Monthly Archives: February 2016

Nutritional Keys for Intestinal Barrier Modulation

·

Abstract

The intestinal tract represents the largest interface between the external environment and the human body. Nutrient uptake mostly happens in the intestinal tract, where the epithelial surface is constantly exposed to dietary antigens. Since inflammatory response toward these antigens may be deleterious for the host, a plethora of protective mechanisms take place to avoid or attenuate local damage. For instance, the intestinal barrier is able to elicit a dynamic response that either promotes or impairs luminal antigens adhesion and crossing. Regulation of intestinal barrier is crucial to control intestinal permeability whose increase is associated with chronic inflammatory conditions. The cross talk among bacteria, immune, and dietary factors is able to modulate the mucosal barrier function, as well as the intestinal permeability. Several nutritional products have recently been proposed as regulators of the epithelial barrier, even if their effects are in part contradictory. At the same time, the metabolic function of the microbiota generates new products with different effects based on the dietary content. Besides conventional treatments, novel therapies based on complementary nutrients are now growing. Fecal therapy has been recently used for the clinical treatment of refractory Clostridium difficile infection instead of the classical antibiotic therapy. In the present review, we will outline the epithelial response to nutritional components derived from dietary intake and microbial fermentation focusing on the consequent effects on the integrity of the epithelial barrier.

Front Immunol. 2015; 6: 612.

Figure 1 - Diet Modulation of Intestinal Permeability - De Santis et al.

Figure 2 - Diet Modulation of Intestinal Permeability

 

Download (PDF, 3.45MB)

Oral, capsulized, frozen fecal microbiota transplantation for relapsing Clostridium difficile infection.

·
  • 1Division of Infectious Diseases, Massachusetts General Hospital, Boston2Harvard Medical School, Boston, Massachusetts3Division of Infectious Diseases, Boston Children’s Hospital, Boston, Massachusetts.
  • 2Harvard Medical School, Boston, Massachusetts4Department of Gastroenterology and Nutrition, Boston Children’s Hospital, Boston, Massachusetts.
  • 3Division of Infectious Diseases, Massachusetts General Hospital, Boston.
  • 4Department of Epidemiology and Preventive Medicine, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
  • 5Harvard Medical School, Boston, Massachusetts6Division of Gastroenterology, Massachusetts General Hospital, Boston.
  • 6Division of Infectious Diseases, Massachusetts General Hospital, Boston2Harvard Medical School, Boston, Massachusetts.

Abstract

IMPORTANCE:

Fecal microbiota transplantation (FMT) has been shown to be effective in treating relapsing or refractory Clostridium difficile infection, but practical barriers and safety concerns have prevented its widespread use.

OBJECTIVE:

To evaluate the safety and rate of resolution of diarrhea following administration of frozen FMT capsules from prescreened unrelated donors to patients with recurrent C. difficile infection.

DESIGN, SETTING, AND PARTICIPANTS:

Open-label, single-group, preliminary feasibility study conducted from August 2013 through June 2014 at Massachusetts General Hospital, Boston. Twenty patients (median age, 64.5 years; range, 11-89 years) with at least 3 episodes of mild to moderate C. difficile infection and failure of a 6- to 8-week taper with vancomycin or at least 2 episodes of severe C. difficile infection requiring hospitalization were enrolled.

INTERVENTIONS:

Healthy volunteers were screened as potential donors and FMT capsules were generated and stored at -80°C (-112°F). Patients received 15 capsules on 2 consecutive days and were followed up for symptom resolution and adverse events for up to 6 months.

MAIN OUTCOMES AND MEASURES:

The primary end points were safety, assessed by adverse events of grade 2 or above, and clinical resolution of diarrhea with no relapse at 8 weeks. Secondary end points included improvement in subjective well-being per standardized questionnaires and daily number of bowel movements.

