Evidence for Modulation of Substance Use Disorders by the Gut Microbiome: Hidden in Plain Sight

Angoa‐Pérez, Mariana; Kuhn, Donald M.

doi:10.1124/pharmrev.120.000144

Cited by 33 publications

(18 citation statements)

References 345 publications

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“…In the brain, there is evidence that butyrate downregulated lipopolysaccharide-induced neuroinflammation in microglia, a specialized population of immune cells important for neuroprotection and neural remodeling [ 104 ]. Indeed, microbiome composition and SCFA levels have been implicated in the pathogenesis of substance use disorders, Parkinson’s disease and depression [ 107 , 108 , 109 ].…”

Section: Scfa and The Gut–brain Axismentioning

confidence: 99%

Butyrate and the Intestinal Epithelium: Modulation of Proliferation and Inflammation in Homeostasis and Disease

Salvi

Cowles

2021

Cells

215

114

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The microbial metabolite butyrate serves as a link between the intestinal microbiome and epithelium. The monocarboxylate transporters MCT1 and SMCT1 are the predominant means of butyrate transport from the intestinal lumen to epithelial cytoplasm, where the molecule undergoes rapid β-oxidation to generate cellular fuel. However, not all epithelial cells metabolize butyrate equally. Undifferentiated colonocytes, including neoplastic cells and intestinal stem cells at the epithelial crypt base preferentially utilize glucose over butyrate for cellular fuel. This divergent metabolic conditioning is central to the phenomenon known as “butyrate paradox”, in which butyrate induces contradictory effects on epithelial proliferation in undifferentiated and differentiated colonocytes. There is evidence that accumulation of butyrate in epithelial cells results in histone modification and altered transcriptional activation that halts cell cycle progression. This manifests in the apparent protective effect of butyrate against colonic neoplasia. A corollary to this process is butyrate-induced inhibition of intestinal stem cells. Yet, emerging research has illustrated that the evolution of the crypt, along with butyrate-producing bacteria in the intestine, serve to protect crypt base stem cells from butyrate’s anti-proliferative effects. Butyrate also regulates epithelial inflammation and tolerance to antigens, through production of anti-inflammatory cytokines and induction of tolerogenic dendritic cells. The role of butyrate in the pathogenesis and treatment of intestinal neoplasia, inflammatory bowel disease and malabsorptive states is evolving, and holds promise for the potential translation of butyrate’s cellular function into clinical therapies.

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Section: Scfa and The Gut–brain Axismentioning

confidence: 99%

Butyrate and the Intestinal Epithelium: Modulation of Proliferation and Inflammation in Homeostasis and Disease

Salvi

Cowles

2021

Cells

215

114

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“…Metabolites of commensal bacterial play a key role in microbe–host interactions [39, 40]. Metabolomic analyzes of fecal samples were also performed in FMT mouse models to determine the bacterial metabolite changes in response to METH withdrawal and metformin treatment using liquid chromatography-mass spectrometry.…”

Section: Resultsmentioning

confidence: 99%

Metformin modulates microbiota-derived inosine and ameliorates methamphetamine-induced anxiety and depression-like withdrawal symptoms in mice

Yang

Zhang

Xie

et al. 2021

Preprint

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Objective: Metformin exhibits therapeutic potential in behavioural deficits induced by methamphetamine (METH) in rats. Emerging studies suggest gut microbiota may impact psychiatric symptoms, but there is no direct evidence supporting metformin's participation in the pathophysiology of withdrawal symptoms via modulation of gut microbiota. Methods: In order to define the functional contributions by gut microbiota and metformin to the behavioural deficits during METH withdrawal, we utilized a combination of fecal microbiota transplantation (FMT), high-throughput sequencing, and untargeted metabolomics technologies. Results: First, METH addicts exhibited higher alpha diversity and distinct microbial structures compared to heathy controls. In particular, the relative abundance of Rikenellaceae was positively correlated with the severity of anxiety and depression. Second, both human-to-mouse and mouse-to-mouse FMTs confirmed that METH-altered-microbiota transplantation is sufficient to promote anxiety and depression-like behaviours in recipient germ-free mice, and these behavioural disturbances could be ameliorated by metformin. In-depth analysis revealed that METH significantly altered the bacterial composition and structure as well as relative abundance of several bacterial taxa and metabolites, including Rikenellaceae and inosine, respectively, whereas add-on metformin could remodel these alterations. Finally, the inosine complementation successfully restored METH-induced anxiety and depression-like behaviours in mice. Discussion: This study demonstrates that METH withdrawal-induced anxiety and depression-like behaviours are convertible and transmissible via gut microbiota in a mouse model. The therapeutic effects of metformin on psychiatric manifestations are associated with microbiota-derived metabolites, highlighting the role of the gut microbiota in substance use disorders and the pathophysiology of withdrawal symptoms.

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“…Addictive substances implicated in substance use disorder (SUD), such as opiates, cocaine, psychostimulants, and alcohol, also modulate the microbiome (Angoa-Pérez and Kuhn, 2021). Almost all research on SUD has primarily focused on the underlying CNS elements and ignored the microbiome link.…”

Section: Drugsmentioning

confidence: 99%

Recent Advances in Understanding the Structure and Function of the Human Microbiome

2022

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Trillions of microbes live within our bodies in a deep symbiotic relationship. Microbial populations vary across body sites, driven by differences in the environment, immunological factors, and interactions between microbial species. Major advances in genome sequencing enable a better understanding of microbiome composition. However, most of the microbial taxa and species of the human microbiome are still unknown. Without revealing the identity of these microbes as a first step, we cannot appreciate their role in human health and diseases. A shift in the microbial balance, termed dysbiosis, is linked to a broad range of diseases from simple colitis and indigestion to cancer and dementia. The last decade has witnessed an explosion in microbiome research that led to a better understanding of the microbiome structure and function. This understanding leads to potential opportunities to develop next-generation microbiome-based drugs and diagnostic biomarkers. However, our understanding is limited given the highly personalized nature of the microbiome and its complex and multidirectional interactions with the host. In this review, we discuss: (1) our current knowledge of microbiome structure and factors that shape the microbial composition, (2) recent associations between microbiome dysbiosis and diseases, and (3) opportunities of new microbiome-based therapeutics. We analyze common themes, promises, gaps, and challenges of the microbiome research.

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Evidence for Modulation of Substance Use Disorders by the Gut Microbiome: Hidden in Plain Sight

Cited by 33 publications

References 345 publications

Butyrate and the Intestinal Epithelium: Modulation of Proliferation and Inflammation in Homeostasis and Disease

Butyrate and the Intestinal Epithelium: Modulation of Proliferation and Inflammation in Homeostasis and Disease

Metformin modulates microbiota-derived inosine and ameliorates methamphetamine-induced anxiety and depression-like withdrawal symptoms in mice

Recent Advances in Understanding the Structure and Function of the Human Microbiome

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