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 Table of Contents  
REVIEW ARTICLE
Year : 2022  |  Volume : 16  |  Issue : 3  |  Page : 245-251

Pittadhara Kala Sahayo Majjadhara Kala and brain gut microbiota axis: A comparative review study


1 PhD Scholar, Ayurved Samhita Siddhant Department, Dr. D. Y. Patil College of Ayurved & Research Centre, Pimpri, Pune, Dr. D. Y. Patil Vidyapeeth (Deemed to be University), Pune; Assistant Professor, Ayurved Samhita Siddhant Department, K.G. Mittal Ayurved College, Mumbai, Maharashtra, India
2 Professor, Ayurved Samhita Siddhant Department, Dr. D. Y. Patil College of Ayurved & Research Centre, Pimpri, Pune, Dr. D. Y. Patil Vidyapeeth (Deemed to be University), Pune, India

Date of Submission17-Nov-2020
Date of Decision31-Dec-2020
Date of Acceptance01-Jan-2021
Date of Web Publication28-Sep-2022

Correspondence Address:
Rakesh Ramraj Tiwari
K. G. Mittal Ayurved College, Mittal Foundation Trust, Next to Taraporewala Aquarium, Netaji Subhash Road, Marine Drive, Mumbai - 400 002, Maharashtra
India
Login to access the Email id

Source of Support: None, Conflict of Interest: None


DOI: 10.4103/joa.joa_290_20

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  Abstract 


Objective: The Ayurvedic principle of Pittadhara kala sahayo majjadhara kala (PDK-MDK) was propogated by Acharya Dalhan's commentary of Sushruta Samhita. Modern scientists agree on the existence of gut microbiota (GM) and their influence on the nervous system but have not explored it in light of PDK-MDK even though the later has formed the backbone of Ayurveda practice for over a millenia. This makes it imperative to not only extensively research PDK-MDK better but also to promote its evidence-based utilization in clinical practice. Data Source: Detailed review on Ayurveda literature (Bruhatrayi, Laghutarayi) and evidence-based resources (journals, dissertations, and gray literature) was performed. Review Methods: The keywords like pitta, jatharagni, pittadharakala, majja, majjadharakala, GM, gut brain microbiota axis, neurological disorder, Alzheimer, Parkinson were searched for our study. Result: This study reveals that the bidirectional, mutualistic relationship between Pittadhara kala and Majjadhara Kala is similar to the interdependency exhibit by the GM and Brain. Neurophyschiatric conditions (depression, anxiety, autistic spectrum disorder) found to be correlated with altered GM similar to conditions such as unmaad, apsmaar and pittadhara kala dysfunction due to low-quality food. Neurodegenerative conditions (Parkinson's Disease, Alzheimer's Disease) correlate with the dysfunctional autonomic and enteric nervous system, whereas the Ayurveda concept of Medhya Rasayan that needs to pass through Jatharagni suggests relation between grahani and majjadhatu. Conclusion: While PDK can broadly be linked to small and large microflora and the bile acid and substrate interactions there in, extensive collaborative research is needed to confirm this fundamentally.

Keywords: Brain gut microbiota, gut microbiota, majjadhara kala, Pittadhara kala


How to cite this article:
Tiwari RR, Pandey B. Pittadhara Kala Sahayo Majjadhara Kala and brain gut microbiota axis: A comparative review study. J Ayurveda 2022;16:245-51

How to cite this URL:
Tiwari RR, Pandey B. Pittadhara Kala Sahayo Majjadhara Kala and brain gut microbiota axis: A comparative review study. J Ayurveda [serial online] 2022 [cited 2022 Nov 29];16:245-51. Available from: http://www.journayu.in/text.asp?2022/16/3/245/357300




  Introduction with Study Rationale Top


Ayurveda is an ancient clinical science that helps in understanding the healthy way of life by preventing disease and treating the patient amicably when diseased. The treatment is based on principles (siddhant) which were established by testing the hypothesis time and again. These principles need to be checked and verified over the time to understand its relevance in the current era. Modern science today has developed a lot, with lots of understanding gathered through in vitro and in vivo studies. However all sciences, including neurology, have their limitations. If the principle established in Ayurveda is used to understand pathophysiology in the current era, it will help both the science equivocally. Pittadhara Kala Sahayo Majjadhara Kala (PDK-MDK) is one such siddhant explained by Acharya Dalhan a commentator on Sushrut Samhita, to understand the pathophysiology of the brain better in relation to the gut microbiota (GM). The recent advances in brain GM (BGM) where a dynamic part of Gut which is found to be influencing the Brain through enteroendocrine and enteroneural transmitters. In the long term, this may affect neurological pathology. The brain also affects the GM through the vagus nerve and affecting the Gut secretions. The present study is selected to explore both the conditions and to correlate for better understanding.