RESULTS:

No serious adverse events attributed to FMT were observed. Resolution of diarrhea was achieved in 14 patients (70%; 95% CI, 47%-85%) after a single capsule-based FMT. All 6 nonresponders were re-treated; 4 had resolution of diarrhea, resulting in an overall 90% (95% CI, 68%-98%) rate of clinical resolution of diarrhea (18/20). Daily number of bowel movements decreased from a median of 5 (interquartile range [IQR], 3-6) the day prior to administration to 2 (IQR, 1-3) at day 3 (P = .001) and 1 (IQR, 1-2) at 8 weeks (P < .001). Self-ranked health scores improved significantly on a scale of 1 to 10 from a median of 5 (IQR, 5-7) for overall health and 4.5 (IQR, 3-7) for gastrointestinal-specific health on the day prior to FMT to 8 (IQR, 7-9) after FMT administration for both overall and gastrointestinal health (P = .001). Patients needing a second treatment to obtain resolution of diarrhea had lower pretreatment health scores (median, 6.5 [IQR, 5-7.3] vs 5 [IQR, 2.8-5]; P = .02).

CONCLUSIONS AND RELEVANCE:

This preliminary study among patients with relapsing C. difficile infection provides data on adverse events and rates of resolution of diarrhea following administration of FMT using frozen encapsulated inoculum from unrelated donors. Larger studies are needed to confirm these results and to evaluate long-term safety and effectiveness.

JAMA. 2014 Nov 5;312(17):1772-8. doi: 10.1001/jama.2014.13875.

Frozen vs Fresh Fecal Microbiota Transplantation and Clinical Resolution of Diarrhea in Patients With Recurrent Clostridium difficile Infection

·
Christine H. Lee, MD1,2,3; Theodore Steiner, MD4; Elaine O. Petrof, MD5; Marek Smieja, MD, PhD1,2,3; Diane Roscoe, MD6; Anouf Nematallah, MD4; J. Scott Weese, DVM7; Stephen Collins, MBBS8; Paul Moayyedi, MB8; Mark Crowther, MD2,3; Mark J. Ropeleski, MD5; Padman Jayaratne, PhD1,3; David Higgins, MB3; Yingfu Li, PhD9; Neil V. Rau, MD11,12; Peter T. Kim, PhD1,10

Importance  Clostridium difficile infection (CDI) is a major burden in health care and community settings. CDI recurrence is of particular concern because of limited treatment options and associated clinical and infection control issues. Fecal microbiota transplantation (FMT) is a promising, but not readily available, intervention.

Objective  To determine whether frozen-and-thawed (frozen, experimental) FMT is noninferior to fresh (standard) FMT in terms of clinical efficacy among patients with recurrent or refractory CDI and to assess the safety of both types of FMT.

Design, Setting, and Participants  Randomized, double-blind, noninferiority trial enrolling 232 adults with recurrent or refractory CDI, conducted between July 2012 and September 2014 at 6 academic medical centers in Canada.

Interventions  Patients were randomly allocated to receive frozen (n = 114) or fresh (n = 118) FMT via enema.

Main Outcomes and Measures  The primary outcome measures were clinical resolution of diarrhea without relapse at 13 weeks and adverse events. Noninferiority margin was set at 15%.

Results  A total of 219 patients (n = 108 in the frozen FMT group and n = 111 in the fresh FMT group) were included in the modified intention-to-treat (mITT) population and 178 (frozen FMT: n = 91, fresh FMT: n = 87) in the per-protocol population. In the per-protocol population, the proportion of patients with clinical resolution was 83.5% for the frozen FMT group and 85.1% for the fresh FMT group (difference, −1.6% [95% CI, –10.5% to ∞]; P = .01 for noninferiority). In the mITT population the clinical resolution was 75.0% for the frozen FMT group and 70.3% for the fresh FMT group (difference, 4.7% [95% CI, –5.2% to ∞]; P < .001 for noninferiority). There were no differences in the proportion of adverse or serious adverse events between the treatment groups.

Conclusions and Relevance  Among adults with recurrent or refractory CDI, the use of frozen compared with fresh FMT did not result in worse proportion of clinical resolution of diarrhea. Given the potential advantages of providing frozen FMT, its use is a reasonable option in this setting.

JAMA. 2016;315(2):142-149. doi:10.1001/jama.2015.18098.