Harnessing AI and Gut Microbiome Research for Precision Health

Psychosocial environments impact normative behavioral development in children, increasing the risk of problem behaviors and psychiatric disorders across the life span. Converging evidence demonstrates that early normative development is affected by the gut microbiome, which itself can be altered by early psychosocial environments. However, much of our understanding of the gut microbiome's role in early development stems from nonhuman animal models and predominately focuses on the first years of life, during peri- and postnatal microbial colonization. As a first step to identify if these findings translate to humans and the extent to which these relationships are maintained after initial microbial colonization, we conducted a metagenomic investigation among a cross-sectional sample of early school-aged children with a range of adverse experiences and caregiver stressors and relationships. Our results indicate that the taxonomic and functional composition of the gut microbiome correlates with behavior during a critical period of child development. Furthermore, our analysis reveals that both socioeconomic risk exposure and child behaviors associate with the relative abundances of specific taxa (e.g., Bacteroides and Bifidobacterium species) as well as functional modules encoded in their genomes (e.g., monoamine metabolism) that have been linked to cognition and health. While we cannot infer causality within this study, these findings suggest that caregivers may moderate the gut microbiome's link to environment and behaviors beyond the first few years of life.IMPORTANCE Childhood is a formative period of behavioral and biological development that can be modified, for better or worse, by the psychosocial environment that is in part determined by caregivers. Not only do our own genes and the external environment influence such developmental trajectories, but the community of microbes living in, on, and around our bodies-the microbiome-plays an important role as well. By surveying the gut microbiomes of a cross-sectional cohort of early school-aged children with a range of psychosocial environments and subclinical mental health symptoms, we demonstrated that caregiving behaviors modified the child gut microbiome's association to socioeconomic risk and behavioral dysregulation.

Sex differences in gut microbiota, hypertension, and cardiovascular risk.

Air pollution has been reported to be an environmental risk factor for autism spectrum disorder. However, the gut microbiome's role as a potential mediator has not been investigated. We aimed to clarify whether particulate matter with an aerodynamic diameter ≤10μm (PM₁₀) and nitrogen dioxide (NO₂) exposure impact autistic traits through the gut microbiome. Using 170 mother-child pairs, PM₁₀ and NO₂ exposure levels during pregnancy (1st, 2nd, and 3rd trimesters) and annual residential PM₁₀ levels at age 2, 4, and 6 years were estimated. Autistic traits and gut microbiome were assessed at age 6 years. The associations of PM₁₀ or NO₂ exposure, gut microbiome composition, and autistic traits were explored, and mediation analyses of statistically significant findings were also conducted. Exposure to PM₁₀ during the 1st trimester of pregnancy was associated with increased autistic traits (10.6% change per interquartile range (IQR) increase, 95% confidence interval [CI]: 1.1, 21.0) and with Proteobacteria relative abundance at age 6 years (66.9% change per IQR increase, 95% CI: 21.3, 129.8). First trimester NO₂ exposure was associated with autistic traits (12.1% change, 95% CI: 0.1, 25.5) and Proteobacteria relative abundance at age 6 years (48.1% change, 95% CI: -0.1, 119.6). Proteobacteria relative abundance was related to autistic traits (4.4% change per 2-fold increase, 95% CI: 1.3, 7.5). Relations between PM₁₀ or NO₂ exposure during the 1st trimester and autistic traits at age 6 years were partially mediated by Proteobacteria (proportion mediated 23.2%, p=0.01 and 16.7%, p=0.06; respectively). PM₁₀ and possibly NO₂ exposure during early pregnancy may affect autistic traits at age 6 years through the alteration of Proteobacteria abundance.

