Exploring Microbiome–Host Interactions via Metagenomics & Transcriptomics

Exploring the Role of the Microbiome in Diverse Health Domains

The microbiome refers to the collection of microorganisms—including bacteria, archaea, fungi, and viruses—that inhabit various ecological niches of the body, such as the gastrointestinal tract, oral cavity, skin, lungs, and urogenital tract. These communities are highly diverse and play critical roles in maintaining host physiology, immune function, metabolism regulation.

Among these, the gut microbiome has emerged as a key player in host–microbe interactions, with growing evidence linking its dysregulation to a variety of diseases, including inflammatory bowel disease, metabolic syndrome, and neurodegenerative disorders such as Alzheimer’s disease (AD).

Microbiome Composition and Profiling

The intestinal microbiome is predominantly composed of bacterial phyla such as Firmicutes, Bacteroidetes, Proteobacteria, and Actinobacteria. Its composition is dynamic and influenced by a range of factors including diet, age, antibiotic exposure, and host genetics.

To characterize these communities, two primary metagenomic approaches are employed:

• Microbial Profiling

This technique involves sequencing conserved taxonomic marker genes, allowing identification and estimation of microbial abundance:

• 16S rRNA gene sequencing (for prokaryotes)

• 18S rRNA gene or Internal Transcribed Spacer (ITS) sequencing (for eukaryotes and fungi)

These methods provide a cost-effective and efficient way to explore community structure and diversity, though they are limited in functional resolution (1)

• Microbial functional analysis through Shotgun Metagenomics

This method sequences the entire genomic content of a sample, enabling both taxonomic and functional analysis. It provides insights into the metabolic capabilities, the antimicrobial resistance genes, the virulence factors and microbial interactions.

Beyond Composition: Transcriptomic Profiling

While compositional data provide important insights, transcriptomic analyses add a layer of functional relevance by identifying:

• Microbial gene expression patterns under various conditions (e.g., infection, antibiotic treatment)

• Host transcriptional responses to microbiome changes, offering a dual perspective on host–microbiota interactions

These could be perform by global transcriptomic approach such as Bulk RNA sequencing (2,3) or single cell RNA sequencing (4) or targeted transcriptomic with qPCR or digital PCR (5).

Applications of Microbiome Research

Beyond basic taxonomic composition, microbiome studies have revealed profound implications across a wide range of physiological systems and disease contexts. Multi-omics approaches now enable researchers and clinicians to move from observational correlations to mechanistic insights.

• Nutrition and Obesity

The gut microbiome plays a pivotal role in energy harvest from food, lipid metabolism, adipogenesis, appetite regulation. Alterations in microbial composition are associated with obesity, type 2 diabetes, and response to dietary interventions.

• Brain-Gut Axis

Microbial metabolites and immune signaling influence the neurodevelopment, behavior, mood regulation, neuroinflammation. Gut microbiome has been implicated in mental health and neurodegenerative disorders such as Alzheimer's Disease.(6)

• Cardiovascular Health

The microbiome contributes to cardiovascular functions such as cholesterol metabolism and vascular function. It has been also shown that microbiota can be linked with cardiovascular risk (e.g. microbial production of TMAO) (7)

• Vaginal Flora Health

A balanced vaginal microbiota—typically dominated by Lactobacillus spp.—is essential for the prevention of infections (e.g. bacterial vaginosis), fertility and resistance to sexually transmitted infection.

• Dental Hygiene and Oral Health

The oral microbiome is involved in several conditions like dental caries, gingivitis, peridontal disease. Shifts in oral microbial ecology may also influence respiratory health and Alzheimer’s disease risk. (8)

• Cosmetics and Dermatology

Skin microbiota interact with barrier function, inflammatory responses. It has been implicated in conditions such as acne, eczema, and psoriasis. Microbiome-friendly or modulating products are a growing focus in dermocosmetic innovation.

Case Study: The Gut Microbiome and Alzheimer’s Disease

Recent studies have highlighted the involvement of the gut-brain axis in neurodegenerative diseases. The gut-brain axis is a bidirectional communication system involving the nervous system, immune pathways, hormonal signaling, and microbial metabolites.

Microbial Alterations in Alzheimer’s Patients

An increasing body of evidence points toward specific alterations in the gut microbiome of Alzheimer’s disease (AD) patients. In a recent study by Heravi et al. (2023), (9) , the authors reported that:

• Bacteroides and Acidobacteriota were abundant in the AD cases

• Acidaminococcaceae, Firmicutes, Lachnospiraceae, and Ruminiclostridium were abundant in the control

• The microbial signature study showed the association of Ruminococcaceae, Bacteroides, and Actinobacteria taxa with AD.

  
  

Such microbial imbalances may promote chronic systemic inflammation and disrupt immune–neural communication, contributing to disease pathology.

