Author Interview:
1. Abhishek Goel is an analyst at Axtria – Ingenious Insights, specializing in data-driven solutions for pharmaceutical clients. With a background in Computational Biology (M.Tech, IIIT Delhi) and Pharmacy (B.Pharm, DPSRU), he integrates machine learning, Python, and SQL to analyze sales data and optimize incentive plans. His research expertise includes pharmaceutical analytics and translational health sciences, earning him multiple academic awards. Passionate about scientific innovation, Abhishek aims to bridge computational and pharmaceutical sciences for impactful insights.
2. Omprakash Shete is a PhD scholar in the department of Computational Biology at Indraprastha Institute of Information Technology, Delhi (IIIT-Delhi). He has done his B.Tech in Biotechnology from College of Agriculture Biotechnology, Loni, Maharashtra. And masters from Department of Computational Biology, IIIT Delhi. His research interest is in Human Metagenomics, specifically the Oral-Gut axis and Gut-Renal axis.
3. Sourav Goswami is currently pursuing his Ph.D. in the Microbiome Informatics Lab under the supervision of Dr. Tarini Shankar Ghosh at IIIT-Delhi. He has completed his bachelor’s in Chemistry (Hons.) from University of Calcutta and later on moved to School of Computational and Integrative Sciences, Jawaharlal Nehru University, New Delhi to complete his Master’s in Computational Biology. His research interest lies in the area of functional metagenomics and gut-microbiome related disease risk predictions using explainable machine learning and deep learning algorithms.
Lab: Dr. Tarini Shankar Ghosh, Indraprastha Institute of Information Technology
Research Summary: The HACK index ranks 201 gut microbiome taxa based on global prevalence, long-term-stability and health associations leveraging 141 study cohorts spanning 42 countries facilitating its utility in interventions and therapeutics.
What was the core problem you aimed to solve with this research?
Gut microbiome has been shown to be both a ‘sensor’ and ‘modulator’ of our health. It has also been implicated as a ‘translator’ of the environmental signals, diet and life-style on our health. We cannot alter our genome, but we can modulate our gut microbiome. Consequently, the utilization of the gut microbiome as a diagnostic ‘sensor’ as well as the therapeutic manipulation of the gut microbiome using different intervention strategies represent two frontier areas of gut microbiome research.
Microbiome-based therapeutics aim to restore gut health using probiotics, prebiotics, synbiotics, and fecal transplants like intervention strategies. However, the formulation, evaluation and success of both gut microbiome-targeted diagnostic and therapeutic strategies requires an understanding of what constitutes a ‘health-associated’ microbiome. While multiple meta-analyses evaluating the differential abundance of different microbes in different scenarios have identified taxa based on their differential abundances that commonly denote depleted or enriched taxa across multiple diseases, there have been many examples of context-dependent health association for different microbes including certain ‘probiotic’ microbes like Akkermansia muciniphila and Dorea (i.e. associated with health in a certain scenario and disease in others). This has been further complicated by the considerable variation of the gut microbiome across different populations (different microbes associated with non-diseased individuals in different populations). Therefore, a standardized universal definition of a health-associated gut microbiome is very challenging. This is also evident in the variable success rates of different interventions across populations.
Nevertheless, the gut microbiome is essentially a community of microbes residing in close homeostasis with both its human host and its environmental exposure. The overall picture of a ‘healthy’ microbiome may vary depending upon the environment and the demographics of the host (which may be hyper-variable across populations). However, certain features, which are associated with its direct homeostasis of the human physiology and gut micro-environment, are expected to be conserved. These should be the universal hallmarks of the human gut microbiome. We hypothesized that the identification of these hallmarks should be possible if we investigate the global microbiome and rank various microbiome members as a spectrum based on the consistency of their association with host/microbiome health. Looking into their genomic functions could further reveal the potential functional characteristics of these universal hallmarks. This formed the core basis of the current study.
How did you go about solving this problem?
We hypothesized that a global ranking index of gut microbial taxa based upon these properties would provide a basis of building universal microbiome-health indices as well as for building a priority list of microbes for formulating and evaluating the efficacies of microbiome-based therapeutics. Such an index should be computed utilizing longitudinal and cross-sectional gut microbiome sequence data from several population cohorts covering a broad range of disorders that are publicly available.
