Substance use disorders have a complex etiology. Genetics, the environment, and behavior all play a role in the initiation, escalation, and relapse of drug use. Recently, opioid use disorder has become a national health crisis. One aspect of opioid addiction that has yet to be fully examined is the effects of alterations of the microbiome and gut-brain axis signaling on central nervous system activity during opioid intoxication and withdrawal. The effect of microbiome depletion on the activation of neuronal ensembles was measured by detecting Fos-positive (Fos1) neuron activation during intoxication and withdrawal using a rat model of oxycodone dependence. Daily oxycodone administration (2 mg/kg) increased pain thresholds and increased Fos1 neurons in the basolateral amygdala (BLA) during intoxication, with a decrease in pain thresholds and increase in Fos1 neurons in the periaqueductal gray (PAG), central nucleus of the amygdala (CeA), locus coeruleus (LC), paraventricular nucleus of the thalamus (PVT), agranular insular cortex (AI), bed nucleus of the stria terminalis (BNST), and lateral habenula medial parvocellular region during withdrawal. Microbiome depletion produced widespread but region-and state-specific changes in neuronal ensemble activation. Oxycodone intoxication and withdrawal also increased functional connectivity among brain regions. Microbiome depletion resulted in a decorrelation of this functional network. These data indicate that microbiome depletion by antibiotics produces widespread changes in the recruitment of neuronal ensembles that are activated by oxycodone intoxication and withdrawal, suggesting that the gut microbiome may play a role in opioid use and dependence. Future studies are needed to better understand the molecular, neurobiological, and behavioral effects of microbiome depletion on addiction-like behaviors.

Substance use disorders (SUDs) represent a significant public health crisis. Worldwide, 5.4% of the global disease burden is attributed to SUDs and alcohol use, and many more use psychoactive substances recreationally. Often associated with comorbidities, SUDs result in changes to both brain function and physiological responses. Mounting evidence calls for a precision approach for the treatment and diagnosis of SUDs, and the gut microbiome is emerging as a contributor to such disorders. Over the last few centuries, modern lifestyles, diets, and medical care have altered the health of the microbes that live in and on our bodies; as we develop, our diets and lifestyle dictate which microbes flourish and which microbes vanish. An increase in antibiotic treatments, with many antibiotic interventions occurring early in life during the microbiome's normal development, transforms developing microbial communities. Links have been made between the microbiome and SUDs, and the microbiome and conditions that are often comorbid with SUDs such as anxiety, depression, pain, and stress. A better understanding of the mechanisms influencing behavioral changes and drug use is critical in developing novel treatments for SUDSs. Targeting the microbiome as a therapeutic and diagnostic tool is a promising avenue of exploration. This review will provide an overview of the role of the gut-brain axis in a wide range of SUDs, discuss host and microbe pathways that mediate changes in the brain’s response to drugs, and the microbes and related metabolites that impact behavior and health within the gut-brain axis. Graphic Abstract

Advances in science have ushered in a wave of new potential curative and control strategies for HIV that could eliminate the current requirement for life-long antiretroviral therapy (ART) for people living with HIV (PLWH). In this article, we argue that it is critical to consider social contexts in the development of HIV cure trial protocols. The biological and behavioral risk factors for HIV acquisition by study participants are inseparable from the social context in which these participants live. The article discusses an example of a cohort established to further HIV cure research that included social context, called the FRESH Acute HIV study, which combines a sociostructural intervention while conducting HIV prevention, treatment and cure-related research in Durban, South Africa. We make an urgent call to action to include sociobehavioral components as instrumental in future HIV cure trials in global context.

The gut brain axis is thought to play a role in behavior and physiological responses through chemical, immunological, and metabolite signaling. Antibiotics, diet, and drugs can alter the transit time of gut contents as well as the makeup of the microbiome. Heterogeneity in genetics and environment are also well-known factors involved in the initiation and perpetuation of substance use disorders. Few viable genetic or biological markers are available to identify individuals who are at risk of escalating opioid intake. Primarily, the addiction field has focused on the nervous system, limiting the discovery of peripheral factors that contribute to addiction. To address this gap, we characterized the microbiome before and after drug exposure, and after antibiotics depletion in male and female heterogenous stock rats to determine if microbiome constituents are protective of escalation. We hypothesized that individuals that are prone to escalation of opioid self-administration will have distinct microbial and metabolic profiles. The fecal microbiome and behavioral responses were measured over several weeks of oxycodone self-administration and after antibiotic treatment. Antibiotic treatment reduces circulating short-chain fatty acids (SCFA) by depleting microbes that ferment fiber into these essential signaling molecules for the gut-brain axis. Depletion of the microbiome increased oxycodone self-administration in a subpopulation of animals (Responders). Supplementation of SCFAs in antibiotic depleted animals decreased elevated oxycodone self-administration. Phylogenetic functional analysis reveals distinct metabolic differences in the subpopulations of animals that are sensitive to antibiotic depletion and animals rescued by SCFA supplementation. In conclusion, this study identifies pre-existing microbiome and metabolic vulnerabilities to escalation of oxycodone self-administration, demonstrates that escalation of oxycodone self-administration dysregulates the microbiome and metabolic landscape, and identifies a causal role of short-chain fatty acids in addiction-like behaviors.