Maria Ines Pinto-Sanchez

Transplantation of fecal microbiota from patients with irritable bowel syndrome alters gut function and behavior in recipient mice

Fecal microbiota transplants from patients with irritable bowel syndrome and anxiety alter gut function and behavior in germ-free mice. Connecting the gut-brain axis Irritable bowel syndrome (IBS), the most common gastrointestinal disorder worldwide, is characterized by abdominal pain and altered gut function and often is accompanied by anxiety. An association between intestinal dysbiosis and IBS has been reported, but the functional relevance remains unknown. De Palma and colleagues colonized germ-free mice with fecal microbiota from healthy controls or IBS patients with diarrhea (IBS-D) who did or did not have anxiety. They demonstrated that transplantation of fecal microbiota from patients with IBS-D and anxiety resulted in altered gut function and behavior in mouse recipients, including faster gastrointestinal transit, low-grade inflammation, and anxiety-like behavior. Irritable bowel syndrome (IBS) is a common disorder characterized by altered gut function and often is accompanied by comorbid anxiety. Although changes in the gut microbiota have been documented, their relevance to the clinical expression of IBS is unknown. To evaluate a functional role for commensal gut bacteria in IBS, we colonized germ-free mice with the fecal microbiota from healthy control individuals or IBS patients with diarrhea (IBS-D), with or without anxiety, and monitored gut function and behavior in the transplanted mice. Microbiota profiles in recipient mice clustered according to the microbiota profiles of the human donors. Mice receiving the IBS-D fecal microbiota showed a taxonomically similar microbial composition to that of mice receiving the healthy control fecal microbiota. However, IBS-D mice showed different serum metabolomic profiles. Mice receiving the IBS-D fecal microbiota, but not the healthy control fecal microbiota, exhibited faster gastrointestinal transit, intestinal barrier dysfunction, innate immune activation, and anxiety-like behavior. These results indicate the potential of the gut microbiota to contribute to both intestinal and behavioral manifestations of IBS-D and suggest the potential value of microbiota-directed therapies in IBS patients.

Anxiety and Depression Increase in a Stepwise Manner in Parallel With Multiple FGIDs and Symptom Severity and Frequency.

Objectives:Anxiety and depression occur frequently in patients with functional gastrointestinal disorders (FGIDs), but their precise prevalence is unknown. We addressed this issue in a large cohort of adult patients and determined the underlying factors.Methods:In total, 4,217 new outpatients attending 2 hospitals in Hamilton, Ontario, Canada completed questionnaires evaluating FGIDs and anxiety and depression (Hospital Anxiety and Depression scale). Chart review was performed in a random sample of 2,400 patients.Results:Seventy-six percent of patients fulfilled Rome III criteria for FGIDs, but only 57% were diagnosed with FGIDs after excluding organic diseases, and the latter group was considered for the analysis. Compared with patients not meeting the criteria, prevalence of anxiety (odds ratio (OR) 2.66, 95% confidence interval (CI): 1.62–4.37) or depression (OR 2.04, 95% CI: 1.03–4.02) was increased in patients with FGIDs. The risk was comparable to patients with organic disease (anxiety: OR 2.12, 95% CI: 1.24–3.61; depression: OR 2.48, 95% CI: 1.21–5.09). The lowest prevalence was observed in asymptomatic patients (OR 1.37; 95% CI 0.58–3.23 and 0.51; 95% CI 0.10–2.48; for both conditions, respectively). The prevalence of anxiety and depression increased in a stepwise manner with the number of co-existing FGIDs and frequency and/or severity of gastrointestinal (GI) symptoms. Psychiatric comorbidity was more common in females with FGIDs compared with males (anxiety OR 1.73; 95% CI 1.35–2.28; depression OR 1.52; 95% CI 1.04–2.21). Anxiety and depression were formally diagnosed by the consulting physician in only 22% and 9% of patients, respectively.Conclusions:Psychiatric comorbidity is common in patients referred to a secondary care center but is often unrecognized. The prevalence of both anxiety and depression is influenced by gender, presence of organic diseases, and FGIDs, and it increases with the number of coexistent FGIDs and frequency and severity of GI symptoms.

Ecobiotherapy Rich in Firmicutes Decreases Susceptibility to Colitis in a Humanized Gnotobiotic Mouse Model.