Emerging evidence suggests that gut microbiota imbalances may influence the onset of musculoskeletal disorders (MSDs), yet conclusive evidence establishing causation remains limited. This study investigates the causal relationship between gut microbiota and a range of MSDs, aiming to identify potential therapeutic targets. Using data on 211 gut microbiome taxa from a genome-wide association study (GWAS) and summary statistics for 26 MSDs from the Finnish Biobank, we employed Mendelian randomization (MR) with inverse-variance weighting (IVW) as the primary analytical approach, complemented by Bayesian model validation to ensure robust results. Our MR analyses revealed significant causal associations between gut microbiota and nine MSDs within four categories, including osteoporosis (IVW-Beta = 0.011, P = 0.025), rheumatoid arthritis (IVW-Beta = − 0.016, P < 0.001), rotator cuff syndrome (IVW-Beta = − 0.007, P = 0.022), and calcific tendonitis of the shoulder (IVW-Beta = − 0.021, P = 0.034). Bayesian validation underscored the plausibility of these relationships, supporting the potential causal role of gut microbiota in the development of these disorders. Our findings present a library of causal associations that underscore the gut microbiome's role in MSD pathogenesis, providing genetic evidence that highlights specific gut microbiota taxa as prospective therapeutic targets. This research offers novel insights into the pathogenic mechanisms underlying MSDs and points toward new directions for future investigation into microbiome-based therapies.

Fermentable oligosaccharides disaccharides monosaccharides and polyols (FODMAP) dietary restriction ameliorates irritable bowel syndrome (IBS) symptoms; however, not all individuals with IBS respond. Given the gut microbiome's role in carbohydrate fermentation, investigators have evaluated whether the gut microbiome may predict low FODMAP diet efficacy. Gut microbiome fermentation, even to the same carbohydrate, is not uniform across all individuals with several factors (e.g. composition) playing a role. In both children and adults with IBS, studies are emerging suggesting the gut microbiome may predict low FODMAP diet efficacy. However, there is significant heterogeneity in the approaches (study population, microbiome assessment methods, statistical techniques, etc.) used amongst these studies. The gut microbiome holds promise as a predictor of low FODMAP diet efficacy. However, further investigation using standardized approaches to evaluate the microbiome while concomitantly assessing other potential predictors are needed to more rigorously evaluate this area.

BackgroundAlteration of the gut microbiota through diet and environmental contaminants may disturb physiological homeostasis, leading to various diseases including obesity and type 2 diabetes. Because most exposure to environmentally persistent organic pollutants (POPs) occurs through the diet, the host gastrointestinal tract and commensal gut microbiota are likely to be exposed to POPs.ObjectivesWe examined the effect of 2,3,7,8-tetrachlorodibenzofuran (TCDF), a persistent environmental contaminant, on gut microbiota and host metabolism, and we examined correlations between gut microbiota composition and signaling pathways.MethodsSix-week-old male wild-type and Ahr–/– mice on the C57BL/6J background were treated with 24 μg/kg TCDF in the diet for 5 days. We used 16S rRNA gene sequencing, 1H nuclear magnetic resonance (NMR) metabolomics, targeted ultra-performance liquid chromatography coupled with triplequadrupole mass spectrometry, and biochemical assays to determine the microbiota compositions and the physiological and metabolic effects of TCDF.ResultsDietary TCDF altered the gut microbiota by shifting the ratio of Firmicutes to Bacteroidetes. TCDF-treated mouse cecal contents were enriched with Butyrivibrio spp. but depleted in Oscillobacter spp. compared with vehicle-treated mice. These changes in the gut microbiota were associated with altered bile acid metabolism. Further, dietary TCDF inhibited the farnesoid X receptor (FXR) signaling pathway, triggered significant inflammation and host metabolic disorders as a result of activation of bacterial fermentation, and altered hepatic lipogenesis, gluconeogenesis, and glycogenolysis in an AHR-dependent manner.ConclusionThese findings provide new insights into the biochemical consequences of TCDF exposure involving the alteration of the gut microbiota, modulation of nuclear receptor signaling, and disruption of host metabolism.CitationZhang L, Nichols RG, Correll J, Murray IA, Tanaka N, Smith PB, Hubbard TD, Sebastian A, Albert I, Hatzakis E, Gonzalez FJ, Perdew GH, Patterson AD. 2015. Persistent organic pollutants modify gut microbiota–host metabolic homeostasis in mice through aryl hydrocarbon receptor activation. Environ Health Perspect 123:679–688; http://dx.doi.org/10.1289/ehp.1409055

