Unravelling the gut-lung axis: insights into microbiome interactions and Traditional Indian Medicine's perspective on optimal health

Abstract The microbiome of the human gut is a complex assemblage of microorganisms that are in a symbiotic relationship with one another and profoundly influence every aspect of human health. According to converging evidence, the human gut is a nodal point for the physiological performance matrixes of the vital organs on several axes (i.e. gut-brain, gut-lung, etc). As a result of COVID-19, the importance of gut-lung dysbiosis (balance or imbalance) has been realised. In view of this, it is of utmost importance to develop a comprehensive understanding of the microbiome, as well as its dysbiosis. In this review, we provide an overview of the gut-lung axial microbiome and its importance in maintaining optimal health. Human populations have successfully adapted to geophysical conditions through traditional dietary practices from around the world. In this context, a section has been devoted to the traditional Indian system of medicine and its theories and practices regarding the maintenance of optimally customized gut health.


Introduction
The human body is inhabited by a community of microorganisms that live in a symbiotic relationship with their host.Microbiota is the term used to describe the collection of micr oor ganisms, including bacteria, archaea, and some unicellular eukaryotes, that inhabit a specific environment or niche, such as the gut, mouth, or skin, etc. (Lederber g and McCr ay 2001 , Marc hesi and Ra vel 2015 ).T he microbiome includes the community of microorganisms ( i.e. microbiota) and the molecules that they produce (Whipps et al. 1988, Berg et al. 2020 ).Among these molecules are nucleic acids , proteins , carbohydrates , and lipids , as well as their metabolites , including toxins , or ganic and inor ganic molecules, signaling molecules, and molecules produced by coexisting hosts and influenced by the envir onment ar ound them.The microbiome also includes other genetic elements such as viruses and plasmids, whic h ar e ca pable of moving fr om one or ganism to another.They form a complex ' theatre of activity ' that influences many aspects of human physiology and health (Berg et al. 2020 ).
Humans are now considered to have two genomes: an inherited genome from a person's biological parents, and the acquired genome post-birth ( i.e. the microbiome) (Grice and Segre 2012 ).The inherited genome remains relatively stable throughout a person's lifetime, whereas the acquired microbiome is dynamic and str ongl y sha ped by factors suc h as a ge (Za pata and Qua gliar ello 2015 ), diet (David et al. 2014 ), lifestyle (Song et al. 2020 ), tr av el (Voorhies and Lorenzi 2016 ), geography (Yatsunenko et al. 2012 ), hormonal cycles (Koren et al. 2012 ), illness (Cho andBlaser 2012 , Pflughoeft andVersalovic 2012 ) and drug interv entions/ther a pies (Ta piainen et al. 2019, Ribeir o et al. 2020 ).The human microbiome plays a pivotal role in homeostatic r egulation, the de v elopment of the immune system, food digestion, and detoxification (D'Argenio and Salv ator e 2015 ).
In this current review, we provide an ov ervie w of the ecology and the functional role of the gut and airway microbiome.The communication between the gut and lung (' gut-lung axis ') provides mechanistic insights into how the (' dysbiotic ') gut microbiota may affect r espir atory imm unology and lung health (e.g.COVID-19 infections) is also discussed here.We further discuss the role of probiotics and prebiotics on the microbiome and the pr e v ention and treatment approaches of the traditional Indian system of medicine.

Microbial ecology and function in the healthy human gut and respir a tory tr act
Microbial ecology, the study of the interactions between microorganisms and their en vironment, pla ys a crucial role in understanding the structure and function of micr obial comm unities in the human gut and r espir atory tr act.The persistence of microbes in the gut is influenced by the complex interplay of factors, including differences in physiological niches and downstream microbial colonization (de Vos et al. 2022 ).T he gut en vironment differs markedly between anatomical regions in terms of physiology, flow r ates, substr ate av ailability, pH, oxygen concentr ations, redox potential, host secretions (i.e .mucus , bile , and antibodies), the gut arc hitectur e , peristalsis , and transit times (de Vos et al. 2022 ).Furthermor e, the micr obiota complexity v aries, and bacterial load increases gradually along the gastrointestinal tract (Shah et al. 2020 ).While fungi and archaea also contribute to the gut microbiota, their load in the gastrointestinal tract are still not well-c har acterized.Fig. 1 illustr ates the micr obial composition, and the typical order of magnitude estimates for the number of bacteria that inhabit different physiological niches of the human gastrointestinal and respiratory tract (Pei et al. 2004, Chen et al. 2010, Ghannoum et al. 2010, Matarazzo et al. 2011, Blaut 2018, Rajilic-Stojanovic et al. 2020 ).The gut microbiome provides the human host with se v er al essential functions .T he gut microbiota converts indigestible foods into metabolites that are easily absorbed (Tr emar oli and Bäc khed 2012 ), synthesizes essential vitamins (LeBlanc et al. 2013 ), r emov es toxic compounds (Claus et al. 2016 ), outcompetes pathogens (Sommer and Bäckhed 2013 ), strengthens the intestinal barrier (Abreu 2010 ), and stimulates and regulates the immune system (Abreu 2010, Hooper Lora et al. 2012 ).Most of these functions are interconnected and tightly intertwined with human physiology.
Similarl y, the r espir atory tr act micr obiome is sha ped by envir onmental exposur es and physiological par ameters suc h as pH, temper atur e, and oxygen and carbon dioxide le v els.Our curr ent understanding of the airway microbiome has been r elativ el y limited compared to the gut microbiome, which has been the focus of most microbiome studies, especially in clinical settings.Nonetheless, the field of airway microbiome research has shown significant pr ogr ess in r ecent years.Although less abundant compar ed to the gut micr obiome, numer ous studies have shown that the airway microbiome is a significant component of the airway ecosystem that is also connected with the immune system (Adami and Cervantes 2015, Lee et al. 2016, Freeman and Curtis 2017, Huffnagle et al. 2017, Stavropoulou et al. 2021, Yagi et al. 2021 ).Microbial spread in the airways is considerably different from that of the gut r egion.The gr adient is a r esult of a gr eater aer obic envir onment, v ariable temper atur e (due to gas exc hange), and coating of bacteriostatic lipopol ysacc haride acr oss the alv eolar surface (Huffnagle et al. 2017 ).In humans , the airwa y micr obiome differs fr om the gut microbiome in its developmental timeline, with the former lar gel y established between birth and three years of age .T his pr ocess is mainl y sha ped by envir onmental factors, r ather than the transmission of microbes from the mother to the child during birth (Fr a gk ou et al. 2021 ).

