The gut microbiome and sociability.

The human gut microbiome plays an important role in the maturation of the neural, immune, and endocrine systems. Research data from animal models shows that gut microbiota communicate with the host's brain in an elaborate network of signaling pathways, including the vagus nerve. Part of the microbiome's influence extends to the behavioral and social development of its host. As a social species, a human's ability to communicate with others is imperative to their survival and quality of life. Current research explores the gut microbiota's developmental influence as well as how these gut-brain pathways can be leveraged to alleviate the social symptoms associated with various neurodevelopmental and psychiatric diseases. One intriguing vein of research in animal models centers on probiotic treatment, which leads to downstream increased circulation of endogenous oxytocin, a neuropeptide hormone relevant to sociability. Further research may lead to therapeutic applications in humans, particularly in the early stages of their lives.

Brain trust.

This narrative describes a personal journey that led to the discovery of a profound connection between microbial symbionts and oxytocin. Pivotal oxytocin discoveries began to emerge in 2011 while this researcher's multidisciplinary team explored gut microbial priming of the immune system and perinatal health. Inspired by oxytocin's role in early life events of milk release, neural connections, and social bonding, the team hypothesized a symbiotic relationship between microbes and oxytocin. Scientific experiments demonstrated that specific milk-borne microbes boosted oxytocin levels through a vagus nerve-mediated gut-brain pathway, affecting immune functions and wound healing capacity in the host animal. The exploration then expanded to microbial impacts on reproductive fitness, body weight, and even mental health. Overarching hypotheses envisioned a nurturing symbiosis promoting survival and societal advancement. Ultimately, this oxytocin-mediated partnership between microbes and mammals is portrayed as a harmonious legacy of neurological stability, empathy, and universal wisdom, transcending generations. The author's personal journey underscores the beauty and inspiration found in her scientific exploration.

Oxytocin and the microbiome.

The mammalian host microbiome affects many targets throughout the body, at least in part through an integrated gut-brain-immune axis and neuropeptide hormone oxytocin. It was discovered in animal models that microbial symbionts, such as Lactobacillus reuteri, leverage perinatal niches to promote multigenerational good health and reproductive fitness. While roles for oxytocin were once limited to women, such as giving birth and nurturing offspring, oxytocin is now also proposed to have important roles linking microbial symbionts with overall host fitness and survival throughout the evolutionary journey.

Maternal Microbiota Modulate a Fragile X-like Syndrome in Offspring Mice.

Maternal microbial dysbiosis has been implicated in adverse postnatal health conditions in offspring, such as obesity, cancer, and neurological disorders. We observed that the progeny of mice fed a Westernized diet (WD) with low fiber and extra fat exhibited higher frequencies of stereotypy, hyperactivity, cranial features and lower FMRP protein expression, similar to what is typically observed in Fragile X Syndrome (FXS) in humans. We hypothesized that gut dysbiosis and inflammation during pregnancy influenced the prenatal uterine environment, leading to abnormal phenotypes in offspring. We found that oral in utero supplementation with a beneficial anti-inflammatory probiotic microbe, Lactobacillus reuteri, was sufficient to inhibit FXS-like phenotypes in offspring mice. Cytokine profiles in the pregnant WD females showed that their circulating levels of pro-inflammatory cytokine interleukin (Il)-17 were increased relative to matched gravid mice and to those given supplementary L. reuteri probiotic. To test our hypothesis of prenatal contributions to this neurodevelopmental phenotype, we performed Caesarian (C-section) births using dissimilar foster mothers to eliminate effects of maternal microbiota transferred during vaginal delivery or nursing after birth. We found that foster-reared offspring still displayed a high frequency of these FXS-like features, indicating significant in utero contributions. In contrast, matched foster-reared progeny of L. reuteri-treated mothers did not exhibit the FXS-like typical features, supporting a key role for microbiota during pregnancy. Our findings suggest that diet-induced dysbiosis in the prenatal uterine environment is strongly associated with the incidence of this neurological phenotype in progeny but can be alleviated by addressing gut dysbiosis through probiotic supplementation.