Background:Alterations in the intestinal microbiota, characterized by depletion of anti-inflammatory bacteria, such as Firmicutes, in patients with ulcerative colitis (UC) have prompted interest in microbiota-modulating strategies for this condition. The aim of this study was to evaluate the role of fecal and synthetic human microbial ecosystems, low or enriched in Firmicutes, on colitis susceptibility and host immune responses. Methods:The microbiota of selected healthy and UC human donors was characterized by culture method and 16S rRNA-based sequencing. Germ-free mice were colonized with fecal or a synthetic ecosystem enriched (healthy donors) or low (UC donors) in Firmicutes. Experimental colitis was induced using dextran sodium sulfate. Colon transcriptome and colon lamina propria cells were evaluated in mice postcolonization by RNA-seq and flow cytometry, respectively, and T helper (TH) 17 differentiation was assessed in vitro. Results:Mice colonized with microbiota from patients with UC low in Firmicutes had increased sensitivity to colitis compared with mice colonized with fecal or synthetic ecosystems rich in Firmicutes. Microbiota low in Firmicutes increased expression of TH17-related genes and expansion of interleukin-17A–expressing CD4+ cells in vivo. Supplementation with bacterial isolates belonging to the Firmicutes phylum abrogated the heightened TH17 responses in vitro. Conclusions:A microbiota rich in Firmicutes derived from fecal samples of a healthy human donor, or assembled synthetically, downregulated colonic inflammation and TH17 pathways in mice. The results support the use of ecobiotherapy strategies, enriched in Firmicutes, for the prevention or treatment of UC.

Extraintestinal Manifestations of Celiac Disease

Case finding for celiac disease (CD) is becoming increasingly common practice and is conducted in a wide range of clinical situations ranging from the presence of gastrointestinal symptoms to failure to thrive in children, prolonged fatigue, unexpected weight loss and anemia. Case finding is also performed in associated conditions, such as autoimmune thyroid disease, dermatitis herpetiformis and type 1 diabetes, as well as in patients with irritable bowel syndrome, unexplained neuropsychiatric disorders and first-degree relatives of patients with diagnosed CD. This aggressive active case finding has dramatically changed the clinical characteristics of newly diagnosed patients. For instance, higher numbers of patients who present with extraintestinal symptoms are now being diagnosed with CD. Current recommendations state that due to a high risk for complications if the disease remains undiagnosed, patients with extraintestinal symptoms due to CD require appropriate diagnosis and treatment. Despite criticism regarding the cost-effectiveness of case finding in CD, such an aggressive approach has been considered cost-effective for high-risk patients. The diagnosis of CD among patients with extraintestinal symptoms requires a high degree of awareness of the clinical conditions that carry a high risk for underlying CD. Also, understanding the correct use of specific serology and duodenal histology is key for an appropriate diagnostic approach. Both procedures combined are able to confirm diagnosis in the vast majority of cases. However, in certain circumstances, serology and even duodenal histology cannot confirm or rule out CD. A common cause of negative IgA serology is IgA deficiency. For such eventuality, IgG-based serological tests can help confirm the diagnosis. Importantly, some histologically diagnosed cases still remain seronegative despite exclusion of IgA deficiency. On the other hand, duodenal histology may be normal despite the presence of CD-specific antibodies and active CD. This has been clearly demonstrated in some cases of untreated dermatitis herpetiformis, but may also be due to the patchy condition of CD or lesions that are not adequately recognized by nonexpert endoscopists and/or pathologists. The effectiveness of agluten-free diet depends on the clinical end point addressed. A good example is the outcome of bone loss. While risk for fracture normalizes after the first year of dietary treatment, bone parameters measured by densitometry may not be normalized in the long-term follow-up. Moreover, it is still unclear how far an early gluten-free diet will positively affect associated autoimmune diseases like type 1 diabetes and autoimmune thyroiditis.

Dietary Triggers in Irritable Bowel Syndrome: Is There a Role for Gluten?

A tight link exists between dietary factors and irritable bowel syndrome (IBS), one of the most common functional syndromes, characterized by abdominal pain/discomfort, bloating and alternating bowel habits. Amongst the variety of foods potentially evoking “food sensitivity”, gluten and other wheat proteins including amylase trypsin inhibitors represent the culprits that recently have drawn the attention of the scientific community. Therefore, a newly emerging condition termed non-celiac gluten sensitivity (NCGS) or non-celiac wheat sensitivity (NCWS) is now well established in the clinical practice. Notably, patients with NCGS/NCWS have symptoms that mimic those present in IBS. The mechanisms by which gluten or other wheat proteins trigger symptoms are poorly understood and the lack of specific biomarkers hampers diagnosis of this condition. The present review aimed at providing an update to physicians and scientists regarding the following main topics: the experimental and clinical evidence on the role of gluten/wheat in IBS; how to diagnose patients with functional symptoms attributable to gluten/wheat sensitivity; the importance of double-blind placebo controlled cross-over trials as confirmatory assays of gluten/wheat sensitivity; and finally, dietary measures for gluten/wheat sensitive patients. The analysis of current evidence proposes that gluten/wheat sensitivity can indeed represent a subset of the broad spectrum of patients with a clinical presentation of IBS.