In this study, we created a ranking of 201 gut microbes, known as the “HACK index” (Health-Associated Core Keystone Index), by assigning scores to these taxa based on their association with three measurable characteristics: prevalence/community association in subjects who were apparently non-diseased, longitudinal stability, and negative association with disease. A discovery cohort of 39,926 gut microbiomes from 127 cohorts including cross-sectional and longitudinally sampled datasets spanning 42 nations and 28 distinct disease conditions was used to calculate the index.
We showed that the obtained ranking orders were reproducible across cohorts irrespective of microbiome profiling strategies, population lifestyle (industrialized v/s non-industrialized) and also in an ‘unseen’ validation cohort of 14 study cohorts with 5,498 gut microbiomes. We also identified potential genomic functions associated with this order and observed that the microbes higher up on this order had specific conserved functions relating to the production of short-chain fatty acids, multiple vitamins, metabolites associated with improved cognitive function, sporulation and beneficial exo-polysaccharides.
How would you explain your research outcomes (Key findings) to the non-scientific community?
The human gut can be regarded as a gigantic community that includes the human host as well as the multitude of microbes that reside in the gut. The health and the stability of any community is dependent upon two aspects: the adaptability of the community to the external environment and the nature of the interactions of the members amongst themselves (in this between the human host and the different microbes and between the different microbes). Thus a ‘health-associated’ or ‘healthy’ or ‘good’ gut microbiome (or ‘community’) needs to have essentially two kinds of members.
The first kind of members will be those that enable the adaptation of the gut community to our diet, life-style (medication, hygiene, medications) and demographic characteristics (like age). These members can vary widely across individuals and different populations depending on their environmental exposure and form the basis of the wide-spread variations in the normal (or ‘healthy’) microbiomes across different populations and individuals. These members will be highly personalized. Building universal measures of microbiome health using these members is very challenging (though not impossible).
The second kind of members, on the other hand, perform key functions that beneficially impact certain aspects of human physiology in general (that are conserved across all humans irrespective of geography, lifestyle and other demographics) and are essential for our well-being as humans. Many times these functions require multiple members each performing a part of the function and members that bind these members together also belong to this second critical group. Given the conservation of these functions across all humans, this second group members are more likely to be conserved across populations and this subset of the microbiome can act as the universal hallmarks of host and microbiome health. These microbes are expected to be lost across multiple diseases, associated with the stability of gut microbial communities globally and strongly associated with multiple other members in ‘healthy’ gut microbiomes across geographies. In this research, we have investigated the global data of more than 45,000 gut microbiomes to identify specifically this second group of microbes.
“We are now further probing the functions encoded by the high-HACK-microbes and their associations with response to diverse therapeutic interventions.”
What are the potential implications of your findings for the field and society?
Our findings provide a data-driven ranking index to prioritize beneficial gut bacteria for use in microbiome-based therapies. This can help in-
- Developing better probiotics and biotherapeutics by leveraging the health-associated gut microbial taxa based on HACK index.
- Personalized medicine, where doctors could assess a person’s gut health by screening the high-ranked bacteria.
- Enhancing strategies to measure treatment response, since we found that certain gut bacteria improve responses to dietary interventions and cancer therapies.
In the long run, this could lead to more precise and effective gut microbiome treatments, improving overall health and disease management.
What was the exciting moment during your research?
There were multiple exciting moments during this research project. The first was the observation that the ranking order (HACK index) that we obtained in our investigation were remarkably consistent across the global microbiome data despite the usage of different profiling strategies and wide-spread variations in population life-styles. Thus, despite differences in diet, geography, and study techniques, the association of certain microbes associated with gut health and microbiome resilience are remarkably stable and consistent across the globe. The second exciting discovery was finding that just 17 key bacterial species with high HACK index could predict gut health (outperforming existing microbiome health measures in multiple external validation cohorts) as well as driving dietary interventions like Mediterranean Diet. Species at the top of this order were notably also associated with response to Cancer Immunotherapies. Thus, the same index can potentially help in identifying the universal markers of health and microbiome resilience as well as markers of beneficial response to therapeutic interventions. Another exciting discovery was the identification of supplements/compounds (Inulin, Xylan, FOS) that could enrich these markers as well as multitude beneficial genomic/metabolic functions of these microbes that can beneficially impact multiple aspects of human physiology.
Reference: Goel, A., Shete, O., Goswami, S. et al. Toward a health-associated core keystone index for the human gut microbiome. Cell Reports 44, (2025). https://doi.org/10.1016/j.celrep.2025.115378
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