Differential Methylation Profile in Fragile X Syndrome-Prone Offspring Mice after in Utero Exposure to Lactobacillus Reuteri.

Environmental factors such as diet, gut microbiota, and infections have proven to have a significant role in epigenetic modifications. It is known that epigenetic modifications may cause behavioral and neuronal changes observed in neurodevelopmental disabilities, including fragile X syndrome (FXS) and autism (ASD). Probiotics are live microorganisms that provide health benefits when consumed, and in some cases are shown to decrease the chance of developing neurological disorders. Here, we examined the epigenetic outcomes in offspring mice after feeding of a probiotic organism, Lactobacillus reuteri (L. reuteri), to pregnant mother animals. In this study, we tested a cohort of Western diet-fed descendant mice exhibiting a high frequency of behavioral features and lower FMRP protein expression similar to what is observed in FXS in humans (described in a companion manuscript in this same GENES special topic issue). By investigating 17,735 CpG sites spanning the whole mouse genome, we characterized the epigenetic profile in two cohorts of mice descended from mothers treated and non-treated with L. reuteri to determine the effect of prenatal probiotic exposure on the prevention of FXS-like symptoms. We found several genes involved in different neurological pathways being differentially methylated (p ≤ 0.05) between the cohorts. Among the key functions, synaptogenesis, neurogenesis, synaptic modulation, synaptic transmission, reelin signaling pathway, promotion of specification and maturation of neurons, and long-term potentiation were observed. The results of this study are relevant as they could lead to a better understanding of the pathways involved in these disorders, to novel therapeutics approaches, and to the identification of potential biomarkers for early detection of these conditions.

The gut microbiome as a biomarker of differential susceptibility to SARS-CoV-2.

Coronavirus disease 2019 (COVID-19) continues to exact a devastating global toll. Ascertaining the factors underlying differential susceptibility and prognosis following viral exposure is critical to improving public health responses. We propose that gut microbes may contribute to variation in COVID-19 outcomes. We synthesise evidence for gut microbial contributions to immunity and inflammation, and associations with demographic factors affecting disease severity. We suggest mechanisms potentially underlying microbially mediated differential susceptibility to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). These include gut microbiome-mediated priming of host inflammatory responses and regulation of endocrine signalling, with consequences for the cellular features exploited by SARS-CoV-2 virions. We argue that considering gut microbiome-mediated mechanisms may offer a lens for appreciating differential susceptibility to SARS-CoV-2, potentially contributing to clinical and epidemiological approaches to understanding and managing COVID-19.

Non-responder phenotype reveals apparent microbiome-wide antibiotic tolerance in the murine gut.

Broad spectrum antibiotics cause both transient and lasting damage to the ecology of the gut microbiome. Antibiotic-induced loss of gut bacterial diversity has been linked to susceptibility to enteric infections. Prior work on subtherapeutic antibiotic treatment in humans and non-human animals has suggested that entire gut communities may exhibit tolerance phenotypes. In this study, we validate the existence of these community tolerance phenotypes in the murine gut and explore how antibiotic treatment duration or a diet enriched in antimicrobial phytochemicals might influence the frequency of this phenotype. Almost a third of mice exhibited whole-community tolerance to a high dose of the ß-lactam antibiotic cefoperazone, independent of antibiotic treatment duration or dietary phytochemical amendment. We observed few compositional differences between non-responder microbiota during antibiotic treatment and the untreated control microbiota. However, gene expression was vastly different between non-responder microbiota and controls during treatment, with non-responder communities showing an upregulation of antimicrobial tolerance genes, like efflux transporters, and a down-regulation of central metabolism. Future work should focus on what specific host- or microbiome-associated factors are responsible for tipping communities between responder and non-responder phenotypes so that we might learn to harness this phenomenon to protect our microbiota from routine antibiotic treatment.

Analysis of mutations in tumor and normal adjacent tissue via fluorescence detection.

