaged into mice twice a week for 5 weeks.  One group of mice  had received azoxymethane (AOM) which induces neoplasia and the other group were germ-free mice.  Extensive studies involving immunohistochemistry, expresssion microarray, quantitative polymerase chain reaction, immunoblot, and flow cytometry.

Key findings:

  • Conventional, AOM-treated mice who received gavage from patients with CRC had significantly higher proportions of high-grade dysplasia (P<.05) and macroscopic polyps (P<.01)
  • Among the germ-free mice fed with stool from patients with CRC, there was a higher proportion of proliferating Ki-67-positve cells
  • These findings correlated with more dysbiosis in the mice who received stool from patients with CRC and with upregulation of genes involved in cell proliferation, stemness, apoptosis, angiogenesis, and invasiveness

“This study provides evidence that the fecal microbiota from patients with CRC can promote tumorigenesis in germ-free mice and mice given a carcinogen.”

My take: This study shows that microbiota clearly influence the risk of CRC.  I infer from this study that this could explain the potential healthy roles of diets with more fruits and vegetables, that promote healthier microbiota as well as the potential detrimental role of diets with more processed meats.

Related study: L Liu et al. Association between Inflammatory Diet Pattern and Risk of Colorectal Carcinoma Subtypes Classified by Immune Responses to Tumor Gastroenterol 2017; 153 1517-30.  Using two databases from 2 prospective cohorts with followup of 124,433 participants, inflammatory diets had a higher risk of a colorectal cancer subtype.

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What Happens Four Years After Fecal Microbiota Transplantation?

A recent study (J Jalanka et al. AP&T 2018; 47: 371-9-thanks to Ben Gold for this reference) provide long-term data of fecal microbiota transplantation (FMT).

In this study of 84 adult patients who were treated for C difficile infection, 45 who had received FMT and 39 treated with antibiotics, the authors determined the frequency of adverse sequelae at 3.8 years using a retrospective questionnaire.

Key findings:

  • There were no difference in the development of severe diseases between FMT recipients and control patients (eg. IBD, cancer, autoimmune diseases, allergy, and neurological diseases)
  • There were no differences in weight gain
  • FMT patients reported faster improvements in bowel habits and reported that their mental health improved after treatment
  • FMT patients had fewer symptoms of functional gastrointestinal disorders than the control (antibiotic) patients

The authors note that FMT is frequently recommended based on three recurrences of C difficile infection and that their study would support using FMT earlier as a treatment option.

My take: Though a small study, these data suggest that FMT is effective and without long-term consequences.

How Good Is Your ERCPist?

An interesting study and accompanying editorial (RN Keswani et al. Clin Gastroenterol Hepatol 2017; 15: 1866-75, & P Cotton Clin Gastroenterol Hepatol 2017; 15:1855-57) point out that ERCP is more successful in high volume centers and with high volume (HV) endoscopists.

The study was a systematic review and meta-analysis.  The threshold for low volume for endoscopist was < 27 case/year and for centers of <156 cases/year.  However, this data is not widely available.

  • In this study with 59,437 ERCPs, HV endoscopists had OR of 1.6 for success compared to LV endoscopist.
  • Similarly HV centers had OR of 2.0 for successful ERCP.
  • Post-ERCP adverse risks were lower for HV endoscopists with OR of 0.7

In addition, the level of complexity for the cases matters a lot. Dr. Cotton breaks down the complexity of procedures:

  • Standard complexity includes cannulation of bile duct, biliary stent removal/exchange, biliary stone removal <10 mm, treating bile leaks, treating benign and malignant strictures, and placing prophylactic stents..
  • Advanced procedure complexity includes any of the above procedures after Billroth II, minor papilla cannulaiton, removing biliary stents that have migrated internally, fine needle aspiration, treating pancreatic strictures, removing small (< 5 mm), mobile pancreatic stones, treating biliary strictures at hilum or more proximal
  • Highly technical complexity (“advanced tertiary”) includes removal of internally migrated pancreatic stents, intraductal image-guided therapy (eg. PDT EHL), pancreatic stones impacted or >5 mm, intrahepatic stones, pseudocyst drainage, ampullectomy, ERCP after Whipple or roux-en-Y bariatric surgery

My take: The ultimate goal is high success rates and lower complication rates.  Highly proficient endoscopists and high volume centers achieve these goals more consistently, particularly for more complicated ERCP procedures.

