Almost half the cells and 1% of the unique genes found in our bodies are human, the rest are from microbes, predominantly bacteria, archaea, fungi, and viruses. These microorganisms collectively form ...the human microbiota, with most colonizing the gut. Recent technological advances, open access data libraries, and application of high‐throughput sequencing have allowed these microbes to be identified and their contribution to neurological health to be examined. Emerging evidence links perturbations in the gut microbiota to neurological disease, including disease risk, activity, and progression. This review provides an overview of the recent advances in microbiome research in relation to neuro(auto)immune and neurodegenerative conditions affecting humans, such as multiple sclerosis, neuromyelitis optica spectrum disorders, Parkinson disease, Alzheimer disease, Huntington disease, and amyotrophic lateral sclerosis. Study design and terminology used in this rapidly evolving, highly multidisciplinary field are summarized to empower and engage the neurology community in this “newly discovered organ.” Ann Neurol 2017;81:369–382
Nonalcoholic fatty liver disease (NAFLD) is a chronic condition affecting one quarter of the global population. Although primarily linked to obesity and metabolic syndrome, undernutrition and the ...altered (dysbiotic) gut microbiome influence NAFLD progression. Both undernutrition and NAFLD prevalence are predicted to considerably increase, but how the undernourished gut microbiome contributes to hepatic pathophysiology remains far less studied. Here, we present undernutrition conditions with fatty liver features, including kwashiorkor and micronutrient deficiency. We then review the gut microbiota-liver axis, highlighting key pathways linked to NAFLD progression within both overnutrition and undernutrition. To conclude, we identify challenges and collaborative possibilities of emerging multiomic research addressing the pathology and treatment of undernourished NAFLD.
Summary
The concept of a gut microbiota–brain axis has emerged to describe the complex and continuous signalling between the gut microbiota and host nervous system. This review examines key ...microbial‐derived neuromodulators and structural components that comprise the gut microbiota–brain axis. To conclude, we briefly identify current challenges in gut microbiota–brain research and suggest a framework to characterize these interactions. Here, we propose five emerging hallmarks of the gut microbiota–brain axis: (i) Indistinguishability, (ii) Emergence, (iii) Bidirectional Signalling, (iv) Critical Window Fluidity and (5) Neural Homeostasis.
Despite clinical advances, chemotherapy largely fails in metastatic cancers. Commensal bacteria can indicate chemotherapy efficacy. In a recent issue of Nature, Tintelnot et al.1 demonstrate that ...bacterial metabolite 3-IAA amplifies chemotherapy outcomes via autophagy pathways in metastatic pancreatic ductal adenocarcinoma.
Despite clinical advances, chemotherapy largely fails in metastatic cancers. Commensal bacteria can indicate chemotherapy efficacy. In a recent issue of Nature, Tintelnot et al.1 demonstrate that bacterial metabolite 3-IAA amplifies chemotherapy outcomes via autophagy pathways in metastatic pancreatic ductal adenocarcinoma.
Does exploration of the gut microbiota–brain axis expand our understanding of what it means to be human? Recognition and conceptualization of a gut microbiota–brain axis challenges our study of the ...nervous system. Here, integrating gut microbiota–brain research into the metaorganism model is proposed. The metaorganism—an expanded, dynamic unit comprising the host and commensal organisms—asserts a radical blurring between man and microbe. The metaorganism nervous system interacts with the exterior world through microbial‐colored lenses. Ongoing studies have reported that gut microbes contribute to brain function and pathologies, even shaping higher neurological functions. How will continued collaborative efforts (e.g., between neurobiology and microbiology), including partnerships with the arts (e.g., philosophy), contribute to the knowledge of microbe‐to‐mind interactions? While this is not a systemic review, this nascent field is briefly described, highlighting ongoing challenges and recommendations for emerging gut microbiota–brain research. Also see the video here https://youtu.be/lP9gOW8StXg.
The gut microbiota–brain axis expands our concept of the human nervous system. Gut microbes influence brain development and function. These findings support a metaorganism framework, which examines host–microbe interactions as a single, interdependent unit. The authors affirm an interdisciplinary approach (advocating collaboration with the arts) to explore our gut–brain connection.
Non-alcoholic steatohepatitis (NASH) represents the fastest growing underlying cause of hepatocellular carcinoma (HCC) and has been shown to impact immune effector cell function. The standard of care ...for the treatment of advanced HCC is immune checkpoint inhibitor (ICI) therapy, yet NASH may negatively affect the efficacy of ICI therapy in HCC. The immunologic mechanisms underlying the impact of NASH on ICI therapy remain unclear.
Herein, using multiple murine NASH models, we analysed the influence of NASH on the CD8+ T-cell-dependent anti-PD-1 responses against liver cancer. We characterised CD8+ T cells’ transcriptomic, functional, and motility changes in mice receiving a normal diet (ND) or a NASH diet.
NASH blunted the effect of anti-PD-1 therapy against liver cancers in multiple murine models. NASH caused a proinflammatory phenotypic change of hepatic CD8+ T cells. Transcriptomic analysis revealed changes related to NASH-dependent impairment of hepatic CD8+ T-cell metabolism. In vivo imaging analysis showed reduced motility of intratumoural CD8+ T cells. Metformin treatment rescued the efficacy of anti-PD-1 therapy against liver tumours in NASH.
We discovered that CD8+ T-cell metabolism is critically altered in the context of NASH-related liver cancer, impacting the effectiveness of ICI therapy – a finding which has therapeutic implications in patients with NASH-related liver cancer.