ABSTRACTIt is believed that establishment of the gut microbiome starts very early in life and is crucial for growth, immunity, and long-term metabolic health. In this longitudinal study, we recruited 25 mothers in their third trimester, of whom 15 had vaginal delivery while 10 had an unplanned cesarean section (C-section). The mother-neonate pairs were followed for 1 year, and we generated 16S metagenomic data to study the neonatal gut microbiome along with mother’s breast milk and vaginal microbiomes through 12 months after delivery, at 1, 3, 6, and 12 months. We inferred (i) mode of delivery is an important factor influencing both composition and entropy of the neonatal gut microbiome, and the genus Streptococcus plays an important role in the temporal differentiation. (ii) Microbial diversity monotonically increases with age, irrespective of the mode of delivery, and it is significantly altered once exclusive breastfeeding is stopped. (iii) We found little evidence in favor of the microflora of mother’s breast milk and a vaginal swab being directly reflected in the offspring’s gut microbiome; however, some distinction could be made in the gut microbiome of neonates whose mothers were classified as community state type III (CSTIII) and CSTIV, based on their vaginal microbiomes. (iv) A lot of the mature gut microbiome is possibly acquired from the environment, as the genera Prevotella and Faecalibacterium, two of the most abundant flora in the neonatal gut microbiome, are introduced after initiation of solidified food. The distinction between the gut microbiome of babies born by vaginal delivery and babies born by C-section becomes blurred after introduction of solid food, although the diversity in the gut microbiota drastically increases in both cases.IMPORTANCE Gut microbiome architecture seems to have a potential impact on host metabolism, health, and nutrition. Early life gut microbiome development is considered a crucial phenomenon for neonatal health as well as adulthood metabolic complications. In this longitudinal study, we examined the association of neonatal gut microbiome entropy and its temporal variation. The study revealed that adult-like gut microbiome architecture starts taking shape after initiation of solidified food. Further, we also observed that the difference of microbial diversity was reduced between vaginally delivered and C-section babies compared to exclusive breastfeeding tenure. We found evidence in favor of the inheritance of the microflora of mother’s posterior vaginal wall to the offspring’s gut microbiome.

Polyphenols exert beneficial effects on host metabolism, which may be mediated by the gut microbiota. We investigated sex-specific differences in microbiota composition and interactions with cardiometabolic parameters after polyphenol supplementation in individuals with overweight/obesity. In a double-blind, randomized, placebo-controlled trial, 19 women and 18 men with normal glucose tolerance and body mass index >25 kg/m2 received epigallocatechin-3-gallate and resveratrol (EGCG+RES, 282 + 80 mg/d) or placebo supplements for 12 weeks. Fecal microbiota composition (16S rRNA gene amplicon sequencing, V3-V4 region), in vivo whole-body fat oxidation (indirect calorimetry), and mitochondrial respiration in permeabilized skeletal muscle fibers (SkM-Ox; ex vivo respirometry) were determined pre- and post-intervention. Overall, EGCG+RES supplementation did not affect gut microbiota composition. Akkermansia, Ruminococcaceae UCG-002, Subdoligranulum, and Lachnospiraceae UCG-004 were more abundant, while Veillonella, Tyzzerella 4, Clostridium innocuum group, Ruminococcus gnavus group, Escherichia-Shigella, and an uncultured Ruminococcaceae family genus were less abundant in women compared to men. In women, only baseline Eubacterium ventriosum group abundance correlated with EGCG+RES-induced changes in SkM-Ox. In men, low Dorea, Barnsiella, Anaerotruncus, Ruminococcus, Subdoligranulum, Coprococcus, Eubacterium ventriosum group, Ruminococcaceae UCG-003, and a Ruminococcaceae family genus abundance, and high Blautia abundance at baseline were associated with improvements in SkM-Ox. Changes in whole-body fat oxidation were not associated with gut microbiota features. We conclude that baseline microbiota composition predicts changes in SkM-Ox as a result of EGCG+RES supplementation in men but not in women. Men may be more prone to diet-induced, gut microbiota-related improvements in cardiometabolic health. These sex-differences should be further investigated in future precision-based intervention studies.

