The Brain-Intestinal Mucosa-Appendix- Microbiome-Brain Loop.

Luis Vitetta,Gemma Vitetta,Sean Hall

doi:10.3390/diseases6020023

Abstract

The brain and the gut are connected from early fetal life. The mother’s exposure to microbial molecules is thought to exert in utero developmental effects on the fetus. These effects could importantly underpin the groundwork for subsequent pathophysiological mechanisms for achieving immunological tolerance and metabolic equilibrium post birth, events that continue through to 3–4 years of age. Furthermore, it is understood that the microbiome promotes cues that instruct the neonate’s mucosal tissues and skin in the language of molecular and cellular biology. Post birth mucosal lymphoid tissue formation and maturation (most probably including the vermiform appendix) is microbiota-encouraged co-establishing the intestinal microbiome with a developing immune system. Intestinal mucosal tissue maturation loops the brain-gut-brain and is postulated to influence mood dispositions via shifts in the intestinal microbiome phyla. A plausible appreciation is that dysregulated pro-inflammatory signals from intestinal resident macrophages could breach the loop by providing adverse mood signals via vagus nerve afferents to the brain. In this commentary, we further suggest that the intestinal resident macrophages act as an upstream traffic controller of translocated microbes and metabolites in order to maintain local neuro-endocrine-immunological equilibrium. When macrophages are overwhelmed through intestinal microbiome and intestinal epithelial cell dysbiosis, pro-inflammatory signals are sustained, which may then lead to mood disorders. The administration of probiotics as an adjunctive medicine co-administered with antidepressant medications in improving depressed mood may have biological and clinical standing.

Highlights

The brain and the gut are connected from early fetal life
A plausible appreciation is that dysregulated pro-inflammatory signals from intestinal resident macrophages could breach the loop by providing adverse mood signals via vagus nerve afferents to the brain
We further suggest that the intestinal resident macrophages act as an upstream traffic controller of translocated microbes and metabolites in order to maintain local neuro-endocrine-immunological equilibrium

Summary

Macrophages and Intestinal Tissue

Both the intestines and the brain develop from the same cluster of embryonic tissue that can be traced back to the primitive streak in early vertebrate fetal growth. In the intestines there is recognized a tripartite co-operation in order to maintain intestinal steady state homeostasis This occurs between the intestinal epithelium barrier, the intestinal microbiome and gut mucosal immune cells such as macrophages [2,7,8]. Intestinal resident macrophages (CX3CR1hi ) are specialized cells that are involved in antigen presentation to T cells that in turn shape the T cell responses generated [11] As such intestinal resident macrophages are important participants in contributing and maintaining the steady state equilibrium of mucosal immunity. This activity induces the expression of IL-10 that in turn further promotes intestinal homeostasis These cumulative actions combine components of the local innate immune system (i.e., macrophages and dendritic cells and others) and the intestinal epithelia in an interaction that preserves a tolerogenic functional steady state [13]. We have reported [36] (as have others [37]) that resistant depression can be accompanied by systemic inflammatory states that are posited to originate from intestinal inflammation and the resultant intestinal dysbiosis

The Vermiform Appendix

Probiotics

Findings

Reprise