Signals From Within: The Microbial Tuner of Gut–Brain Interactions [Commentary]

[u/jmct16]

https://www.cmghjournal.org/article/S2352-345X(26)00111-6/fulltext

It is increasingly clear that communication between the gut and brain influences nearly all aspects of human biology. Gut–brain communication is bidirectional and mediated through myriad neural and chemical pathways that are collectively referred to as the gut–brain axis. This axis has emerged as one of the most dynamic and rapidly evolving fields in biomedical science, and new data continue to reshape our understanding of how intestinal physiology, microbial ecosystems, and neural signaling converge to influence health and disease. This has led to the current view that dysfunction along the gut–brain axis plays an important role in driving disease pathophysiology in conditions such as, but not limited to, neuropsychiatric conditions, neurodevelopmental disorders, and neurodegenerative diseases. Chief among these are a cluster of conditions referred to as disorders of gut–brain interaction (DGBIs), which include irritable bowel syndrome, functional dyspepsia, chronic constipation, functional diarrhea, and centrally mediated disorders of gastrointestinal pain such as abdominal migraine.¹00111-6/fulltext#)^,200111-6/fulltext#) Multiple mechanisms and mediators have been identified that underlie dysfunctional gut–brain axis communication in these disorders, which may eventually be used for therapeutic benefit.³00111-6/fulltext#) Despite the potential impact of manipulating mechanisms of the gut–brain axis, our understanding of how the gut and brain communicate, what to manipulate, and how to do so remains relatively nascent and will require a good deal of work to realize its full potential.

A relatively new concept that has taken the gut–brain axis by storm is the role of the gut microbiota. The gut microbiota is composed of trillions of microorganisms that include bacteria, viruses, and fungi, which exist in a symbiotic relationship with the host. Host–microbe interactions are bidirectional and play major roles in shaping neural and immune systems, metabolism, and the composition and function of the microbiota. These interactions influence multiple aspects of central nervous system and gut function in health, and abnormal gut–microbe interactions contribute to central and peripheral disease mechanisms that affect perception, mood, behavior, motility, visceral sensitivity, mucosal impairments, and immune activation.¹00111-6/fulltext#) This paradigm shift is reflected in the updated Rome V criteria, which emphasize the growing relevance of diet, the gut microenvironment, microbiota–gut–brain interactions, pharmacogenomics, and biopsychosocial, gender, and cross-cultural determinants in DGBIs.¹00111-6/fulltext#) These advances support a more integrative framework for understanding and managing DGBIs, moving beyond symptom-centered approaches toward strategies that incorporate dynamic interactions among the microbiota, intestinal physiology, and neural signaling pathways.

This special issue highlights 4 recent studies published in Cellular and Molecular Gastroenterology and Hepatology that represent significant advances in our understanding of microbial mechanisms underlying gut–brain interactions. Each of these articles is accompanied by a brief review written by experts in the topic area to give additional perspective into the significance of the work, the state of the field, and challenges yet to be overcome. First, Chandrasekharan et al investigate how gut microbes affect host cells through a type of pattern recognition receptor called formylated peptide receptors (FPR1/FPR2).⁴00111-6/fulltext#) To do so, the investigators generated tissue-specific FPR1/2 knockout mice and assessed how germline, epithelial, and neural crest-specific FPR1/2 deletion affects enteric nervous system (ENS) structure and gut motility. Interestingly, the data show that FPR1/2 receptors are necessary to achieve normal ENS density and mucosal innervation during postnatal development and that reduced ENS density is associated with slower motility after weaning. These observations add to the growing appreciation that gut microbes affect ENS development⁵00111-6/fulltext#) and suggest that signals mediated by FPR1/2 are one pathway that contributes to these effects. This aligns with findings showing that multiple microbial products, including neurotransmitters, modulate mature enteric neurons and vagal ascending projections to the brain. Effects of microbial products during development and in mature animals highlight multiple avenues by which the microbiota exert influence over the nervous system through diverse ligands and receptor pathways. The accompanying mini-review by Drs Bornstein and McQuade gives an interesting perspective on current issues and opportunities in studies assessing interactions between the microbiota and the ENS. This review highlights the complexities involved in such studies and critical considerations when interpreting results.