To examine the effects and interactions between gut microbia and chronic pain. The gut microbiome has been an area of interest in both the scientific and general audience due to a growing body of evidence suggesting its influence in a variety of health and disease states. Communication between the central nervous system (CNS) and gut microbiome is said to be bidirectional, in what is referred to as the gut-brain axis. Chronic pain is a prevalent costly personal and public health burden and so, there is a vested interest in devising safe and efficacious treatments. Numerous studies, many of which are animal studies, have been conducted to examine the gut microbiome's role in the pathophysiology of chronic pain states, such as neuropathy, inflammation, visceral pain, etc. As the understanding of this relationship grows, so does the potential for therapeutic targeting of the gut microbiome in chronic pain.

The gut microbiota, shaped by factors such as diet, lifestyle, and genetics, plays a pivotal role in regulating host metabolism, immune function, and overall health. The diversity and balance of the gut microbiota are closely linked to the onset and progression of various chronic diseases. A growing body of evidence has demonstrated that alterations in the composition, function, and metabolites of the gut microbiota are significantly associated with cardiovascular diseases, including hypertension, atherosclerosis, and heart failure; metabolic disorders such as obesity, type 2 diabetes, and metabolic dysfunction-associated steatotic liver disease; and gastrointestinal conditions like inflammatory bowel disease and colorectal cancer. Despite substantial advances in microbiome research, challenges remain in fully elucidating the causal relationships between the gut microbiota and disease, as well as in translating these insights into clinical applications. This review aims to investigate the regulatory pathways via which the gut microbiota affects cardiovascular health, metabolic function, and gastrointestinal disease. Additionally, it highlights emerging strategies for the prevention and treatment of these chronic conditions, focusing on microbiota-targeted therapies and personalized dietary interventions as promising approaches for improving health outcomes.

To better adapt to seasonal environmental changes, physiological processes and behaviors are regulated seasonally. The gut microbiome interacts with the physiology, behavior, and even the diseases of host animals, including humans and livestock. Seasonal changes in gut microbiome composition have been reported in several species under natural environments. Dietary content significantly affects the composition of the microbiome, and, in the natural environment, the diet varies between different seasons. Therefore, understanding the seasonal regulatory mechanisms of the gut microbiome is important for understanding the seasonal adaptation strategies of animals. Herein, we examined the effects of changing day length and temperature, which mimic summer and winter conditions, on the gut microbiome of laboratory mice. Principal coordinate analysis and analysis of the composition of microbiomes of 16S rRNA sequencing data demonstrated that the microbiomes of the cecum and large intestine showed significant differences between summer and winter mimicking conditions. Similar to previous studies, a daily rhythm was observed in the composition of the microbiome. Furthermore, the phylogenetic investigation of communities by reconstruction of unobserved states predicted seasonal changes in several metabolic pathways. Changing day length and temperature can affect the composition of the gut microbiome without changing dietary contents.