The gut-lung axis
As distant as they are physical, the r espir atory and gastr ointestinal tracts share the same embryonic origin and common structure, suggesting that their interactions may be multifaceted.There is a clear crosstalk between the two sites known as the gutlung axis, which was reported recently (Budden et al. 2017 ).The gut-lung axis refers to the reciprocal exchanges of microorganisms and/or their metabolites and immunomodulatory signals between the gut and lungs (Fig. 2 ).While such crosstalk occurs in both directions, the mechanisms underlying these transfers are not w ell understood.Ho w e v er, ther e is consider able e vidence in the liter atur e that indicates the role of micr obial cr osstalk in r espiratory disorders.

Micr obial cr osstalk between the gut and lungs
The mucosal epithelial surfaces of the gastrointestinal and respir atory tr acts ar e continuousl y exposed to a v ariety of micr oorganisms .T he micr oor ganisms can gain access due to inhalation or ingestion, and the transfer of micr oor ganisms fr om the or al cavity and upper gastrointestinal tract to the lung can occur due to aspiration (Budden et al. 2017 ).While the gut and the respiratory tr act micr obiota ar e v ery similar at the phylum structur e le v el, the members that dominate these phyla are very different.Actinobacteria, Firmicutes, and Bacter oidetes pr edominate in the gut, and Proteobacteria, Firmicutes and Bacteroidetes dominate in the lungs (Trivedi and Barve 2020 ).The gut and lung microbiota show a close relationship throughout life, indicating a host-wide netw ork betw een them (Grier et al. 2018 ).It w as also reported that gut and lung abundances are highly correlated over time (Madan et al. 2012 ).Madan et al. ( 2012 ) suggested that changes in diet alter gut colonisation patterns and that colonization with Roseburia , Dorea , Coprococcus , Blautia , or Esc heric hia pr esa ged their a ppear ance in the r espir atory tr act.The liter atur e on the dir ect tr ansfer of micr oor ganisms between the gut and lungs is very limited.Various hypotheses have been postulated to explain gut-lung translocation such as the gut-lymph theory (Trivedi and Barve 2020 ) or the common m ucosal imm une system (He et al. 2020 ).Scientific e vidence shows that the barrier integrity is compromised in cystic fibrosis , sepsis , and acute r espir atory distr ess syndr ome suggesting gut-lung translocation of microorganisms (Madan et al. 2012, Dickson et al. 2016 ).Similarly, Dickson et al. ( 2016 ) demonstrated that the lung microbiota is enriched with gut bacteria, such as Bacteroides spp.after sepsis and acute r espir atory distr ess syndr ome.

Perturbation of the gut-lung axis by bacterial components and metabolites
The gut microbiota communicates with the lungs via soluble microbial components and bacterial metabolites which r eac h the systemic circulation.Microbial components include pathogen-associated molecular patterns (PAMPs), such as peptidoglycans and lipopolysaccharides.Host cells that express pattern r ecognition r eceptors suc h as Toll-like r eceptors (TLRs) or nucleotide-binding and oligomerization domain (NOD)-like receptors (NLRs) can recognise peptidoglycans and lipopolysaccharides, among other PAMPs (Wypych et al. 2019 ).The TLRs are a wellc har acterised famil y of r eceptors, widel y expr essed in imm une cells (including macr opha ges , mast cells , natural killer cells , neutrophils , eosinophils , basophils , and dendritic cells) and body cells (including intestinal epithelial cells).The activation of TLRs induces the activation of antigen-presenting cells and triggers the signalling cascade to encounter the inv ading micr obes and/or repair the damaged tissue.Excessi ve acti vation of TLRs disrupts The host also senses microbial metabolites (e.g.short-chain fatty acids; SCFAs) produced from the metabolism of indigestible nutrients (e.g.dietary fibres).Most of the SCFAs are either consumed by the colonocytes for energy or used by the epithelial cells in the gut to shape local immunity (Fig. 2 ).The remainder is transported to the liver via the portal vein for metabolism.Any unmetabolised SCFAs are then redistributed through the circulation to peripheral tissues (Yip et al. 2021 ).For example, in bone marr ow, SCFAs influence imm une cell de v elopment (Wypyc h et al. 2019 ) by impairing the ability of dendritic cells (DCs) resulting in an attenuated allergic response (Trompette et al. 2014, Cait et al. 2018 ), or by pr omoting differ entiation of regulatory T cells (T reg cells) resulting in a reduced asthmatic response (Thorburn et al. 2015 ), or by reducing neutrophil recruitment to the airways during influenza (Trompette et al. 2018 ) (Fig. 2 ).Desaminotyrosine, produced by an obligate clostridial anaerobe from the digestion of plant fla vonoids , was found to protect from influenza through type I interferons (Steed et al. 2017 ) (Fig. 2 ).

Migr a tion of immune cells
Another significant route of communication in the gut-lung axis involves the migration of immune cells from the intestine to the r espir atory tr act thr ough circulation.Pu et al. ( 2021 ) demonstrated that the gut microbiota directs the migration of innate lymphoid cells type 2 (ILC2) from the gut to the lung via the gut-lung axis.ILC2s play a critical role in regulating the immune response, controlling bacterial infections, and maintaining lung homeostasis.The host produces interleukin (IL)-33 in response to an increase in Proteobacteria within the gut microbiome , which pla ys a critical role in facilitating the natural migration of ILC2 (Pu et al. 2021 ) (Fig. 2 ).The sensing of commensal bacteria by intestinal DCs induces the secretion of IL-22.These cytokines are needed to prime the mucosal ILC3 to migrate from the intestine to the lungs (Gray et al. 2017 ) (Fig. 2 ).Ho w e v er, these cells hav e different roles in the immune system, with ILC3s being involved in the maintenance of mucosal immunity in the gut and r espir atory tract, while ILC2s primarily regulate allergic and anti-parasitic responses.ILC3s produce cytokines such as IL-22 and IL-17 to protect against infections and maintain the integrity of the mucosal barrier, while ILC2s produce cytokines such as IL-5 and IL-13 to activate eosinophils and promote IgE antibody production.Furthermor e, this cr osstalk between gut and lung might also occur during diseases , e .g. the migr ation of T H -17 cells co-expr essing T cell antigen receptors that recognize segmented filamentous bacteria (SFB) epitope and self-antigen to lungs, contributing to lung pathology (Bradley et al. 2017 ) (Fig. 2 ).Another example of the gutlung axis crosstalk can be seen in the case of fungal overgrowth in the gut.Candida spp.(as well as many other fungi) dir ectl y pr oduce pr osta glandin E2 (PGE 2 ), a potent immunomodulator that is produced by immune cells from host arachidonic acid (Underhill and Iliev 2014 ).Kim et al. ( 2014 ) demonstrated that PGE 2 produced due to the ov er gr owth of commensal Candida species in the gut can r eac h the lungs through the bloodstream, induce macrophage polarisation in the lungs, and influence systemic responses, including allergic inflammation.