We extensively review the Ayurveda and Modern science Literature to translate the observational axiom around the PDK-MDK introduced by Ayurveda scholars to the molecular evidence generated by BGM to better understand functional causes of gastrointestinal and neurological conditions.


  Literature Review Top


In Ayurveda classical texts like Charak Samhita, Sushrut Samhita, Ashtang hridaya, Ashtang Sangraha, Madhav nidan, Sharangdhar Samhita and all Samhita's available referred to understand physiological concepts. Evidence-based resources such as Journals, Books, and database information from search engines such as PubMed, Google Scholars, EMBASE, Indus Copernicus journals for recent information. The search strategy used keywords like pitta, jatharagni, pittadharakala, majja, majjadharakala, GM, gut-brain microbiota axis, neurological disorder, Alzheimer's disease, Parkinson's Disease used for the study. A detailed literature review was performed on the aforementioned articles in an attempt to correlate the observations in Ayurvedic Samhita and link them with Modern evidence.


  Pittadhara Kala Sahayo Majjadhara Kala Top


According to Ayurveda Dosha, Dhatu and Mala are the basic pillars of life. Three doshas help in the physiological function of the body by influencing seven dhatus, dhatus help in the formation and maintenance of the human physical structure, in this process three major by-products formed called Mala. Jatharagni provides the energy required to keep these physiological activities in harmony.[1] Jatharagni is located in the Pitta dosha regulates all the dhatu[2] hence the efficiency of dhatus depends on jatharagni.

Jatharagni is located in pitta which is secreted during dwitiya-avasthapaak in pittadhara kala. Pittadhara kala is situated between Aamashaya and Pakvashaya also called grahani.[3] According to panchbhautika chikitsa, there are 2 types of pitta, Amla-pitta and kshar-pitta. For digestion to take place amlapitta and ksharpitta has to be mixed up causing madhuryta which protects other dhatus from getting digested, also explained by charak as “ksharo hi laati madhuryam amlopsamhitam.”[4] It helps in the development of medha (intelligence), digestion, appetite and satiety, vision, courage, generating heat, hunger.[5] Hence the development of majjadhatu depends on PDK.

Pitta is secreted as the mala (excretory product) of Rakta.[6] Rakta along with Rasa nourishes all the dhatu including majja. Majjadhatu is one of the seven dhatus, who's basic function is Asthipuran, which can be correlated as bone marrow fills up the long bone cavity becomes the major site of RBC production and blood formation.[7]

PDK helps in grahanati, pachati, vivechayati, munchati with the help of Saman vayu[8] resides near Agni may lead to absorption of elements required in blood formation. When compared PDK can be correlated with the lining membrane of the small intestine which plays a vital role in digestion and absorption of all nutritive substances such as Vitamin B12, folate, and iron which are the main source of development and maturation of RBCs.[7]

According to Indu's commentary on Asthtangsangraha Medo dhatu transforms into Mastulunga and majjadhatu both are synonymous, having solid ghrit like appearance. Mastulunga is present inside the flat bone of the skull. As inside the bone, there is marrow, majjadhatu is present in asthi. Skull and Vertebral column can be considered as casing on Brain and spinal cord respectively, where both are the part of CNS hence majja dhatu is related to the nervous system and MDK is associated with Nervous system.[9] Majja dhatu depletion causes mental instability like bhrama and tama darshan (blackout).[10]

MDK-PDK[11] is an established principle that explains the relation between the pittadhara kala and majja dhatu. A potential bidirectional relation between pittadhara and majjadhara is explained while explaining the vishaveg lakshan[12] in shashti kala out of sapta kala.