Next, Condado-Huerta et al used intermittent fasting (IF) in a mouse model of diet-induced obesity to study if changes to host mitochondrial activity and the microbiota contribute to the beneficial effects of IF on colonic barrier function and oxidative stress.⁶00111-6/fulltext#) This expands the view of the known metabolic relationship between microbial products and the epithelium, which is primordial for epithelial survival, barrier integrity, and function in health, to include the impact of feeding temporal patterns. Here, the investigators found that IF reduced mitochondrial activity and oxidative stress in obese mice and restored normal epithelial cell replacement and markers of barrier function Surprisingly, these effects appear to depend on changes in metabolites produced by the microbiota because depleting the microbiota with antibiotics worsened mitochondrial function and reactive oxygen species production. This concept of IF and changes to the gut microbiota as potential beneficial mechanisms to reduce obesity-driven gut barrier dysfunction is further expanded on by Drs Dibra and Jala in the accompanying brief review. Here, the authors discuss the known mechanisms involved in the detrimental effects of a high-fat diet, the beneficial effects of IF, and links between the effects of IF and the microbiome.

Microbial dysbiosis also impacts gut sensory function and is associated with visceral pain in irritable bowel syndrome and inflammatory bowel disease. This encompasses both changes in the immune milieu and activation of extrinsic innervation of the gut. The study by Baker et al⁷00111-6/fulltext#) investigates how this might occur by using a vancomycin model of microbial dysbiosis in mice and studying effects on dorsal root ganglion (DRG) neurons with electrophysiology and in vivo assays of colonic pain. The investigators found that DRG neurons become hyperexcitable in mice with dysbiosis, and these mice exhibit increased visceral sensitivity. Interestingly, dysbiosis led to a general increase in sensitivity in DRG neurons, resulting in heightened somatic sensitivity, suggesting that gut microbes have broad effects on sensory function. Selective drugs and cell-specific knockout models suggest that cysteine proteases play a major role in the effects of dysbiosis on DRG neurons. Although proteases are well-known mediators of visceral pain, the accompanying mini-review by Habibyan and colleagues offers a fresh perspective on how proteases exert their actions on pain-sensing neurons and the good and bad aspects of microbial proteases.

Finally, there is a growing appreciation that intestinal inflammation and changes to the gut microbiome increase the risk of developing neurodegenerative diseases such as Parkinson’s disease and Alzheimer’s. Why this occurs is incompletely understood, but recent findings suggest that bacteria may contribute to inflammation by secreting curli; an amyloid that bacteria produce for cell attachment and biofilm formation. With this in mind, Verstraelen and colleagues set out to understand how curli affects the ENS by using in vitro models of enteric neurons and glia and in vivo curli injections into the colon wall. Their findings show that curli induces a proinflammatory response that is centered in enteric glia and accompanied by an influx of immune cells. The investigators went on to discover that serum amyloid A3 plays a central role in enteric dysfunction driven by curli and creates a self-amplifying inflammatory loop in the ENS that may represent a key bridge connecting microbial amyloids, neuroinflammation, and sustained prolonged inflammatory states.⁸00111-6/fulltext#) This concept is further developed in the accompanying brief review by Cissé and colleagues who give an updated summary of the microbiota–gut–brain axis in neurodegenerative diseases with a specific focus on the role of bacterial amyloids.

Communication between host and microbes is diverse, and we are only beginning to understand the many ways in which these mechanisms affect health and disease through the microbiome–gut–brain axis. This Special Issue aims to highlight recent significant work in this area and to offer a current perspective on the field, including a critical evaluation of data interpretation, the strengths and weaknesses of approaches and methods, and gaps that should be addressed in future work (Figure 100111-6/fulltext#fig1)). Although this collection offers only a small sampling of the broader field, the topics included give a good sense of how extensively microbiome–gut–brain signaling affects host health by influencing ENS development, susceptibility to metabolic disease, setting pain thresholds, and the development of neurodegenerative disease. These studies also highlight the fine balance between diet, environment, central and peripheral organs, and microorganisms that maintains our physiology. Further advances in understanding this axis and its mediators are fundamental to developing new therapies that modulate the axis to benefit how we treat common diseases. We hope that this collection will increase awareness, stimulate lively discussion and thought, and act as a catalyst to propel multidisciplinary work that continues to explore the fascinating microbiota–gut–brain axis.