Dysbiosis: detrimental deviation in microbiome
T he microbiome pla ys an important role in maintaining homeostasis in a healthy body.Many of the modern multifactorial diseases such as obesity, allergies , diabetes , asthma, inflammatory bo w el disease (IBD), and neur odegener ation that are becoming mor e common hav e been linked to ' d ysbiosis ', an aberr ant micr obiome structure that alters the taxonomic composition as well as the metagenomic function of the microbial community with the human host.Dysbiosis is defined as a change in the composition and function of the microbiota, caused by a combination of environmental and host-related factors that disrupt the commensal ecosystem to a degree that exceeds its resistance and resilience capabilities (Figs 3 and 4 ).
Dysbiosis continues as a stable condition once the microbiota configuration is modified, and it can take on numerous compositional expressions depending on the causative influence (David Figure 2. Sc hematic r epr esentation illustr ating the concept of cr oss-talk between the gut and lung in the context of the human gut-lung axis.SFB: segmented filamentous bacteria, Ag: antigen, ILC: innate lymphoid cells, IFN: interferon, IEC: intestinal epithelial cells.Please note, this figure is not intended to provide an anatomically accurate depiction of the organs or their precise spatial arrangement.Rather, it serves to visually demonstrate the communication and interactions between these systems.The figure highlights the interplay between the gut and lung and their potential influence on each other's microbiomes.Please note that the spatial relationships and anatomical details are simplified for conceptual clarity.This figure is intended to support the discussion on the role of traditional medicines in managing the gut-lung axis, rather than providing detailed anatomical information.Created with BioRender.com. et al. 2014 ).The commensal microbial community in the human body can be thought of as a stable system, where healthy and dysbiotic states exist in different configurations, akin to an ener gy landsca pe.Ho w e v er, for the system to tr ansition fr om one state to another, external forces stronger than the system's inherent stability are required.In simpler terms, the human microbial community can exist in both healthy and unhealthy states, but a significant disruption is necessary to shift the system from one state to another (Lloyd-Price et al. 2016 ).The enormous variability in taxonomic microbiota composition among healthy individuals due to geogr a phical distribution, a ge, and dietary habits raises the question of what constitutes a r efer ence population, allowing almost any gut microbial configuration to be classified as ' dysbiotic ' when compared to a specific control.Even in vivo experimental models of dysbiosis are not able to address this lacuna.The micr obiome's ada ptations to alter ed envir onmental conditions or changes in the host's state ultimately result in atypical community composition and function and can have favour able, neutr al, or detrimental effects on the host.Ada ptiv e c hanges in the micr obiome in response to perturbations of the steady state, like host tissue deviations from homeostasis , ma y be harmful if the microbial community does not return to its pr e vious state after normalisation of environmental conditions, and instead persists c hr onically in a 'maladaptive' state with adverse repercussions for the host (Fonseca et al. 2015, Thaiss et al. 2016 ).Ther efor e, it would be r ather a ppr opriate to define dysbiosis as a micr obial comm unity state within the human body that is not just statistically related to the disease but also functionally contributes to the disease's aetiology, diagnosis, or treatment.
Dysbiosis is c har acterized by an explosion in pathobiont population (Frank et al. 2007, Garrett et al. 2007, Stecher et al. 2013 )  .Molecular links between gut microbiota and host health in healthy and dysbiotic state.In a healthy gut, intestinal epithelial cells (IECs) utilise butyrate through mitochondrial beta-oxidation, maintaining an anaerobic environment.Butyrate binds to peroxisome proliferator-activated receptor gamma (PPAR γ ), reducing inducible nitric oxide synthase (iNOS) expression and nitric oxide (NO) production.G-protein-coupled receptor (GPR)109 serves as a major receptor for butyrate.In dysbiosis, low butyrate levels decrease PPAR γ activity, increase glycolysis, and elevate iNOS expression, leading to an increased NO production and nitrates.Butyrate stimulates immune cells, like regulatory T cells (T reg ), through GPR109, exerting anti-inflammatory effects.Reduced aryl hydrocarbon receptor (AhR) activity disrupts gut barrier function.short-chain fatty acids (SCFAs: butyr ate, pr opionate and acetate), endocannabinoids, and bile acids activate receptors on L-cells and IECs, promoting gut peptide secretion.SCFAs activate GPR41 and GPR43 on L-cells, promoting secretion of gut peptides including glucagon-like peptide-1 (GLP-1), GLP-2, and peptide YY (PYY).Endocannabinoids interact with cannabinoid receptors type 1 (CB1), CB2, PPAR α, PPAR γ , and transient receptor potential vanilloid type-1 (TRPV1) receptors, while bile acids activate farnesoid X receptor (FXR) and Takeda G protein-coupled receptor 5 (TGR5) receptors.Gut pattern recognition r eceptors suc h as toll-like r eceptors (TLRs) detect pathogen-associated molecular patterns (PAMPs) and lipopol ysacc harides (LPS) fr om the micr obiota.These interactions reduce intestinal permeability, enhance insulin sensitivity and secretion, decrease food intake, lo w er plasma lipids, and mitigate hepatic steatosis and endotoxemia risk, associated with reduced inflammation.Dysbiosis leads to opposite effects.Ov er all, inter actions among gut microbiota, IECs, immune cells, and molecular receptors maintain gut homeostasis and impact metabolism and inflammation.Created with BioRender.com.
Experimentally, dysbiosis was first observed in mouse models of Citrobacter rodentium (Lupp et al. 2007 ) and Salmonella enterica subsp.enterica ser ov ar Typhim urium infection (Stec her et al. 2007 ).Inflammation-induced expansion of Enterobacteriaceae members can enhance the de v elopment of colorectal cancer (Arthur et al. 2012 ) and sepsis (Ayres et al. 2012 ), in addition to intestinal infection.The release of nutrients (Ng et al. 2013 ), the use of metal ions (Deriu et al. 2013 ), inter-microbial competition and horizontal gene transfer (Stecher et al. 2012 ), the exploitation of antimicrobial peptides (Behnsen et al. 2014 ), and the harnessing of aerobic and anaerobic cellular respiration (Winter et al. 2013, Lopez et al. 2016 ) are all molecular mechanisms that lead to the establishment of Enterobacteriaceae in the inflamed gut.
Diet has significant short (David et al. 2014 ) and long-term (Wu et al. 2011 ) impacts on the microbiota composition in the intestine.Dietary xenobiotics could modify homeostatic commensal colonization in addition to negativ el y affecting the nutrition content of the food.This is most obvious in the case of antibiotics (Cho et al. 2012 ), but it has also been observed for non-caloric artificial sweeteners (Suez et al. 2014 ) and dietary emulsifiers (Chassaing et al. 2015 ), though the mechanisms by which the latter two influence the microbiota is unknown.Dysbiosis caused by diet and xenobiotics is an important driver of illness symptoms in mice (Yoshimoto et al. 2013 ) and, in some situations, humans (Zhu et al. 2016 ).In addition to the parameters described abo ve , host genetics play a significant role in the composition of the microbiota, particularly, that of the gut (Levy et al. 2015 ).Genome-wide association studies that linked genetic loci with microbial taxa and functional pathways (Bonder et al. 2016, Turpin et al. 2016 ) discov er ed this and other associations.In addition, many human loci Figur e 4. T he micr obiome-imm une pr oteins-cellular inter action in the lungs.Cr eated with BioRender.com.involv ed in imm unological and metabolic activities, including the one encoding for the human vitamin D r eceptor, wer e identified as potential drivers of microbial regulation through host genetics (Wang et al. 2016 ).It is important to consider that dysbiosis is not limited to the gut.Epithelial cell m utations wer e found to lead to lung microbiome dysbiosis in patients diagnosed with squamous cell carcinoma (Greathouse et al. 2018 ).The epithelial cell mutations were attributed to smoking.Similarly, in the case of lung cancer patients, the enriched Acidovorax temporans population was associated with tumour suppressor gene TP53 m utations, whic h cause epithelial impairment in the lungs.