Fecal Microbiota Transplantation (FMT) and Causality

To establish a causal relationship of the microbiota on AD, Grabrucker et al. (2023) (10) performed fecal microbiota transplantation (FMT) from AD patients into rats. Remarkably, the recipient animals developed:

• Adult hippocampal neurogenesis impairments

• Cognitive impairments

• Synaptic dysfunction

  
  

This compelling evidence suggests that microbial dysbiosis is not merely a consequence of neurodegeneration but may play a contributory role in its progression.

References:

(1) Lakshmanan V, Ray P, Craven KD. Rhizosphere Sampling Protocols for Microbiome (16S/18S/ITS rRNA) Library Preparation and Enrichment for the Isolation of Drought Tolerance-Promoting Microbes. Methods Mol Biol. 2017;1631:349-362. doi: 10.1007/978-1-4939-7136-7_23. PMID: 28735410.

(2) Pisu D, Huang L, Grenier JK, Russell DG. Dual RNA-Seq of Mtb-Infected Macrophages In Vivo Reveals Ontologically Distinct Host-Pathogen Interactions. Cell Rep. 2020 Jan 14;30(2):335-350.e4. doi: 10.1016/j.celrep.2019.12.033. PMID: 31940480; PMCID: PMC7032562.

(3) Westermann AJ, Barquist L, Vogel J. Resolving host-pathogen interactions by dual RNA-seq. PLoS Pathog. 2017 Feb 16;13(2):e1006033. doi: 10.1371/journal.ppat.1006033. PMID: 28207848; PMCID: PMC5313147.

(4) Huang W, Wang D, Yao YF. Understanding the pathogenesis of infectious diseases by single-cell RNA sequencing. Microb Cell. 2021 Aug 4;8(9):208-222. doi: 10.15698/mic2021.09.759. PMID: 34527720; PMCID: PMC8404151.

(5) Gliddon HD, Kaforou M, Alikian M, Habgood-Coote D, Zhou C, Oni T, Anderson ST, Brent AJ, Crampin AC, Eley B, Heyderman R, Kern F, Langford PR, Ottenhoff THM, Hibberd ML, French N, Wright VJ, Dockrell HM, Coin LJ, Wilkinson RJ, Levin M. Identification of Reduced Host Transcriptomic Signatures for Tuberculosis Disease and Digital PCR-Based Validation and Quantification. Front Immunol. 2021 Mar 2;12:637164. doi: 10.3389/fimmu.2021.637164. PMID: 33763081; PMCID: PMC7982854.

(6) Heravi FS, Naseri K, Hu H. Gut Microbiota Composition in Patients with Neurodegenerative Disorders (Parkinson's and Alzheimer's) and Healthy Controls: A Systematic Review. Nutrients. 2023 Oct 13;15(20):4365. doi: 10.3390/nu15204365. PMID: 37892440; PMCID: PMC10609969.

(7) Canyelles M, Borràs C, Rotllan N, Tondo M, Escolà-Gil JC, Blanco-Vaca F. Gut Microbiota-Derived TMAO: A Causal Factor Promoting Atherosclerotic Cardiovascular Disease? Int J Mol Sci. 2023 Jan 18;24(3):1940. doi: 10.3390/ijms24031940. PMID: 36768264; PMCID: PMC9916030.

(8) Jungbauer G, Stähli A, Zhu X, Auber Alberi L, Sculean A, Eick S. Periodontal microorganisms and Alzheimer disease - A causative relationship? Periodontol 2000. 2022 Jun;89(1):59-82. doi: 10.1111/prd.12429. Epub 2022 Mar 4. PMID: 35244967; PMCID: PMC9314828.

(9) Heravi FS, Naseri K, Hu H. Gut Microbiota Composition in Patients with Neurodegenerative Disorders (Parkinson's and Alzheimer's) and Healthy Controls: A Systematic Review. Nutrients. 2023 Oct 13;15(20):4365. doi: 10.3390/nu15204365. PMID: 37892440; PMCID: PMC10609969.

(10) Grabrucker S, Marizzoni M, Silajdžić E, Lopizzo N, Mombelli E, Nicolas S, Dohm-Hansen S, Scassellati C, Moretti DV, Rosa M, Hoffmann K, Cryan JF, O'Leary OF, English JA, Lavelle A, O'Neill C, Thuret S, Cattaneo A, Nolan YM. Microbiota from Alzheimer's patients induce deficits in cognition and hippocampal neurogenesis. Brain. 2023 Dec 1;146(12):4916-4934. doi: 10.1093/brain/awad303. Erratum in: Brain. 2024 Aug 1;147(8):e61. doi: 10.1093/brain/awae208. PMID: 37849234; PMCID: PMC10689930.