The gastrointestinal epithelium forms the boundary between the body and external environment. It effectively provides a selective permeable barrier that limits the permeation of luminal noxious molecules, such as pathogens, toxins, and antigens, while allowing the appropriate absorption of nutrients and water. This selective permeable barrier is achieved by intercellular tight junction (TJ) structures, which regulate paracellular permeability. Disruption of the intestinal TJ barrier, followed by permeation of luminal noxious molecules, induces a perturbation of the mucosal immune system and inflammation, and can act as a trigger for the development of intestinal and systemic diseases. In this context, much effort has been taken to understand the roles of extracellular factors, including cytokines, pathogens, and food factors, for the regulation of the intestinal TJ barrier. Here, I discuss the regulation of the intestinal TJ barrier together with its implications for the pathogenesis of diseases.

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Regulation of intestinal epithelial permeability by tight junctions

https://www.zora.uzh.ch/id/eprint/187509/1/PIIS2213858720301522.pdf

Practical recommendations for the management of diabetes in patients with COVID-19.

A fundamental function of the intestinal epithelium is to act as a barrier that limits interactions between luminal contents such as the intestinal microbiota, the underlying immune system and the remainder of the body, while supporting vectorial transport of nutrients, water and waste products. Epithelial barrier function requires a contiguous layer of cells as well as the junctions that seal the paracellular space between epithelial cells. Compromised intestinal barrier function has been associated with a number of disease states, both intestinal and systemic. Unfortunately, most current clinical data are correlative, making it difficult to separate cause from effect in interpreting the importance of barrier loss. Some data from experimental animal models suggest that compromised epithelial integrity might have a pathogenic role in specific gastrointestinal diseases, but no FDA-approved agents that target the epithelial barrier are presently available. To develop such therapies, a deeper understanding of both disease pathogenesis and mechanisms of barrier regulation must be reached. Here, we review and discuss mechanisms of intestinal barrier loss and the role of intestinal epithelial barrier function in pathogenesis of both intestinal and systemic diseases. We conclude with a discussion of potential strategies to restore the epithelial barrier.

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The intestinal epithelial barrier: a therapeutic target?

A recent study using a rat model found significant differences at the time of diabetes onset in the bacterial communities responsible for type 1 diabetes modulation. We hypothesized that type 1 diabetes in humans could also be linked to a specific gut microbiota. Our aim was to quantify and evaluate the difference in the composition of gut microbiota between children with type 1 diabetes and healthy children and to determine the possible relationship of the gut microbiota of children with type 1 diabetes with the glycemic level. A case-control study was carried out with 16 children with type 1 diabetes and 16 healthy children. The fecal bacteria composition was investigated by polymerase chain reaction-denaturing gradient gel electrophoresis and real-time quantitative polymerase chain reaction. The mean similarity index was 47.39% for the healthy children and 37.56% for the children with diabetes, whereas the intergroup similarity index was 26.69%. In the children with diabetes, the bacterial number of Actinobacteria and Firmicutes, and the Firmicutes to Bacteroidetes ratio were all significantly decreased, with the quantity of Bacteroidetes significantly increased with respect to healthy children. At the genus level, we found a significant increase in the number of Clostridium, Bacteroides and Veillonella and a significant decrease in the number of Lactobacillus, Bifidobacterium, Blautia coccoides/Eubacterium rectale group and Prevotella in the children with diabetes. We also found that the number of Bifidobacterium and Lactobacillus, and the Firmicutes to Bacteroidetes ratio correlated negatively and significantly with the plasma glucose level while the quantity of Clostridium correlated positively and significantly with the plasma glucose level in the diabetes group. This is the first study showing that type 1 diabetes is associated with compositional changes in gut microbiota. The significant differences in the number of Bifidobacterium, Lactobacillus and Clostridium and in the Firmicutes to Bacteroidetes ratio observed between the two groups could be related to the glycemic level in the group with diabetes. Moreover, the quantity of bacteria essential to maintain gut integrity was significantly lower in the children with diabetes than the healthy children. These findings could be useful for developing strategies to control the development of type 1 diabetes by modifying the gut microbiota.