Lung microbiome and gut-lung axis: a COVID-19 perspective
Recent r esearc h has shown that the composition of upper airway bacteria is altered during COVID-19 infection.While Veillonella parvula was observed to be more abundant during moderate infection, Actinomyces meyeri and Halomonas spp.were more abundant during mild conditions .T his differential abundance suggests a possible role for these species in modulating the immune response to COVID-19 infection, which may lead to increased metabolic activity during mild or moderate disease (Devi et al. 2022 ).Nardelli et al. ( 2021 ) studied both upper and lower r espir atory regions during COVID-19.They observed that the abundance of Veillonella, Staph ylococcus , Corynebacterium, Neisseria, Actinobacillus , and Selenomonas increased in the upper airway of COVID-19 patients in comparison with healthy participants.On the other hand, Haemophilus and Alloiococcus abundance decreased in COVID-19 patients with respect to healthy participants.In the lo w er airw ay region, the abundance of Prevotella, Staph ylococcus , Haemophilus , and Enterococcus increased, while that of Veillonella spp.decreased in fatal infections.During se v er e but non-fatal conditions, an increased abundance of Streptococcus, Neisseria, Abiotrophia , and Actinobacillus was observed.The differential bacterial abundance in the nasopharyngeal cavity was also shown during se v er e SARS-CoV-2 infection (ICU patients) with respect to mild COVID-19, other coronavirus infections, and uninfected individuals (Rueca et al. 2021 ).Furthermore, Fusobacterium periodonticum population depletion, resulting in the perturbation of sialic acid metabolism, has been observed in the nasopharyngeal region of COVID-19 patients with respect to healthy people (Nardelli et al. 2021, Gupta et al. 2022 ).Another recent study also indicated this pattern, where bacterial species such as Corynebacterium accolens and C. macginleyi gr aduall y decr eased in the upper airway r egion as the se v erity of SARS-CoV-2 infection increased (Shilts et al. 2022 ).An increase in opportunistic pathogens during SARS-CoV-2 infection has been shown to include fungal co-infection (Miao et al. 2021 ) in addition to the opportunistic bacterial infections mentioned above (Liu et al. 2021 ).Bronchoalveolar fluid lavage and endotr ac heal aspir ation anal ysis sho w ed infection of these spaces b y Candida spp., Aspergillus spp., and Cryptococcus spp., among all patients (Miao et al. 2021 ).In se v er e cases leading to the death of patients, these fungi a ppear ed to co-infect the circulatory systems as well, causing candiduria and candidemia.Miao et al. ( 2021 ) also sho w ed that prolonged intubation and mec hanical v entilation, rather than SARS-CoV-2 infection, resulted in a less diverse microbiome but a greater enrichment of non-fermentative bacteria such as Acinetobacter spp., Pelomonas spp ., Ralstonia spp ., and Sphingomonas spp.The study indicated the importance of shorter mec hanical v entilation to maintain a normal airway micr obiome, and likely prevent co-infections in patients infected with SARS-CoV-2.
When multi-omic analyses were applied to such conditions, it was observed that opportunistic pathogens such as Prevotella histicola, Streptococcus sanguinis , and Veillonella dispar increased in the nasopharyngeal region during COVID-19 infections.In addition, the decreased abundance of natural commensals such as Gemella haemol ysans and Leptotric hia hofstadii was found to be correlated with serum c hlor ogenic acid methyl ester (CME) depletion (Liu et al. 2021 ).Our study utilizing ferret models has indicated that the citric acid cycle, purine metabolism, and pentose phosphate pathw ays w er e significantl y impacted in the nasal cavity during SARS-CoV-2 infection.On the other hand, glutamate and arginine metabolism increased during the infection (Beale et al. 2021 ), indicating the likely hijacking of glutamate metabolism by viral particles (Thaker et al. 2019 ), and the promotion of pathogens such as Pasteurella multocida (Ren et al. 2013 ).Ov er all, these studies indicated that alterations in the lung microbiome can be used as biomarkers of the se v erity of SARS-CoV-2 infection (Hernández-Terán et al. 2021 ).
Gut-lung axis although lar gel y r emained a neglected area of r esearc h, has gained consider able gr ound since the advent of COVID-19.The SARS-CoV-2 viral has been reported by numerous studies to be found in stool samples (Jin et al. 2020, Pan et al. 2020 ), with some patients e v en showing digestiv e issues postinfection (Jin et al. 2020 ).Meta genomic anal ysis of faecal samples collected from COVID-19 patients revealed elevated levels of Coprobacillus spp., Clostridium ramosum , C. hathew ayi , Actinom yces viscous , and Bacteroides nordii which were associated with the severity of COVID-19 symptoms (Walton et al. 2021 ).Ad ditionally, he patic injury also has been shown in COVID-19 patients (Groff et al. 2021 ).Alter ed angiotensin-conv erting enzyme 2 (ACE2) receptor expr ession, whic h has been seen in lung injury during COVID-19, has also been observed in the gut, across numerous studies (Jin et al. 2021 ), leading to leaky gut and microbiome dysbiosis (Penninger et al. 2021 ), among other disorders.
Although COVID-19 infections in the lungs and gut occur independentl y of eac h other, the underlining cr oss-linka ge still exists, as sho wn b y non-COVID-19 studies.Functional gastrointestinal disorders (FGID) studies have shown that genes related to asthma, such as DENND1B, SMAD3, SLC22A4/5 (5q31/IBD5), and ORMDL3, have been co-associated with Crohn's disease and ulcer ativ e colitis (Lees et al. 2011 ).This co-occurrence has been ascribed to the common embryonic origin of cellular structures in these organs.Both br onc hus-and gut-associated l ymphoid tissues (BALT and GALT) are subtypes of mucosa-associated lymphoid tissue (MALT) (K eel y et al. 2012 , P a panik olaou et al. 2014 ).This relationship has been observ ed e v en mor e starkl y in patients who hav e under gone colectomy (P a panik olaou et al. 2014 ), and high intestinal permeability (Adenis et al. 1992 ).
In the context of infections, the crosstalk of the gut-lung axis is e v en mor e explicit.In the study conducted by Sencio et al. ( 2020 ), it was seen that the faecal transplantation done from Influenza infected mice to healthy mice caused significant gut microbiome dysbiosis.In turn, it caused an SCFA depletion in the gut, follo w ed b y an SCFA depletion in the blood and lungs .T he cascade not only depleted alveolar macrophage activity but also increased host susceptibility to w ar d pneumococcal infection.Furthermore, when acetate was supplemented in the gut, it impr ov ed the alveolar macr opha ge activity (Sencio et al. 2020 ).Similarly, supplementation of desaminotyrosine, a metabolite gener all y pr oduced by gut Clostridium spp. in an influenza mouse model, has been shown to diffuse to the lungs through circulation.The metabolite when diffused into the lungs increased type I IFN-stimulated genes (ISGs).Resultingly, the mortality rate due to influenza infection was seen to be significantly decreased in the mice fed with desaminotyrosine for 1 week before infection, when compared to antibiotics-treated mice (Steed et al. 2017 ).In the context of COVID-19 infections, there is a clear crosstalk between the gut and lungs .Recent studies ha ve shown that COVID-19 patients , e v en after r ecov ery, exhibit depleted populations of butyr ate-pr oducing bacteria in the gut, such as Faecalibacterium spp., Clostridium spp., and Eubacterium spp.(Tang et al. 2020 ) compared to non-COVID-19-infected individuals (Zuo et al. 2021 ).This correlation was also sho wn b y Gutiérr ez-Castr ellón et al. ( 2021) who found that pre-biotic supplementation with Lactiplantibacillus plantarum and Pediococcus acidilactici strains not only reduced diarrhea and abdominal pain, but also decreased viral loads in the lo w er nasopharyngeal cavity, and high SARS-CoV2-binding IgG and IgM titres in the serum.Conv ersel y, COVID-19 patients have also been observed to experience gut dysbiosis that is reflected in their lung health.In a study by El Moheb et al. ( 2020), COVID-19 patients with acute r espir atory distr ess syndr ome (ARDS) de v eloped twice as m uc h tr ansaminitis and se v er e ileus, and slightl y higher bo w el isc hemia/mesenteric isc hemia compar ed to non-COVID-19 ARDS patients (El Moheb et al. 2020 ).This is likely due to the high accumulation of ACE2 receptors in gut enterocytes, making the gut an important target for SARS-CoV-2 infection and replication (Zhang et al. 2020 ).
Given the crucial role of gut microbiota in modulating host immunity and susceptibility to respiratory infections, there is a gr owing inter est in identifying str ategies to maintain a healthy and diverse microbiome.Probiotics and prebiotics, for instance, hav e been pr oposed as potential interv entions that can pr omote beneficial bacterial growth and improve gut barrier function.Similarl y, Ayurv eda, an ancient Indian medical system, emphasizes the importance of diet and lifestyle modifications to maintain a balance of do S .as, which has been linked to ov er all health and disease pr e v ention.In the follo wing sections, w e will discuss the curr ent e vidence on the potential of these interventions in modulating the gut-lung axis and improving respiratory health.