The Commensal Microbiota and Enteropathogens in the Pathogenesis of Inflammatory Bowel Diseases

Pregnancy prompts a cascade of anatomical, metabolic, hormonal, and immunological adaptations important for foetal development, labour and birth(1). These multi–system adaptations interact with the maternal gut microbiome and may affect pregnancy and infancy outcomes(2). However, the nature and extent of changes to gut microbiome composition and diversity during pregnancy and the influence of dietary intake remains contentious. The ‘BABY1000’ pilot prospective birth cohort study based in Sydney, Australia(3) sought to explore associations between maternal diet, the maternal gut microbiome before and across pregnancy, and the infant gut microbiome. Primary aims were to (1) explore the composition and diversity of the gut microbiome of women at preconception, at 12-, 28- and 36-weeks’ gestation, and in infants at six weeks of age; and (2) determine how maternal and infant gut microbiomes are influenced by diet quality and fibre intake during pregnancy. Mothers (n = 146) and infants (n = 105), encompassing 86 mother–infant dyads were involved. RStudio (v 4.2.3) was used to perform microbiome composition and diversity analyses using 350 maternal and 102 infant stool samples. Maternal dietary quality was assessed at recruitment (preconception or 12 weeks’ gestation) and at 36 weeks’ gestation using the Australian Eating Survey (AES)(4). At the group level, maternal dietary quality was suboptimal and did not change significantly across pregnancy (mean scores of 37.5 ± 7.3 and 38.3 ± 6.7 out of 73 points at recruitment and late pregnancy, respectively; p &gt; 0.05). Although differences in gut microbiome alpha (within–person) diversity between mothers and infants was highly significant (p &lt; 0.0001), no differences in gut microbiome composition or diversity related to pregnancy status or gestational stage were observed. Maternal diet quality in pregnancy was also not significantly correlated with microbial beta (between–people) diversity in samples taken in late pregnancy (PERMANOVA: R2 = 0.039, p &gt; 0.05). When fibre intake was separated into quartiles, there was a significant (p &lt; 0.01) difference in alpha diversity between the lowest and highest quartiles of intake, though differences in beta diversity were not significant (PERMANOVA: R2 = 0.06, p &gt; 0.05). Microbiota composition and diversity in infant samples was also not significantly affected by maternal dietary quality or fibre intake, but rather by birth mode and feeding type. Significantly different clustering of infant samples was clear between vaginal and caesarean births (PERMANOVA: R2 = 0.029, p = 0.005). Gut bacterial alpha diversity was significantly lower (p &lt; 0.01) between infants receiving breastmilk compared to formula. As this area of research is still in its ‘infancy’, appropriately powered longitudinal studies are required to understand the processes that shape diet and microbiome interactions during the critical first 1,000 days of life and beyond.