Inflammation is a major risk factor for many types of cancer, including colorectal. There are two fundamentally different mechanisms by which inflammation can contribute to carcinogenesis. First, reactive oxygen and nitrogen species (RONS) can damage DNA to cause mutations that initiate cancer. Second, inflammatory cytokines and chemokines promote proliferation, migration, and invasion. Although it is known that inflammation-associated RONS can be mutagenic, the extent to which they induce mutations in intestinal stem cells has been little explored. Furthermore, it is now widely accepted that cancer is caused by successive rounds of clonal expansion with associated de novo mutations that further promote tumor development. As such, we aimed to understand the extent to which inflammation promotes clonal expansion in normal and tumor tissue. Using an engineered mouse model that is prone to cancer and within which mutant cells fluoresce, here we have explored the impact of inflammation on de novo mutagenesis and clonal expansion in normal and tumor tissue. While inflammation is strongly associated with susceptibility to cancer and a concomitant increase in the overall proportion of mutant cells in the tissue, we did not observe an increase in mutations in normal adjacent tissue. These results are consistent with opportunities for de novo mutations and clonal expansion during tumor growth, and they suggest protective mechanisms that suppress the risk of inflammation-induced accumulation of mutant cells in normal tissue.

The role of the microbiome in the neurobiology of social behaviour.

Microbes colonise all multicellular life, and the gut microbiome has been shown to influence a range of host physiological and behavioural phenotypes. One of the most intriguing and least understood of these influences lies in the domain of the microbiome's interactions with host social behaviour, with new evidence revealing that the gut microbiome makes important contributions to animal sociality. However, little is known about the biological processes through which the microbiome might influence host social behaviour. Here, we synthesise evidence of the gut microbiome's interactions with various aspects of host sociality, including sociability, social cognition, social stress, and autism. We discuss evidence of microbial associations with the most likely physiological mediators of animal social interaction. These include the structure and function of regions of the 'social' brain (the amygdala, the prefrontal cortex, and the hippocampus) and the regulation of 'social' signalling molecules (glucocorticoids including corticosterone and cortisol, sex hormones including testosterone, oestrogens, and progestogens, neuropeptide hormones such as oxytocin and arginine vasopressin, and monoamine neurotransmitters such as serotonin and dopamine). We also discuss microbiome-associated host genetic and epigenetic processes relevant to social behaviour. We then review research on microbial interactions with olfaction in insects and mammals, which contribute to social signalling and communication. Following these discussions, we examine evidence of microbial associations with emotion and social behaviour in humans, focussing on psychobiotic studies, microbe-depression correlations, early human development, autism, and issues of statistical power, replication, and causality. We analyse how the putative physiological mediators of the microbiome-sociality connection may be investigated, and discuss issues relating to the interpretation of results. We also suggest that other candidate molecules should be studied, insofar as they exert effects on social behaviour and are known to interact with the microbiome. Finally, we consider different models of the sequence of microbial effects on host physiological development, and how these may contribute to host social behaviour.

Consuming cholera toxin counteracts age-associated obesity.

During the past forty years there has been an inexplicable increase in chronic inflammatory disorders, including obesity. One theory, the 'hygiene hypothesis', involves dysregulated immunity arising after too few beneficial early life microbe exposures. Indeed, earlier studies have shown that gut microbe-immune interactions contribute to smoldering inflammation, adiposity, and weight gain. Here we tested a safe and well-established microbe-based immune adjuvant to restore immune homeostasis and counteract inflammation-associated obesity in animal models. We found that consuming Vibrio cholerae exotoxin subunit B (ctB) was sufficient to inhibit age-associated obesogenic outcomes in wild type mice, including reduced crown-like structures (CLS) and granulomatous necrosis histopathology in fat depots. Administration of cholera toxin reduced weight gain irrespective of age during administration; however, exposure during youth imparted greater slenderizing effects when compared with animals receiving ctB for the first time during adulthood. Beneficial effects were transplantable to other obesity-prone animals using immune cells alone, demonstrating an immune-mediated mechanism. Taken together, we concluded that oral vaccination with cholera toxin B helps stimulate health-protective immune responses that counteract age-associated obesity.