Role of probiotics and prebiotics on the gut microbiome
Pr obiotics and pr ebiotics hav e gained gr eater attention to maintain a healthy and diverse microbial composition in recent years.T hey ha v e been de v eloped as a pr e v entiv e a ppr oac h to maintaining health and well-being based on growing evidence that the gut microbiome plays a significant role in homeostasis (Zucko et al. 2020 ).

Pr obiotics: definition, pr operties, and mechanism of action
According to the Food and Agriculture Organization (FAO) and the World Health Organization (WHO), probiotics are 'live microorganisms that confer health benefits to the host when administrated in adequate amounts' (Sanders 2008(Sanders , K ec ha gia et al. 2013 ) ). Lactobacilli , Bifidobacteria , and other lactic acid-producing bacteria (LAB) hav e been tr aditionall y used as pr obiotics and hav e been primaril y isolated fr om fermented dairy pr oducts and the faecal microbiome.To confer the beneficial effects of probiotics, a bacterial strain should (a) demonstrate antimicrobial activity against pathogenic bacteria, (b) be acid-and bile-tolerant, (c) adhere to mucosal and epithelial surfaces for immune-modulatory action, and (d) possess bile salt hydrolase activity (K ec ha gia et al. 2013 , Geor ge K erry et al. 2018 ).
The mechanism of action of probiotics is quite complex and interactions occur with the host as well as the microbiome via the molecular effectors present on the cell structure or secreted as metabolic products (Aureli et al. 2011, Cunningham et al. 2021 ).Probiotic molecular effectors influence the microbiota by enhancing the intestinal barrier integrity, modulating the inflammatory signalling system, inducing the production of cytopr otectiv e heat shoc k pr oteins, and r egulating a poptosis.
Probiotic metabolites can influence the microbiota by changing the micr o-envir onment of the gastr o-intestinal tr act, competing for nutrients, and binding sites, inhibiting growth via the production of antibacterial compounds, such as bacteriocins, and maintaining the v a ginal and or al m ucosa micr obiomes wher e pathogen ov er gr owth is common.