Pittadhara kala regulation of majjadhara kala

PDK or grahani holds the jatharagni required for digestion, when it gets affected, it affects PDK and leads to a disease named after it.[13] According to Vagbhatta, samanya lakshan of grahani shows symptoms like tama darshana which is related to majjadhatu depletion.[14] In Panchakarma, Virechana is utilized to treat Pitta related disease effectively[15] by giving medicine which acts not only on the pittadharakala, but is also related to the distant Rakta and majja dhatu related conditions e. g. haritaki.[16] Correlation of Terminalia chebula extract on Parkinson's disease and Alzheimer's are proven.[17] Poor quality of food leads to Unmaad and Apasmaar (maanas vyaadhi). Kapha dosha helps in retaining the memory but aggravation of pitta causes kapha depletion leading to maanas vyadhi.[18] Bhrama is the common symptom found in adhogamlapitta and majjakshaya caused due to vitiation of pitta. In such cases, Rasayogasagar suggests Sootshekhar Rasa, which shows treating PDK affects MDK.[19]

Majjadhara kala regulation of pittadhara kala

Induction of Stress level i.e., chinta causes jatharagni depletion leads to rasa dhatu kshaya.[20]

Shokaj atisaar is a loose motion like condition caused due to sudden emotional disturbance caused by loss of valuables or person.[21] Causes mentioned in pandurog (Anemia) are chinta, bhayas, or shoka krodha which causes mental instability.[22]

Other observations

According to sushruta pitta dosha plays an important role in Murcha[23] which is also found in majjadhara kala disorder.[24] Tanu mardavta is a sign found common in Pitta function[25] and in Majja sarta lakshan.[26]

These are few conditions which explain the bidirectional relationship of pattadhara kala and majjadhara kala Axis.


  Brain Gut Microbiota Axis Top


With human evolution, microbes in the human gut also evolved metabolically. This co-evolution led to a symbiotic GM that communicate with the brain, the BGM. Around 1014 microbes (bacteria, viruses, fungi, and protozoa) are scattered around the throat, skin, and gut, i.e., 10-fold entire human cells.[27] Bacteria belonging to phyla: Firmicutes, bacteroidetes form the most abundant of all 1000 species of BGM.[28] GM are found between the small intestine to the descending colon, most abundant in the proximal colon. Wherever most abundant, their species are more diverse and mucosa thicker. Normal gut flora has more anaerobic bacteria than aerobic. GM are established at birth and diversify throughout life affected by external factors such as medication, diet, and lifestyle.[29],[30]

The looped, bidirectional communication between brain and GM uses three signaling mechanisms; viz., nervous, endocrine and immune system.[31] Microbes secrete 5-HT serotonin, short chain fatty acid (SCFA), interleukin-1, and leptin into blood that influence cognitive and limbic functions. Brain in turn controls myenteric nerve plexuses indirectly through parasympathetic nervous system (vagus nerve). This controls intestinal secretions, motility, transit time, permeability and local endocrine influences.[29] Derangement in BGM affects both gut (irritable bowel syndrome) and brain (schizophrenia, Alzheimer's disease, autism and depression-anxiety). Such malfunction is precipitated by stress, cortisol, age, and antibiotic.[32]

Since these communications are yet to be understood completely and hold potential to functional disease therapeutics, we chose to review the BGM axis.


  Gut Microbiota Influencing Brain Top


GM influences the brain through SCFAs, secondary bile acids (2BA), and tryptophan metabolites[33] directly or indirectly through enteroendocrine cells (EECs), enterochromaffin cells (ECCs), and the mucosal immune system. Besides these GM also independently produce neurosignaling molecules gamma-aminobutyric acid, 5-HT (5 hydroxy tryptamine), norepinephrine, and dopamine.[34]

Neuroendocrine signalling

GM influences CNS through 20+ signaling molecules released by EECs of the gut and liver. These cells signal in response to chemical and mechanical stimuli and stimulate the hypothalamus and vagal nuclei to produce satiety and hunger.[35]

One interesting example is bile acid (produced in the liver from cholesterol metabolism) that stimulates the Farnesoid x receptor to produce fibroblast growth factor 19 that crosses the blood-brain barrier and suppresses the hypothalamo-pituitary axis through the arcuate nucleus.[36]

