Introduction

The gut microbiota, a complex community of microorganisms residing in the digestive tract, has emerged as a critical player in human health and disease. Over the past five years, research has significantly advanced our understanding of the intricate relationships between the gut microbiota, host physiology, and various disease states. This mini-review synthesizes recent findings, focusing on the mechanistic roles of gut microbiota in disease pathogenesis and the therapeutic potential of targeting the gut microbiota.

Gut Microbiota and Metabolic Disorders

A significant body of research has focused on the role of the gut microbiota in metabolic disorders, including obesity, type 2 diabetes, and non-alcoholic fatty liver disease (NAFLD). Patrice D. Cani's group at the Louvain Drug Research Institute has consistently investigated the gut microbiota's role in obesity, with a recent review summarizing the complex interplay between microbes and weight management (Matthias Van Hul et al., 2023, Nature Reviews Endocrinology). In 2020, Karine Clément's team at the Institute of Cardiometabolism and Nutrition provided a comprehensive review disentangling microbial signatures from metabolic disorders in the context of NAFLD (Judith Aron‐Wisnewsky et al., 2020, Nature Reviews Gastroenterology & Hepatology). Subsequent research has identified specific microbial species and metabolites involved in these processes. For instance, Jun Kunisawa's group at the National Institutes of Biomedical Innovation, Health and Nutrition demonstrated that oral administration of Blautia wexlerae ameliorates obesity and type 2 diabetes through metabolic remodeling of the gut microbiota (Koji Hosomi et al., 2022, Nature Communications). Furthermore, Weiping Jia's team at Shanghai Jiao Tong University School of Medicine showed that hyodeoxycholic acid alleviates NAFLD by modulating the gut-liver axis (Junliang Kuang et al., 2023, Cell Metabolism). Yanxing Jia's group at Shanghai Jiao Tong University School of Medicine found that gut symbionts alleviate MASH through a secondary bile acid biosynthetic pathway (Qixing Nie et al., 2024, Cell). Hiroshi Ohno's group at the RIKEN Center for Integrative Medical Sciences demonstrated that gut microbial carbohydrate metabolism contributes to insulin resistance (Tadashi Takeuchi et al., 2023, Nature). These studies highlight the potential for targeted microbial interventions to treat metabolic diseases.

Gut Microbiota and Neurological Disorders

The gut-brain axis, a bidirectional communication network between the gut and the brain, has gained increasing attention in the context of neurological disorders. Lívia H. Morais and colleagues reviewed the role of the gut microbiota-brain axis in behavior and brain disorders (Lívia H. Morais et al., 2020, Nature Reviews Microbiology). Dan Zhang's group at Nanjing Medical University demonstrated that fecal microbiota transplantation protects rotenone-induced Parkinson’s disease mice via suppressing inflammation mediated by the lipopolysaccharide-TLR4 signaling pathway through the microbiota-gut-brain axis (Zhe Zhao et al., 2021, Microbiome). Keqiang Ye's team at Emory University found that gut microbiota regulate Alzheimer’s disease pathologies and cognitive disorders via PUFA-associated neuroinflammation (Chun Chen et al., 2022, Gut). Brittany D. Needham's group at the University of North Carolina at Chapel Hill discovered that a gut-derived metabolite alters brain activity and anxiety behavior in mice (Brittany D. Needham et al., 2022, Nature). Yaoxing Chen's team at Naval Medical University showed that gut microbiota-derived metabolites mediate the neuroprotective effect of melatonin in cognitive impairment induced by sleep deprivation (Xintong Wang et al., 2023, Microbiome). Lijian Chen's group at the First Affiliated Hospital of Nanjing Medical University found a correlation between gut microbiota, circulating cytokines and dementia (Dong Ji et al., 2024, Journal of Neuroinflammation). These findings suggest that modulating the gut microbiota could offer novel therapeutic strategies for neurological conditions.

Gut Microbiota and Cancer Immunotherapy

The gut microbiota has also emerged as a key factor influencing the efficacy of cancer immunotherapy. Erez N. Baruch and Gal Markel's group at Sheba Medical Center, and Diwakar Davar and Hassane M. Zarour's team at the University of Pittsburgh Medical Center independently demonstrated that fecal microbiota transplant (FMT) can overcome resistance to anti-PD-1 therapy in melanoma patients (Erez N. Baruch et al., 2020, Science; Diwakar Davar et al., 2020, Science). Joseph Tintelnot's group at the University of Chicago discovered that microbiota-derived 3-IAA influences chemotherapy efficacy in pancreatic cancer (Joseph Tintelnot et al., 2023, Nature). Bertrand Routy's team at the University of Montreal conducted a phase I trial of fecal microbiota transplantation plus anti-PD-1 immunotherapy in advanced melanoma (Bertrand Routy et al., 2023, Nature Medicine). Weiwei Cui's group at Zhejiang University found that a gut microbial metabolite facilitates colorectal cancer development via ferroptosis inhibition (Weiwei Cui et al., 2024, Nature Cell Biology). These studies highlight the potential of manipulating the gut microbiota to enhance cancer treatment outcomes.

Short-Chain Fatty Acids (SCFAs) and Gut Health

Short-chain fatty acids (SCFAs), produced by the microbial fermentation of dietary fibers, have emerged as crucial mediators of gut health and host physiology. Jerry M. Wells's group at Wageningen University reviewed the microbial regulation of host physiology by SCFAs (Bart van der Hee et al., 2021, Trends in Microbiology). Cristina Menni's team at King's College London investigated the role of SCFAs in the interplay between gut microbiota and diet in cardio-metabolic health (Ana Nogal et al., 2021, Gut Microbes). Zhi-Xiang Xu's group at Nanjing Medical University reviewed the role of short-chain fatty acids in diseases (Dan Zhang et al., 2023, Cell Communication and Signaling). Holm H. Uhlig's group at the University of Oxford reviewed the link between short-chain fatty acids, diet, the microbiome and immunity (Elizabeth R. Mann et al., 2024, Nature reviews. Immunology). Edoardo Savarino's team at the University of Padua discussed the therapeutic implications of short-chain fatty acids in human health (Sonia Facchin et al., 2024, Life (Basel)). These studies underscore the importance of dietary fiber and microbial fermentation in maintaining gut health and overall well-being.

Conclusion

The past five years have witnessed remarkable progress in our understanding of the gut microbiota's role in health and disease. From metabolic disorders and neurological conditions to cancer immunotherapy, the gut microbiota has emerged as a critical player in various aspects of human physiology. Future research should focus on identifying specific microbial targets and developing personalized interventions to harness the therapeutic potential of the gut microbiota.

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