Probiotics in respir a tory tr act infections
To understand the mechanism of action of probiotics on r espir atory tract infections (RTIs), it is important to note that they oper ate thr ough the gut-lung axis.Although the exact mechanism is not yet fully understood, it is known that probiotics modulate m ucosal imm une function, particularl y by influencing dendritic cell polarization in inductive sites such as P ey er's patches and mesenteric lymph nodes .T hese dendritic cells , in turn, influence T and B cell responses.Once these T and B cells enter circulation, they migrate to extra-intestinal sites such as the respiratory tract.Various studies have shown that probiotics can effectively reduce virus titer in the lungs and inhibit the replication of se v er al r espir atory viruses, including influenza viruses and r espir atory syncytial virus (RSV) (Lehtoranta et al. 2020, Trottein and Sokol 2020, Darbandi et al. 2021, Picó-Monllor et al. 2021 ) As stated pr e viousl y, ACE2 expr ession is down-r egulated in patients during SARS-CoV-2 infection.Downregulation of ACE2 impairs the conversion of ang iotensin II to ang iotensin(1-7), which further inhibits the angiotensin II receptor type 2 (AT2R) that pr ovides lung pr otection.This stim ulates angiotensin II r eceptor type 1 (AT1R) which further leads to hypokalemia, causing lung and cardiovascular injury (Silhol et al. 2020 ).ACE2 is also found in the epithelial cells of the gut and regulates the expression of amino acid transporters that control the intestinal uptake of tryptophan.Tryptophan further regulates anti-microbial peptides; down-regulation leads to impairment in the absorption of intestinal tryptophan and decreases secretion of antimicrobial peptides and, thus, increases the survival of pathogenic micr oor ganisms and causes dysbiosis (He et al. 2020, Zhou et al. 2021 ).Ho w e v er, the exact mec hanism of pr obiotics is not yet established in R TIs, ho w e v er, the effects are influenced by specific str ains, micr obiota composition, and immune status of an individual (Lehtoranta et al. 2020 ).

Prebiotics
Pr ebiotics ar e defined as non-digestible foods such as plant oligosaccharides that pass intact into the intestinal tract and beneficially affect the host by selectively stimulating the growth, composition, and activity of intestinal micr obiota, impr oving host health (Peredo-Lovillo et al. 2020 ).Plant oligosaccharides and pol ysacc harides ar e fermentable and indigestible fibers that feed the intestinal microbes and contribute to SCFA production and thus are good sources of prebiotics.Examples of foods used as prebiotics are given in Table 1 (Batista et al. 2021, Pujari and Banerjee 2021, Walton et al. 2021 ).
Fermented food products (e.g.butter, cheese, yogurt, milk, lentils, meat, fish, and sourdough bread) have been consumed since pre-historic times .T he benefits of fermented foods ha ve been mentioned in ancient texts such as Āyurveda, the Bible, and archaic text from Uruk (Lemmen and Khan 2012 ).Fermented foods (e.g.sauerkr aut, kimc hi, tofu, ghee and tempeh) and be v er a ges (e.g.kefir-fermented milk, kaanji-fermented carrot drink with spices, k ombuc ha-fermented tea, tod d y-fermented palm nectar, koji-fermented drink of s weet potato, rice , or barley, merissa-fermented product of malted sorghum and jiufermented drink of sorghum) have been used traditionally (Gasmi et al. 2021, Ilango and Antony 2021, Pammi et al. 2021 ).Various beneficial micr oor ganisms suc h as lactic acid bacteria, yeast, and Rhizopus spp.have been isolated from fermented foods (Ilango and Antony 2021 ).
The understanding of prebiotics has constantly been updated and shows that the effects are indirect and regular consumption of prebiotics can be used as a potential strategy for maintaining general health and preventing diseases (Cheng et al. 2022 ).Metabolism of fermentable fibers produces SCFAs including butyr ate, pr opionate, and acetate that regulate the intestinal barrier, produce anti-inflammatory signalling molecules , and impro ve the bioavailability of vitamins and minerals.Cellulose and lignins also increase the bulk of faecal matter and increase the transit time (Lama Tamang et al. 2022 ).
Se v er al dietary substances have the potential to act as prebiotics and must confer the following pr operties: m ust be fermented and not absorbed in the upper part of the gastrointestinal tract; m ust selectiv el y stim ulate the gr owth of beneficial bacteria; m ust change the intestinal microbiota of the colon to make it healthier; must induce systemic effects beneficial to the health of the host (Cheng et al. 2022 ).Food processing, pH, amount of salt, sugar, food ad diti v es, pr eserv ativ es, temper atur e, moistur e, pac ka ging, and water content of the food are all factors that can affect prebiotic properties (Ugural and Ak y ol 2022 ).
P olyphenols , such as anthoc y anins , fla vonoids , and fla vanones , act as prebiotics by favouring the growth of beneficial bacteria and regulating the diversity of intestinal bacteria.Epigallocatechin (EGCG) sho w ed anti-viral activity including inhibition of SARS-COV-2 (Xu et al. 2022 ).EGCG (a compound found in green tea), gr een tea extr acts, and Kimc hi (Kor ean fermented food) hav e been found to have potential benefits in suppressing SARS-CoV-2 (Jaffal and Abbas 2021 ).This is ac hie v ed by inhibiting the main protease (M Pro , also known as 3C-like pr otease), whic h is crucial for the virus's life cycle.Additionally, these substances provide mitoc hondrial pr otection by suppr essing pr o-oxidant enzymes, activ ate the cytopr otectiv e tr anscription factor pathway known as nuclear factor erythroid 2 p45-related factor 2 (NrF2) pathway and downregulate ACE2 and transmembrane serine protease 2 (TM-PRSS2).By reducing the o xidati ve stress and cytokine storm, they can lo w er the risk of pulmonary fibr osis, thr ombosis and sepsis in COVID-19 patients (Zhang et al. 2021 ).Fermented vegetables and Br assica famil y v egetables contain sulfor a phane that activates the NrF2 pathway and, hence, has shown viral protection and pr otection a gainst earl y o xidati v e str ess and thus can help mitigate the se v erity of COVID-19 (K esika et al. 2022 ), though mor e evidence is needed to w ar ds the diet as a preventive approach for COVID-19 patients.

Synbiotics
Synbiotics are combinations of live microorganisms added to fermentable foods, which can have synergistic effects on health.There is a growing interest in the food industry to develop products that can impr ov e gut health.Mixtur es of living or dead micr oor ganisms with fermentable substrates , vitamins , minerals , Ra w potatoes , green bananas , and grains polyphenols, or other phytochemicals can provide dietary supplements that can help manage the delicate balance between health and disease (Cunningham et al. 2021 ).Synbiotics r epr esent a nov el str ategy to pr omote the gr owth of healthy bacteria thr ough pr ebiotics while sim ultaneousl y enric hing the gr owth and colon y of healthy bacteria through probiotics.
A synbiotic formulation consisting of L. plantarum , L. acidophilus , L. reutri , and prebiotic fibers inulin and fructo-oligosaccharides (FOS) for 2 months has been shown to deplete the markers of insulin resistance related to metabolic syndrome and several cardiovascular risk factors (Cunningham et al. 2021 ).To further investigate the potential of microbiome regulation as a treatment strategy for COVID-19, a clinical study was conducted utilizing a novel symbiotic formula (SIM01) (Zhang et al. 2022 ).This formula contained Bifidobacterium strains , galactooligosaccharides , xylooligosacc harides, and r esistant dextrin, and was administer ed to hospitalized COVID-19 patients.Results sho w ed a significant reduction in inflammatory markers, an improvement in antibody formation against SARS-CoV-2, and a reduction in nasopharyngeal viral load (Zhang et al. 2022 ).Additionally, the symbiotic form ula was effectiv e in r estoring gut dysbiosis in these patients, indicating the potential for micr obiome-tar geted ther a pies in the treatment of COVID-19 (Zhang et al. 2022 ).Ther efor e, the innov ation and de v elopment of functional foods such as synbiotics can provide a beneficial approach to health promotion and wellness amongst patients with RTIs.