Orthogonal Dietary Niche Enables Reversible Engraftment of a Gut Bacterial Commensal.

Interest in manipulating the gut microbiota to treat disease has led to a need for understanding how organisms can establish themselves when introduced into a host with an intact microbial community. Here, we employ the concept of orthogonal niche engineering: a resource typically absent from the diet, seaweed, creates a customized niche for an introduced organism. In the short term, co-introduction of this resource at 1% in the diet along with an organism with exclusive access to this resource, Bacteroides plebeius DSM 17135, enables it to colonize at a median abundance of 1% and frequently up to 10 or more percent, both on pulsed and constant seaweed diets. In a two-month follow-up after the initial treatment period, B. plebeius stops responding to seaweed in mice initially on the constant seaweed diet, suggesting treatment regime will affect controllability. These results offer potential for diet-based intervention to introduce and control target organisms.

Correction: Beneficial bacteria inhibit cachexia.

[This corrects the article DOI: 10.18632/oncotarget.7730.].

Microbial lysate upregulates host oxytocin.

Neuropeptide hormone oxytocin has roles in social bonding, energy metabolism, and wound healing contributing to good physical, mental and social health. It was previously shown that feeding of a human commensal microbe Lactobacillus reuteri (L. reuteri) is sufficient to up-regulate endogenous oxytocin levels and improve wound healing capacity in mice. Here we show that oral L. reuteri-induced skin wound repair benefits extend to human subjects. Further, dietary supplementation with a sterile lysate of this microbe alone is sufficient to boost systemic oxytocin levels and improve wound repair capacity. Oxytocin-producing cells were found to be increased in the caudal paraventricular nucleus [PVN] of the hypothalamus after feeding of a sterile lysed preparation of L. reuteri, coincident with lowered blood levels of stress hormone corticosterone and more rapid epidermal closure, in mouse models. We conclude that microbe viability is not essential for regulating host oxytocin levels. The results suggest that a peptide or metabolite produced by bacteria may modulate host oxytocin secretion for potential public or personalized health goals.

Gut microbiota modulate host immune cells in cancer development and growth.

Emerging evidence shows that microbe interactions with the host immune system impact diverse aspects of cancer development and treatment. As a result, exciting new opportunities exist for engineering diets and microbe cocktails to lower cancer risks with fewer adverse clinical effects than traditional strategies. Microbe-based therapies may ultimately be used to reinforce host immune balance and extinguish cancer for generations to come.

Beneficial bacteria inhibit cachexia.

Muscle wasting, known as cachexia, is a debilitating condition associated with chronic inflammation such as during cancer. Beneficial microbes have been shown to optimize systemic inflammatory tone during good health; however, interactions between microbes and host immunity in the context of cachexia are incompletely understood. Here we use mouse models to test roles for bacteria in muscle wasting syndromes. We find that feeding of a human commensal microbe, Lactobacillus reuteri, to mice is sufficient to lower systemic indices of inflammation and inhibit cachexia. Further, the microbial muscle-building phenomenon extends to normal aging as wild type animals exhibited increased growth hormone levels and up-regulation of transcription factor Forkhead Box N1 [FoxN1] associated with thymus gland retention and longevity. Interestingly, mice with a defective FoxN1 gene (athymic nude) fail to inhibit sarcopenia after L. reuteri therapy, indicating a FoxN1-mediated mechanism. In conclusion, symbiotic bacteria may serve to stimulate FoxN1 and thymic functions that regulate inflammation, offering possible alternatives for cachexia prevention and novel insights into roles for microbiota in mammalian ontogeny and phylogeny.

Commensal bacteria modulate the tumor microenvironment.

It has been recently shown that gut microbes modulate whole host immune and hormonal factors impacting the fate of distant preneoplastic lesions toward malignancy or regression. This raises the possibility that the tumor microenvironment interacts with broader systemic microbial-immune networks. These accumulated findings suggest novel therapeutic opportunities for holobiont engineering in emerging tumor microenvironments.