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Gut microbiota in children with type 1 diabetes differs from that in healthy children: a case-control study

The gastrointestinal (GI) microbiota is the collection of microbes which reside in the GI tract and represents the largest source of non-self antigens in the human body. The GI tract functions as a major immunological organ as it must maintain tolerance to commensal and dietary antigens while remaining responsive to pathogenic stimuli. If this balance is disrupted, inappropriate inflammatory processes can result, leading to host cell damage and/or autoimmunity. Evidence suggests that the composition of the intestinal microbiota can influence susceptibility to chronic disease of the intestinal tract including ulcerative colitis, Crohn’s disease, celiac disease and irritable bowel syndrome, as well as more systemic diseases such as obesity, type 1 diabetes and type 2 diabetes. Interestingly, a considerable shift in diet has coincided with increased incidence of many of these inflammatory diseases. It was originally believed that the composition of the intestinal microbiota was relatively stable from early childhood; however, recent evidence suggests that diet can cause dysbiosis, an alteration in the composition of the microbiota, which could lead to aberrant immune responses. The role of the microbiota and the potential for diet-induced dysbiosis in inflammatory conditions of the GI tract and systemic diseases will be discussed.

https://www.mdpi.com/2072-6643/4/8/1095/pdf

Diet-Induced Dysbiosis of the Intestinal Microbiota and the Effects on Immunity and Disease

Aims/hypothesis
Recent observations have shown subclinical intestinal abnormalities in human type 1 diabetes. Whether these are related to the pathogenetic process or secondary to the diabetes remains to be clarified. The aim of this study was to investigate this issue by examining intestinal permeability to sugars in subjects at different stages of type 1 diabetes: preclinical, new-onset and long-term established disease.

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Increased intestinal permeability precedes clinical onset of type 1 diabetes.

Analyze the relationship between obesity and influenza. Basal hormone milieu, defective response of both innate and adaptive immune system and sedentariness are major determinants in the severity of influenza viral infection in obese patients. Being overweight not only increases the risk of infection and of complications for the single obese person, but a large prevalence of obese individuals within the population might increase the chance of appearance of more virulent viral strain, prolongs the virus shedding throughout the total population and eventually might increase overall mortality rate of an influenza pandemic. Waiting for the development of a vaccination against COVID-19, isolation of positive cases and social distancing are the primary interventions. Nonetheless, evidence from previous influenza pandemics suggests the following interventions aimed at improving immune response: (1) lose weight with a mild caloric restriction; (2) include AMPK activators and PPAR gamma activators in the drug treatment for obesity associated with diabetes; and (3) practice mild-to-moderate physical exercise. Due to prolonged viral shedding, quarantine in obese subjects should likely be longer than normal weight individuals.

https://link.springer.com/content/pdf/10.1007/s00592-020-01522-8.pdf

Influenza and obesity: its odd relationship and the lessons for COVID-19 pandemic.

To characterize the clinical signature and etiopathogenetic factors of diabetes associated with pancreas disease [type 3 diabetes mellitus (T3cDM)]. To estimate incidence and identify predictors of both diabetes onset and remission after pancreatic surgery. A prospective observational study was conducted. From January 2008 to December 2012, patients (n = 651) with new diagnosis of pancreatic disease admitted to the Pancreatic Surgery Unit of the San Raffaele Scientific Institute were evaluated. Hospital and/or outpatient medical records were reviewed. Blood biochemical values including fasting blood glucose, insulin and/or C-peptide, glycosylated hemoglobin and anti-islet antibodies were determined. Diabetes onset was assessed after surgery and during follow-up. At baseline, the prevalence of diabetes was 38 % (age of onset 64 ± 11 years). In most cases, diabetes occurred within 48 months from pancreatic disease diagnosis. Among different pancreatic diseases, minor differences were observed in diabetes characteristics, with the exception of the prevalence. Diabetes appeared associated with classical risk factors for type 2 diabetes (i.e., age, sex, family history of diabetes and body mass index), and both beta-cell dysfunction and insulin resistance appeared relevant determinants. The prevalence of adult-onset autoimmune diabetes was as previously reported within type 2 diabetes. Within a few days after surgery, either diabetes remission or new-onset diabetes was observed. In patients with pancreatic cancer, no difference in diabetes remission was observed after palliative or resective surgery. Classical risk factors for type 2 diabetes were associated with the onset of diabetes after surgery. T3cDM appeared as a heterogeneous entity strongly overlapped with type 2 diabetes.

Clinical signature and pathogenetic factors of diabetes associated with pancreas disease (T3cDM): a prospective observational study in surgical patients

Maria Grazia Radaelli

Papers

Increased intestinal permeability precedes clinical onset of type 1 diabetes.

Influenza and obesity: its odd relationship and the lessons for COVID-19 pandemic.

Clinical signature and pathogenetic factors of diabetes associated with pancreas disease (T3cDM): a prospective observational study in surgical patients