Role of ancient Indian medicinal knowledge on the microbiome 'We are what we eat & drink': the ayurvedic concept of gut health
We now recognize that virtually every aspect of our physiology and health is influenced by the collection of micr oor ganisms that live in various parts of our body, especially the gut microbiome.Of numerous external factors influencing the gut microbiome composition, diet and digestion are perhaps the most important.Although Āyurveda does not mention the gut microbiome explicitly, ne v ertheless, this tr aditional system of medicine, whic h liter all y translates to ' knowledge of life ', has focused on diet and digestion for thousands of years.
Āyurv eda highl y v alues the right food, digestion, and all other facets of lifestyle whic h ar e bound to affect gut health.Interestingly, some modern scientists have suggested that the practice of Āyurveda is a form of ancient epigenetics (Sharma 2016 ).Although the Āyurvedic practitioners may not have been aware of the precise molecular mechanisms by which food could have affected gene expr ession, ne v ertheless, they did understand that each individual has a unique psychophysiological constitution that is influenced by factors such as diet, digestion, lifestyle, str ess mana gement, and envir onmental factors (Bordoni and Gabbianelli 2019 ).Modern r esearc h is helping us to understand the relationship between the microbiome and various preventions and tr eatment a ppr oac hes of Āyurv eda (Wallace 2020 ).Trido S .a theory in Āyurveda is the foundation for explaining the functioning of the human mind and body (Dash and Sharma 1995 ).The theory posits that three fundamental principles of physiology, V āta, Pitta, and Kapha, govern our body and mind, and are identified as do S .as .The theory explains how these do S .as interact and influence disease manifestation and pr ogr ession, with a focus on the host rather than the illness (Fiandaca et al. 2017 ).
Each of these do S .as is associated with physiology-specific attributes .T he distribution profile of the three do S .as at birth, with one do S .a more dominant than others, is known as Prakriti in Āyurveda and is one of the first steps in e v aluating a person's health.An y de viation fr om Prakriti or natal do S .a distribution profile is recognized as Vikriti .The Prakriti assignment entails phenotyping a person based on their physical type, dietary and bo w el habits, ability to fight off sickness, healing, memory capacity, metabolism, and other traits (Dey and Pahwa 2014 ).T hus , finding distinctiv e Prakriti -specific micr obial finger prints is an intriguing foundation for customized ther a py (Jnana et al. 2020 ).
These methods of Āyurvedic therapy are comparable to curr ent tr eatment tr ends in modern medicine, whic h emphasize food and lifestyle modifications as a means of reducing sickness (David et al. 2014, Conlon and Bird 2015, Shondelmyer et al. 2018 ).With advanced 'omic' platforms, modern medicine has the scope of improving customized treatments based on the genetic and epigenetic profiles of the patients .T he Trido S .a theory would possibly be the Āyurveda equivalent of precision medicine , wher ein Ayurv edic pr actitioners/physicians r ecommend individualized ther a py based on a patient's Prakriti (Rotti et al. 2014 ).Conv er ging e vidence associates specific c hr omosomal (Govindar aj et al. 2015 ), epigenetic (Rotti et al. 2015 ), and bioc hemical (Pr asher et al. 2008 ) properties with specific Prakriti profiles, supporting the idea of customized care in the Āyurvedic system.It's important to note that Āyurveda considers each individual to be unique, therefor e, the a ppr oac h to health and wellness is highly personalized.While Āyurveda doesn't directly link specific diseases to specific Prakriti types, it suggests that certain imbalances may be more likely in individuals with certain constitutions .T he gene expression profiles vary significantly between the three do S .as .
Studies have shown that each V āta, Pitta, and Kapha primary Prakriti type has a distinct microbiome composition (Chauhan et al. 2018, Chaudhari et al. 2019, Shalini et al. 2021 ).Prior researc h has demonstr ated the impact of envir onment and dietary behaviours on the composition of the gut microbiome (Senghor et al. 2018 ).The maintenance of homeostasis, digestion and metabolism, detoxification, and many other biological processes ar e all gr eatl y influenced by the gut micr obiome, whic h has been pr ov en to hav e a complex biochemical interaction with its host (Nicholson et al. 2012 ).T hus , variations in Prakriti are very likely to affect gut microbiome dysbiosis .T herefore , Prakriti phenotyping, as done in Āyurveda by precisely associating different Prakriti types with phenotypic attributes, could be an effective strategy to predict the stratification of the gut microbiota in a specific population (Jnana et al. 2020 ).In a modern context, these phenotypic attributes identified by Āyurveda for each Prakriti type have been validated through metagenomics studies (Chauhan et al. 2018, Mobeen et al. 2019 ).The Prakriti phenotype-based ther a py of Āyurveda is founded on the idea of a Prakriti -specific microbiome, and treatment is provided considering the patient's gender and ov er all health, among other things.Prakriti -specific microbiome often serves as nature's prophylactic measure to w ar ds disease pathogenesis.

'Let food be thy medicine and medicine be thy food.' -hippocr a tes
Since the gut is belie v ed to be the origin of all illnesses, food is regarded as medicine in Āyurveda.Healthy eating is an integral part of Āyurvedic therapies.Besides a plethora of medicinal herbs, Āyurveda employs a variety of spices , herbs , mineral salts , and other natur al pr oducts, whic h ar e often e v eryday food items in themselves, to aid in restoring and maintaining physiological equilibrium and treating certain illnesses.
Āyurv edic medicines ar e mostl y pol yherbal or herbs-miner al form ulations (Agniv esha 2001 , Dr. P. Himasa gar ac handr am urthy 2001 , Ayurv edic Form ulary of India 2003, Satya pal B 2004, Pt. Krishna Gopalacharya 2005, Shastri 2006, Samhita 2009, Tiwari 2013, Gaur et al. 2014, Sharma 2020 ).Ther e ar e numer ous form ulations ( Altogether, it is getting incr easingl y e vident that lifestyle and dietary habits significantly change the commensal microbial populations of the human gut, and a dysbiosis of these communities can increase pathogen susceptibility, inflammatory disorders, and the current pandemic of metabolic health problems, including non-communicable diseases.Adopting Ritucharya, which integrates lifestyle and diet with seasonal variations, would allow the host to build a season and Prakriti -specific gut microbial profile as a shield against diseases and infections.