Dietary fibers are fermented by GM to produce monosaccharides, SCFA (acetate, propionate, and butyrate) and gases (methane and carbon dioxide).[37] SCFAs maintain colonic homeostasis, absorption of salts and water, mucosal integrity, and reduce mucosal inflammation.[38] They also increase intestinal transit by activating leptin, peptide YY and glucagon-like peptide.[39]

5HT produced by the ECCs under influence of SCFAs and 2BA needs dietary tryptophan as the same isn't produced in the body. Hence, brain regulation by 5HT occurs in response to exogenous tryptophan only.[40]

Neuroimmune signaling

GM exerts bidirectional immunological influence on the microglia and astrocytes in the brain. These cells are responsible not only for brain development and neurotransmission but also for brain immune responses and blood-brain barrier integrity. Influence over these cells by GM can cause therefore cause brain inflammation and injury.[41] Some of these influences could be beneficial too as seen in the lack of glial maturation in germ-free mice versus normally colonized mice.[42]

Neural signaling

Intestinal vagal receptors are activated by inflammatory peptides, dietary antigens, and metabolites. The toll-like receptors also recognize intestinal lipopolysaccharide (LPO) activity.[43] Lactobacillus rhamnosus and Bacteroides fragilis have shown direct influence on intestinal afferents.[44]

Intestinal and blood brain barrier

GM control mucus layer and the intestinal epithelial tissue, both in combination control intestinal permeability and hence the pathogen susceptibility of the intestine. In the absence of dietary fiber, the GM degrades epithelial glycoprotein making it vulnerable to infections.[45] GM also regulate the intestinal barrier by improving the expression of tight gap junction proteins such as occludin and claudin-5. Similarly, SFC control the blood-brain-barrier permeability.[46]


  Brain Influencing Gut Microbiota Top


Role of neurotransmitters on gut microbiota

The brain influences intestinal microbiota by the luminal release of signaling molecules like catecholamines, 5GH, cytokines, etc.[47] Catecholamines like epinephrine and norepinephrine influence several pathogenic and non-pathogenic microbes via quorum sensing through QseC sensor kinase (a bacterial adrenergic receptor).[48] Melatonin is produced in the brain but shows binding similar to GM, hence both their activities show circadian rhythmicity, an interesting link between brain and gut.[49]

Role of autonomic nervous system influencing gut microbiota

The autonomic nervous system influences the gut mobility and intestinal barrier, through the myenteric plexus.

Gut Motility: Increased peristaltic motility reduces intestinal water content, nutrient availability to GM, and bacterial clearance esp. in the proximal gut.[50] Further stress, lack of sleep, etc. can impede migrating motor complexes and hence intestinal transit time.[51] British Stool Scale and radiopaque marker studies have shown how intestinal transit time influences the microbial density, composition, and diversity of the microbial flora.[52],[53] Reduced transit time implying rapid intestinal transit correlates with reduced bacterial biomass and diversity.[54]

Intestinal Barrier: Stress promotes a “leaky gut” by introducing an epithelial barrier defect in the intestinal wall. Studies have shown mRNA-induced production of tight gap junction in colon and jejunum promoting the entry of Escherichia coli and their product like LPOs. These produce an inflammatory environment in the intestinal wall.

Stress can affect the mucopolysaccharide production by the intestinal goblet cells though catecholamine signaling. This reduces the thickness of the mucus layer and promotes the translocation of gut microbes into the intestinal wall.[55],[56],[57]


  Clinical Correlation Top


Brain-gut microbiota in GI-brain interaction

Dysbiotic IBS patients have differed in regional brain volume in comparison with the eubiotic group, suggesting a relationship between microbial community structure and brain structure.[58]

Preclinical and clinical studies have shown that stress is associated with a reduction in lactobacilli. GM and its metabolites modulate the satiety signal and eating behavior[59],[60] which plays an important role in obesity. Fecal microbiota transplant from hyperphagic obese mice to Germ-free mice was able to induce the hyperphagic behavior and weight gain in the recipient.[61] Microbial brain signature in obese is different than lean patients.[62] Post-bariatric surgery composition of GM is seen dramatically, reducing food intake.


