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The process of wound repair in epithelium-lined organs of mammals is complex and is influenced by numerous secreted factors including cytokines, growth factors, and chemokines. However, the cellular organizers of this process are still not understood. Recent studies of tissue regeneration in organisms with simpler development have uncovered details about the activity of stem cells in the mesenchyme (the blastema) during this process. These blastemal cells are well positioned to interpret cues from the environment and to execute decisions about the direction of wound repair. In mammalian wounds, stromal stem cells appear to be positioned to perform functions similar to those of blastemal cells, including communication with both the overlying epithelium and the inflammatory cells in the mesenchyme.

Associations between the dynamic community of microbes (the microbiota) and the host they colonize appear to be vital for ensuring host health. Microbe-host communication is actively maintained across physiological barriers of various body sites and is mediated by a range of bidirectional secreted proteins and small molecules. So far, a range of “omics” methods have succeeded in revealing the multiplicity of associations between members of a microbiota and a wide range of host processes and diseases. Although these advances point to possibilities for treating disease, there has not been much translational success thus far. We know little about which organisms are key contributors to host health, the importance of strain differences, and the activities of much of the chemical “soup” that is produced by the microbiota. Adding to this complexity are emerging hints of the role of interkingdom interactions between bacteria, phages, protozoa, and/or fungi in regulating the microbiota-host interactions. Functional approaches, although experimentally challenging, could be the next step to unlocking the power of the microbiota. [ABSTRACT FROM AUTHOR]

Dietary modulation of T cell immunity: Commensal intestinal bacteria respond to dietary changes by modifying gene expression, leading to shifts in the levels of bacterial antigens encountered by the intestinal immune system. Wegorzewska et al. developed a mouse model system to investigate whether CD4+ T cell recognition of protein antigens of the gut symbiont Bacteroides thetaiotaomicron is subject to dietary modulation. TCR transgenic T cells for an outer membrane vesicle protein differentiated into both regulatory and effector T cells, with colitis emerging after selective regulatory T cell depletion. Dietary glucose was observed to strongly repress the T cell–detected antigen. These findings suggest that dietary modifications that reduce expression of immunodominant antigens targeted by T cells could help ameliorate some forms of human inflammatory bowel disease. T cell responses to symbionts in the intestine drive tolerance or inflammation depending on the genetic background of the host. These symbionts in the gut sense the available nutrients and adapt their metabolic programs to use these nutrients efficiently. Here, we ask whether diet can alter the expression of a bacterial antigen to modulate adaptive immune responses. We generated a CD4+ T cell hybridoma, BθOM, specific for Bacteroides thetaiotaomicron (B. theta). Adoptively transferred transgenic T cells expressing the BθOM TCR proliferated in the colon, colon-draining lymph node, and spleen in B. theta–colonized healthy mice and differentiated into regulatory T cells (Tregs) and effector T cells (Teffs). Depletion of B. theta–specific Tregs resulted in colitis, showing that a single protein expressed by B. theta can drive differentiation of Tregs that self-regulate Teffs to prevent disease. We found that BθOM T cells recognized a peptide derived from a single B. theta protein, BT4295, whose expression is regulated by nutrients, with glucose being a strong catabolite repressor. Mice fed a high-glucose diet had a greatly reduced activation of BθOM T cells in the colon. These studies establish that the immune response to specific bacterial antigens can be modified by changes in the diet by altering antigen expression in the microbe. [ABSTRACT FROM AUTHOR]

Specific gut commensal bacteria improve host health by eliciting mutualistic regulatory T (Treg) cell responses. However, the bacteria that induce effector T (Teff) cells during inflammation are unclear. We addressed this by analyzing bacterial-reactive T cell receptor (TCR) transgenic cells and TCR repertoires in a murine colitis model. Unexpectedly, we found that mucosal-associated Helicobacter species triggered both Treg cell responses during homeostasis and Teff cell responses during colitis, as suggested by an increased overlap between the Teff/Treg TCR repertoires with colitis. Four of six Treg TCRs tested recognized mucosal-associated Helicobacter species in vitro and in vivo. By contrast, the marked expansion of luminal Bacteroides species seen during colitis did not trigger a commensurate Teff cell response. Unlike other Treg cell–inducing bacteria, Helicobacter species are known pathobionts and cause disease in immunodeficient mice. Thus, our study suggests a model in which mucosal bacteria elicit context-dependent Treg or Teff cell responses to facilitate intestinal tolerance or inflammation. [ABSTRACT FROM AUTHOR]

The article discusses research which examined the effects of a gut pathobiont in a gnotobiotic mouse model of childhood malnutrition in Bangladesh. Topics discussed include the causal relation of enterotoxigenetic Bacteroides fragilis strain (ETBF) to weight loss, relation of the phenotype with derangements in host energy metabolism manifested by impaired tricarboxylic acid cycle activity and nontoxigenic strains of Bacteroides fragilis (NTBF) mitigating the effects of ETBF on transcriptomes.