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Oral Capsules for Fecal Microbiota Transplantation

A recent study (D Kao et al.JAMA. 2017;318(20):1985-1993. doi:10.1001/jama.2017.17077showed that oral stool capsules are as effective as stool delivered via colonoscopy for recurrent C difficile infection (RCDI).  Thanks to Ben Gold for this reference.

Findings  In this noninferiority randomized clinical trial that included 116 adults with RCDI, the proportion without recurrence over 12 weeks was 96.2% after a single treatment in a group treated with oral capsules and in a group treated via colonoscopy, meeting the noninferiority margin of 15%.

My take: This study adds to the literature that oral delivery is effective in fecal microbiota transplantation and that capsules could be a convenient way to deliver.

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Another Study: Low FODMAPs Diet for Irritable Bowel Syndrome

Another good study on the low FODMAPs diet for irritable bowel syndrome with diarrhea (IBS-D): S Eswaran et al. Clin Gastroenterol Hepatol 2017; 15: 1890-9

This was a propspective, single-blind trial of 92 patients (84 completed study) with IBS-D (65 women) comparing the low FODMAPs diet to a modified diet recommended by the National Institute for Health and Care Excellence (NICE) for 4 weeks. Key findings:

  • The low FODMAPs group had larger increase in IBS-QOL score (15.0 vs 5.0).  In addition, based on IBS-QOL a meaningful clinical response occurred in 52% compared with 21% in the mNICE group.
  • Activity impairment was significantly reduced in the low FODMAPs group; -22.89 compared with -9.44.  Anxiety scores decreased as well.

My take: This study indicates that the low FODMAPs diet helps patient with IBS-D, and not just with their GI symptoms.

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Low FODMAP –Real World Experience

HM Staduacher et al. Gastroenterol October 2017; 153: 936–47

Key finding:

  • In this randomized, placebo-controlled study with 104 patients with irritable bowel syndrome (IBS), the researchers spent only 10 minutes per patient teaching the low FODMAPs diet; yet 57% reported adequate relief of symptoms.

AGA Journals blog summary: Can a Diet Low in FODMAP Reduce IBS Symptoms in the Real World?

An excerpt:

Heidi Maria Staudacher et al aimed to investigate the effects of a diet low in FODMAPs compared with a sham diet in patients with IBS, and determine the effects of a probiotic on diet-induced alterations in the microbiota.

They performed a 2×2 factorial trial of 104 patients with IBS. Patients were either given counselling to follow a sham diet or diet low in FODMAPs for 4 weeks, but not the actual foods. Patients also received a placebo or multistrain probiotic formulation, resulting in 4 groups (27 receiving sham diet/placebo, 26 receiving sham diet/probiotic, 24 receiving low-FODMAP diet/placebo, and 27 receiving low-FODMAP diet/probiotic)…

In the per-protocol analysis, a significantly higher proportion of patients on the low-FODMAP diet had adequate symptom relief (61%) than in the sham diet group (39%).

The total mean IBS severity score was significantly lower for patients on the low-FODMAP diet (173 ± 95) than the sham diet (224 ± 89), but there was no significantly difference between patients given probiotic (207 ± 98) or placebo (192 ± 93).

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Early Results with Upadacitinib -a JAK1 Inhibitor for Crohn’s Disease

From Gastroenterology & Endoscopy News: New JAK1 Inhibitor Treats Most Challenging Crohn’s Patients

An excerpt:

An experimental oral JAK1 inhibitor, upadacitinib (AbbVie), has been tested in the most clinically challenging patients with Crohn’s and yielded impressive results. The drug led to a clinical response in 61% of these patients and remission in 22%, the new data show…

William Sandborn, MD, chief of gastroenterology at the University of California, San Diego, who led the study. “It seems to be a really effective drug in a very difficult-to-treat patient population, and the oral route of administration is attractive.”

Dr. Sandborn’s group presented the findings at the 2017 Digestive Disease Week (abstract 974h).

The CELEST trial enrolled 220 patients with active, moderate to severe Crohn’s disease. Patients received 16 weeks of induction therapy with one of five dosing regimens of upadacitinib or a placebo…

Dr. Sandborn called the findings particularly impressive given that the study participants are the most refractory patient population ever recruited in a trial for Crohn’s disease. “And this is also one of the first trials to meet new FDA requirements for demonstrating clinical remission using patient-reported outcomes as well as endoscopic improvement,” he noted.

My take: It is exciting that another oral agent may be helpful. Tofacitinib, a different JAK1 inhibitor, has data supporting its use in ulcerative colitis but not with Crohn’s disease.

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