Bifidobacterium infantis NLS Super Strain Reduces the Expression of α-Defensin-5, a Marker of Innate Immunity, in the Mucosa of Active Celiac Disease Patients.

Background: We have previously shown a reduction of gastrointestinal symptoms after the oral administration of Bifidobacterium infantis Natren Life Start super strain (NLS-SS) in untreated celiac disease (CD) patients. The symptomatic improvement was not associated with changes in intestinal permeability or serum levels of cytokines, chemokines, or growth factors. Therefore, we hypothesized that the beneficial symptomatic effect observed previously in patients with CD treated with B. infantis may be related to the modulation of innate immunity. Goals: To investigate the potential mechanisms of a probiotic B. infantis Natren Life Start super strain on the mucosal expression of innate immune markers in adult patients with active untreated CD compared with those treated with B. infantis×6 weeks and after 1 year of gluten-free diet (GFD). Methods: Numbers of macrophages and Paneth cells and &agr;-defensin-5 expression were assessed by immunohistochemistry in duodenal biopsies. Results: We showed that GFD decreases duodenal macrophage counts in CD patients more effectively than B. infantis. In contrast, B. infantis decreases Paneth cell counts and expression of &agr;-defensin-5 in CD (P<0.001). Conclusions: The results identify differential innate immune effects of treatment with B. infantis compared with 1 year of GFD. Further studies are needed to investigate synergistic effects of GFD and B. infantis supplementation in CD.

Should ESPGHAN Guidelines for Serologic Diagnosis of Celiac Disease be Used in Adults? A Prospective Analysis in an Adult Patient Cohort With High Pretest Probability

Should ESPGHAN Guidelines for Serologic Diagnosis of Celiac Disease be Used in Adults? A Prospective Analysis in an Adult Patient Cohort With High Pretest Probability

Derivation and validation of a diagnostic test for irritable bowel syndrome using latent class analysis

The accuracy of symptom‐based diagnostic criteria for irritable bowel syndrome (IBS) is modest.

Motility alterations in celiac disease and non-celiac gluten sensitivity.

Regulation of gut motility is complex and involves neuromuscular, immune and environmental mechanisms. It is well established that patients with celiac disease (CD) often display gut dysmotility. Studies have shown the presence of disturbed esophageal motility, altered gastric emptying, and dysmotility of the small intestine, gallbladder and colon in untreated CD. Most of these motor abnormalities resolve after a strict gluten-free diet, suggesting that mechanisms related to the inflammatory condition and disease process are responsible for the motor dysfunction. Motility abnormalities are also a hallmark of functional bowel disorders such as irritable bowel syndrome (IBS), where it has been proposed as underlying mechanism for symptom generation (diarrhea, constipation, bloating). Non-celiac gluten sensitivity (NCGS) is a poorly defined entity, mostly self-diagnosed, that presents clinically with IBS symptoms in the absence of specific celiac markers. Patients with NCGS are believed to react symptomatically to wheat components, and some studies have proposed the presence of low-grade inflammation in these patients. There is little information regarding the functional characterization of these patients before and after a gluten-free diet. A study suggested the presence of altered gastrointestinal transit in NCGS patients who also have a high prevalence of nonspecific anti-gliadin antibodies. Results of an ongoing clinical study in NCGS patients with positive anti-gliadin antibodies before and after a gluten-free diet will be discussed. Elucidating the mechanisms for symptom generation in NCGS patients is important to find new therapeutic alternatives to the burden of imposing a strict gluten-free diet in patients who do not have CD.

Poor predictive value of lower gastrointestinal alarm features in the diagnosis of colorectal cancer in 1981 patients in secondary care

Clinicians are advised to refer patients with lower gastrointestinal (GI) alarm features for urgent colonoscopy to exclude colorectal cancer (CRC). However, the utility of alarm features is debated.