Sir, The human body is inhabited by a multitude of bacteria, viruses, fungi, phages constituting the microbiota, and their gene pool called the microbiome which is essential for human well-being.[1] The role of gut microbiome in peri-operative medicine is recently being explored. However, most of the literature available is that of animal studies and more extensive research would be needed in humans to establish an association. The mechanism of action of gut-microbiome on various systems of the human body can be explained by the “gut-brain axis.” This is a two-way interaction between the enteric nervous system (ENS) and central nervous system (CNS) [Figure 1]. The gut microbiota secrete various metabolites and products like-short chain fatty acids (SCFA), enzymes, polysaccharides, cytokines, and neurotransmitters, which are released in to the circulation to act on the CNS. The vagus nerve also carries inputs from ENS to CNS. The brain in-turn acts on the gut through the hypothalamic-pituitary-adrenal (HPA) axis and the autonomic nervous system.[2] Immune mediated interaction and alteration of microglial activity are other proposed mechanisms of gut-brain interaction. All these mechanisms have been proven only by preclinical animal studies.[1]Figure 1: Gut brain axis. HPA = Hypothalamic pituitary adrenal axisAnaesthetic agents-like propofol and volatile anaesthetics have been found to alter the gut microbiota composition in animal studies. Han et al. studied gut microbiota of mice after sevoflurane exposure and found that microbiome composition was reduced on day-1, 3, 7, and 14 after sevoflurane anaesthesia compared to the control group. They also noted a significant difference in fecal metabolites of the experimental and control groups.[3] Also an infusion of propofol for 3 hours in rats was found to decrease the number of certain bacterial species for 14 days.[4] Postoperative delirium (POD) and post-surgical pain (PSP) have also been attributed to the gut-microbiome by animal studies. This means, why certain patients have more POD or PSP than others can be determined by their gut-microbiome constitution and may be pre-treatment with pre-biotics, post-biotics, or fecal microbiota transplantation reduces the risk of POD and PSP in these patients. However, this association between POD/PSP and gut-microbiome has been shown mostly in animal studies and human association is yet to be established.[1] Zhang et al. compared the gut-microbiota of rats who developed POD and those who did not develop POD after abdominal surgery. The composition of microbiota was significantly different between the groups. They also conducted fecal microbiota transplantation from rats with POD to antibiotic treated rats, which then developed POD.[5] A human study has proved association of gut microbiome with chronic PSP, where Yao et al. had preoperatively collected gut-microbiome samples for 132 patients undergoing breast cancer surgery. The gut microbiota of 66 patients who developed chronic PSP (CPSP) was significantly different from those who did not develop PSP. Fecal microbiome transplantation from CPSP patients to mice led to development of hyperalgesia in these mice.[6] The gut microbiome composition has been attributed to development of opioid tolerance. Chronic opioid exposure leads to activation of opioid receptors on gut epithelium and destruction of gut mucosal barrier, allowing translocation of gut bacteria leading to an inflammatory response and pain exacerbation.[1] The gut microbiota composition influences many chronic pain conditions like fibromyalgia, headache, neuropathic, visceral, and chronic pelvic pain. The mediators of gut microbiota can alter the neuronal excitability at the dorsal root ganglia and mediate neuro inflammation leading to central sensitization and peripheral sensitization in chronic pain. Thus, targeting the gut-microbiota seems to be a promising treatment of chronic pain.[1,2] In future, gut microbiome analysis might help to screen patients at risk of postoperative cognitive dysfunction, postoperative pain, chronic pain and opioid tolerance and alteration of gut microbiota by use of prebiotics, postbiotics, dietary, and life-style changes might provide therapeutic benefit in such patients. However, this hypothesis is based majorly on animal studies and gut microbiome still needs to be explored in humans. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.

Background: The gastrointestinal disorder Peptic Ulcer Disease (PUD) leads to mucosal damage in either stomach or duodenal tissue because of acid-peptic injury. The available evidence demonstrates that Helicobacter pylori (H. pylori) infection and nonsteroidal anti-inflammatory drug (NSAID) usage serve as proven ulcer causes but new research shows the gut microbiome as contributing to ulcer development and therapeutic approaches. Objective: The purpose of this section is to examine the standard H. pylori ulcer development process while examining host immune responses through gut microbial alterations and their effect on PUD disease progression. Methods: This study reviewed multiple research articles to examine how bacteria affect epithelial cells while studying inflammatory pathways as well as microbial metabolites particularly short-chain fatty acids (SCFAs). The review examined different pharmacy-based and natural therapies from the perspective of their ability to modulate the microbiome. Results: The research shows Non-H. Pylori bacteria damage gastric mucosal tissue by activating pro-inflammatory cytokines which leads to gastric homeostasis disturbances because of SCFA production. The ulcer formation gets worse because dysbiosis makes the intestines more sensitive to oxidative stress while simultaneously making the protective mucosal layer weaker. Antibiotics together with proton pump inhibitors affect gut microbial composition but natural treatments including curcumin combined with ginger and probiotics both contribute to microbial recovery and healing of ulcers. Conclusion: Previous research about the gut microbiome's role in PUD pathogenesis forms a base for future development of tailored therapeutic strategies. Combining microbiome-based therapeutic methods with traditional medical protocols produces better management strategies for ulcers with improved healthcare results for patients. Keywords:Peptic Ulcer Disease, Gut Microbiota, Microbial Dysbiosis, Immunoglobulin A (IgA), Gastrointestinal Inflammation, Mucosal Homeostasis