Conclusions
The human gut microbiome is a dynamic entity; whose compositional equilibrium r equir es constant buffering fr om extrinsic and intrinsic modulators.A br eac h in this equilibrium can snowball into health challenges, as evidenced during the COVID-19 pandemic.The advancement in technologies has undoubtedly empo w ered us in precisely identifying the alteration in the homeostatic pr ofile.Ne v ertheless, r estoring a dysbiotic gut microbiome is still an unmet medical need at se v er al le v els of our contemporary scientific understanding.Ho w ever, an alternative a ppr oac h of delving into the traditional knowledge of healthy living could provide a mechanism to balance the ' imbalance ' predicament.Āyurv eda, the tr aditional Indian system of medicine, and its theories and principles regarding gut health maintenance have indeed enlightened the potential strategies for addressing gut-lung axis dysbiosis .T he practice of co-existing with nature and the time-honored principles of Āyurveda can provide a solid foundation for maintaining a healthy gut micr obiome.By r eturning to these roots, we may find the k e y to balancing our gut microbiome and ac hie ving optimal health.Gastritis (Yoshimoto et al. 2013 )

Figure 1 .
Figure 1.Microbial composition among the physiological niches of the human respiratory and gastrointestinal tracts .T he most abundant bacteria within the niches are denoted in blue text, the most abundant fungi in green, and the most abundant archaea in orange.Please note, the numbers presented in this figure represent the abundance of bacterial members in the human gastrointestinal and respiratory tracts.The focus of this figure is primarily on bacteria due to the limited knowledge available regarding the specific abundance of fungi and archaea in the human gastrointestinal tract.Created with BioRender.com.
, reduction in the commensal population due to microbial death or reduced bacterial multiplication (Korem et al. 2015 ), and compromised alpha diversity of commensals due to dysbiosis caused by aberrant food composition (Sonnenburg et al. 2016 ), IBD (Norman et al. 2015 ), AIDS (Monaco et al. 2016 ), and type 1 diabetes

Figure 3
Figure3.Molecular links between gut microbiota and host health in healthy and dysbiotic state.In a healthy gut, intestinal epithelial cells (IECs) utilise butyrate through mitochondrial beta-oxidation, maintaining an anaerobic environment.Butyrate binds to peroxisome proliferator-activated receptor gamma (PPAR γ ), reducing inducible nitric oxide synthase (iNOS) expression and nitric oxide (NO) production.G-protein-coupled receptor (GPR)109 serves as a major receptor for butyrate.In dysbiosis, low butyrate levels decrease PPAR γ activity, increase glycolysis, and elevate iNOS expression, leading to an increased NO production and nitrates.Butyrate stimulates immune cells, like regulatory T cells (T reg ), through GPR109, exerting anti-inflammatory effects.Reduced aryl hydrocarbon receptor (AhR) activity disrupts gut barrier function.short-chain fatty acids (SCFAs: butyr ate, pr opionate and acetate), endocannabinoids, and bile acids activate receptors on L-cells and IECs, promoting gut peptide secretion.SCFAs activate GPR41 and GPR43 on L-cells, promoting secretion of gut peptides including glucagon-like peptide-1 (GLP-1), GLP-2, and peptide YY (PYY).Endocannabinoids interact with cannabinoid receptors type 1 (CB1), CB2, PPAR α, PPAR γ , and transient receptor potential vanilloid type-1 (TRPV1) receptors, while bile acids activate farnesoid X receptor (FXR) and Takeda G protein-coupled receptor 5 (TGR5) receptors.Gut pattern recognition r eceptors suc h as toll-like r eceptors (TLRs) detect pathogen-associated molecular patterns (PAMPs) and lipopol ysacc harides (LPS) fr om the micr obiota.These interactions reduce intestinal permeability, enhance insulin sensitivity and secretion, decrease food intake, lo w er plasma lipids, and mitigate hepatic steatosis and endotoxemia risk, associated with reduced inflammation.Dysbiosis leads to opposite effects.Ov er all, inter actions among gut microbiota, IECs, immune cells, and molecular receptors maintain gut homeostasis and impact metabolism and inflammation.Created with BioRender.com.

Table 1 .
Plant constituents with examples of food as prebiotics

integr a ting season, diet, and lifestyle to maintain a healthy gut microbiome
Khanal et al. ( 2022 )thi et al. 2021 )fire) and Āma (metabolic toxins) are central to an individual's health.Āyurveda states that all illnesses are the results of dysregulated Agni .T hus , Agni modulation is central to both preventative and treatments in Āyurveda.Āma accumulation is a result of out-of-sync Agni , and their dissi-ery step with adequate and str ategized interv ention thr ough integr ated tr eatment a ppr oac hes that take into consider ation the season, diet, lifestyle, and medication.The Ayurvedic practice of modulating diet and lifestyle according to the season is called Rituc harya (pr onounced as tucary ā), the seasonal lifestyle pr ogr amme.Rituc harya can effectiv el y r egulate the gut micr obiome to k ee p an indi vidual healthy in all seasons .T he Āyurvedic concept of eating with the seasons is crucial, as it emphasises that various foods are beneficial at different times of the year(Deepthi Rani et al. 2021 ).Eating seasonal and locally produced foods can support the body's natur al rhythms, pr omote ov er all health and well-being, and reduce the environmental impact of food production(Macdiarmid 2014, Deepthi et al. 2021 ).Mor eov er, importing non-seasonal food may contribute to imbalances in the body and potentially lead to dysbiosis(Macdiarmid 2014).The r ecent r e vie w by Wallace (2020) is one of the earliest modern science-based reports to indicate the importance of Ritucharya in COVID-19 s context, particularly during a post-infection reco very regimen.T he recent network pharmacology stud y re ported byKhanal et al. ( 2022 )has also indicated the impact of Ritucharya-based food intake on the modulation of HIF-1, p53, PI3K-Akt, MAPK, cAMP, Ras, Wnt, NF-kappa B, IL-17, TNF, and cGMP-PKG signaling pathwa ys , to impr ov e the r ecov ery fr om COVID-19 infection.
concept of Shatkriy ākal ā, dynamic prophylaxis co-ordinated to stages of disease prognosis (Shata = six, Kriy ā = choice of treatment, Kal ā = stage of progress of disease).Six stages of progression during a disease that is r epr esented in modern science as o xidati v e str ess, alter ation in imm une functions, and c hanges in anatomical and physiological mechanisms that further lead to the manifestation of a disease and pr ogr ession of complications.Shatkriy ākal ā offers the opportunity to tackle disease progression at e v

Table 2 .
Differ ent Ayurv edic form ulations for gut health A