Non-alcoholic steatohepatitis represents the fastest growing cause of hepatocellular carcinoma. It is also associated with reduced efficacy of immunotherapy, which is the standard of care for advanced hepatocellular carcinoma. Herein, we show that non-alcoholic steatohepatitis is associated with impaired motility, metabolic function, and response to anti-PD-1 treatment in hepatic CD8+ T cells, which can be rescued by metformin treatment.
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•Multiple murine models of NASH-HCC show CD8+ T-cell-dependent resistance to ICI therapy.•Correlative transcriptomic analysis of hepatic CD8+ T cells revealed NASH-induced mitochondrial aberrations.•Although hepatic CD8+ T cells are activated in NASH mice, they have impaired motility and mitochondrial fitness.•NASH may diminish the efficacy of ICI therapy in patients with HCC.•Metformin can salvage ICI therapy and CD8+ T-cell activity in tumour-bearing NASH mice.
Immunoglobulin (Ig) A controls host-microbial homeostasis in the gut. IgA recognition of beneficial bacteria is decreased in acutely undernourished children, but the factors driving these changes in ...IgA targeting are unknown. Child undernutrition is a global health challenge that is exacerbated by poor sanitation and intestinal inflammation. To understand how nutrition impacts immune-microbe interactions, we used a mouse model of undernutrition with or without fecal-oral exposure and assessed IgA-bacterial targeting from weaning to adulthood. In contrast to healthy control mice, undernourished mice fail to develop IgA recognition of intestinal Lactobacillus. Glycan-mediated interactions between Lactobacillus and host antibodies are lost in undernourished mice due to rapid bacterial adaptation. Lactobacillus adaptations occur in direct response to nutritional pressure, independently of host IgA, and are associated with reduced mucosal colonization and with bacterial mutations in carbohydrate processing genes. Together these data indicate that diet-driven bacterial adaptations shape IgA recognition in the gut.
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•Dietary undernutrition in mice abolishes IgA targeting of intestinal Lactobacillus•Loss of this targeting is the result of bacterial adaptations to nutrient limitation•Lactobacillus-IgA interactions are glycan mediated and linked to sugar metabolism genes
In this paper, Huus et al. demonstrate that undernourished mice fail to develop IgA interactions with commensal Lactobacillus. In response to nutrient restriction, Lactobacillus adapts its surface structure, evading host glycan binding and reducing mucosal colonization. This microbe-host dynamic has implications for the use of Lactobacillus probiotics in undernourished populations.
Mucosal-associated invariant T (MAIT) cells represent an abundant innate-like T cell subtype in the human liver. MAIT cells are assigned crucial roles in regulating immunity and inflammation, yet ...their role in liver cancer remains elusive. Here, we present a MAIT cell-centered profiling of hepatocellular carcinoma (HCC) using scRNA-seq, flow cytometry, and co-detection by indexing (CODEX) imaging of paired patient samples. These analyses highlight the heterogeneity and dysfunctionality of MAIT cells in HCC and their defective capacity to infiltrate liver tumors. Machine-learning tools were used to dissect the spatial cellular interaction network within the MAIT cell neighborhood. Co-localization in the adjacent liver and interaction between niche-occupying CSF1R+PD-L1+ tumor-associated macrophages (TAMs) and MAIT cells was identified as a key regulatory element of MAIT cell dysfunction. Perturbation of this cell-cell interaction in ex vivo co-culture studies using patient samples and murine models reinvigorated MAIT cell cytotoxicity. These studies suggest that aPD-1/aPD-L1 therapies target MAIT cells in HCC patients.
Diet is a critical determinant of variation in gut microbial structure and function, outweighing even host genetics
. Numerous microbiome studies have compared diets with divergent ingredients
, but ...the everyday practice of cooking remains understudied. Here, we show that a plant diet served raw versus cooked reshapes the murine gut microbiome, with effects attributable to improvements in starch digestibility and degradation of plant-derived compounds. Shifts in the gut microbiota modulated host energy status, applied across multiple starch-rich plants, and were detectable in humans. Thus, diet-driven host-microbial interactions depend on the food as well as its form. Because cooking is human-specific, ubiquitous and ancient
, our results prompt the hypothesis that humans and our microbiomes co-evolved under unique cooking-related pressures.
Fecal‐oral contamination promotes malnutrition pathology. Lasting consequences of early life malnutrition include cognitive impairment, but the underlying pathology and influence of gut microbes ...remain largely unknown. Here, we utilize an established murine model combining malnutrition and iterative exposure to fecal commensals (MAL‐BG). The MAL‐BG model was analyzed in comparison to malnourished (MAL mice) and healthy (CON mice) controls. Malnourished mice display poor spatial memory and learning plasticity, as well as altered microglia, non‐neuronal CNS cells that regulate neuroimmune responses and brain plasticity. Chronic fecal‐oral exposures shaped microglial morphology and transcriptional profile, promoting phagocytic features in MAL‐BG mice. Unexpectedly, these changes occurred independently from significant cytokine‐induced inflammation or blood–brain barrier (BBB) disruption, key gut‐brain pathways. Metabolomic profiling of the MAL‐BG cortex revealed altered polyunsaturated fatty acid (PUFA) profiles and systemic lipoxidative stress. In contrast, supplementation with an ω3 PUFA/antioxidant‐associated diet (PAO) mitigated cognitive deficits within the MAL‐BG model. These findings provide valued insight into the malnourished gut microbiota‐brain axis, highlighting PUFA metabolism as a potential therapeutic target.
Main Points
Early‐life malnutrition and specific gut microbes shape cognition and microglia in mice.
Altered microglial features occur independently from significant neuroinflammation or BBB deficits, but
were linked to impaired lipid metabolism.
PAO diet (ω3 PUFA/antioxidant‐associated supplement) improves cognitive features of malnutrition.
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