The article focuses on a research on producing diet-dependent enteropathy by functional characterization of IgA-targeted bacterial taxa from undernourished Malawian children. Topics discussed include analysis of bacterial strains targeted by immunoglobulin A (IgA) from the fecal microbiota of Malawian infants and children; etiologic, diagnostic, and therapeutic implications of bacterial targets of IgA responses for childhood undernutrition; and relationship between IgA responses and growth.

SERPINE1/PAI-1 is elevated in the colon tissue of the most difficult-to-treat patients with IBD and leads to worsening of experimental colitis. A punch to the gut by PAI-1: Only a fraction of patients with inflammatory bowel disease (IBD) respond to therapy. To look for pathways that could distinguish difficult-to-treat patients, Kaiko et al. examined transcriptomic datasets from cohorts of patients with IBD. They found that genes normally associated with the coagulation pathway were increased in those with severe disease. These genes intersected clusters of inflammatory myeloid cells and epithelial cells, two cell types that closely interact. One player of the coagulation pathway, PAI-1, exacerbated mucosal damage in mouse colitis models. Pharmacologic inhibition of PAI-1 alleviated symptoms in these models. Their results highlight this previously unappreciated axis in mucosal wounding in IBD and could open up new avenues of treatment for patients refractory to other biologics. There is a major unmet clinical need to identify pathways in inflammatory bowel disease (IBD) to classify patient disease activity, stratify patients that will benefit from targeted therapies such as anti–tumor necrosis factor (TNF), and identify new therapeutic targets. In this study, we conducted global transcriptome analysis to identify IBD-related pathways using colon biopsies, which highlighted the coagulation gene pathway as one of the most enriched gene sets in patients with IBD. Using this gene-network analysis across 14 independent cohorts and 1800 intestinal biopsies, we found that, among the coagulation pathway genes, plasminogen activator inhibitor-1 (PAI-1) expression was highly enriched in active disease and in patients with IBD who did not respond to anti-TNF biologic therapy and that PAI-1 is a key link between the epithelium and inflammation. Functionally, PAI-1 and its direct target, the fibrinolytic protease tissue plasminogen activator (tPA), played an important role in regulating intestinal inflammation. Intestinal epithelial cells produced tPA, which was protective against chemical and mechanical-mediated colonic injury in mice. In contrast, PAI-1 exacerbated mucosal damage by blocking tPA-mediated cleavage and activation of anti-inflammatory TGF-β, whereas the inhibition of PAI-1 reduced both mucosal damage and inflammation. This study identifies an immune-coagulation gene axis in IBD where elevated PAI-1 may contribute to more aggressive disease. [ABSTRACT FROM AUTHOR]

The article discusses the role of the noncanonical Wnt ligand Wnt5a in the regeneration of stem cell-containing colonic epithelial crypts of Lieberkühn in the wound repair and restoration of homeostasis following intestinal injury. Particular focus is given to the activation of transforming growth factor-β (TGF-β) signalling by Wnt5a. The researchers found that Wnt5a inhibited the proliferation of colonic intestinal epithelial stem cells and that crypts were generated from existing crypts near the wound.

Associations between the dynamic community of microbes (the microbiota) and the host they colonize appear to be vital for ensuring host health. Microbe-host communication is actively maintained across physiological barriers of various body sites and is mediated by a range of bidirectional secreted proteins and small molecules. So far, a range of "omics" methods have succeeded in revealing the multiplicity of associations between members of a microbiota and a wide range of host processes and diseases. Although these advances point to possibilities for treating disease, there has not been much translational success thus far. We know little about which organisms are key contributors to host health, the importance of strain differences, and the activities of much of the chemical "soup" that is produced by the microbiota. Adding to this complexity are emerging hints of the role of interkingdom interactions between bacteria, phages, protozoa, and/or fungi in regulating the microbiota-host interactions. Functional approaches, although experimentally challenging, could be the next step to unlocking the power of the microbiota.