  Brain-Gut Microbiota in Psychiatric and Neurological Disorder with GI Comorbidity Top


BGM in Depression and Anxiety: Preclinical studies have linked depression with altered GM. Further, E. coli outbreaks in Germany and Canada have corresponded to increased incidence of anxiety and depression. Depressed human fecal microbiota transplant if transplanted in rodents induces depression.[63]

Brain gut microbiota in autism spectrum disorder

Besides anxiety and sensory over responsiveness, altered GM correlated strongly with core autism spectrum disorder symptoms.[64]

Brain gut microbiota in neurodegenerative disease

Slow transition constipation and irritable bowel syndrome correlate with the dysfunctional autonomic and enteric nervous system; both seen in Parkinson's disease.[65] The secretion of amyloid and LPOs from GM modulates the signal pathway that causes the production of cytokines, a pro-inflammatory chemical associated with the pathogenesis of Alzheimer's disease.[66] Strong clinical evidence exists on local actions medhya rasayana like Bacopa monnieri, curcumin, etc. that are beneficial in Alzheimer's disease.[67] Further, exploration on alterations in GM that may indirectly contribute to the nootropic effect are vital.

Ayurveda and brain gut microbiota correlation

Pittadhara kala and microbiota function

Pittadhara kala is the site Jatharagani helps in dhatuposhan i. e nourishment and development of dhatus. Oja (immunity), bala (physical and mental strength), swasthya (absence of disease), utsah (energetic), sharir-vriddhi (physical development), Aayu (longevity), varna-prabha (complexion), agni (digestion) are the function of the pittadhara kala related jatharagni. When compared with Gut, jatharagni has a similar function in modulating immunity, nervous system, metabolism, and endocrine system.

Bidirectional nature of Pittadhara kala-Majjadhara kala and brain gut microbiota Axis

Acharya sushrut while discussing the prognosis of snakebite, explained the interdependency and bidirectional relation of pittadhara kala and majjadhara kala. BGM Axis is also found to be bidirectional and mutualistic. Hence, we can utilize this gateway to reach any of this system by influencing the other one.

Purusham purusham vivakshet, prakruti and different composition of microbiota influencing brain

Ayurveda believes that each individual is different. To consider individuals for assessment, one needs to specify the state of the patient based on factors such as Agni (digestion), kostha (consistency of stool), prakruti, etc. Hence, generalizing the disease is of hindrance in treatment. BGM follows the same idea that the composition of GM is different in different individuals and depends on factors such as medicine, diet, lifestyle, stress, etc. The GM stabilizes at the time of birth and is under the constant influence of the factors mentioned which is similar to prakruti mentioned in Ayurveda. Hence, patients suffering from Brain or majja disorder need to evaluate realizing the concept of uniqueness.

Pittadhara kala and location of gut microbiota

Pittadhara kala lies between Amashay and pakvashay whereas the most active part of GM all over the intestine connection lies between small and large intestine due to high substrate availability and site for Bile acid function. The process of digestion requires chyme coming from aamashay to mix with ksharpitta (alkaline salt) excreted in pittadahara kala for digestion is similar to bile acid function.

Medhya rasayan, tryptophan and brain gut microbiota

The concept of medhya rasayan (nootropic) drugs mentioned in Ayurveda requires to pass through jatharagni for nourishing and development of majja dhatu. Tryptophan-enriched diet can modulate the brain function after being metabolized by GM into 5HT.

Disease relating Pittadhara kala sahayo majjadhara kala/brain gut microbiota axis

Shokaj Aatisaar, vibhatsa darshanam and manas bhav are some conditions related to majjadhara kala which leads to symptoms like diarrhea, vomiting, pandu, and vice versa proves the relation of PDK-MDK. In Manas vyadhi like unmaad, apasmaar the major causative factors are the lower quality of food proves the relation of MDK-PDK. While discussing BGM Axis diseases such as depression, stress, Parkinson's, autism spectrum disorder, Alzheimer's disease, IBS correlates Gut-Brain-Microbiota Axis.

Limitations

Since most concepts in PDK-MDK are derived from ancient scripts in Sanskrit and contemporary researchers and clinicians are free to interpret it independently it has been observed that a consensus opinion on the concept of PDK-MDK has never been established. This makes extensive clinical research imperative to not only understand PDK-MDK better but also promote its utilization in clinical practice.

BGM is sparsely understood but the majority of the experiments performed only at the preclinical level. Better understanding of the molecular mechanisms needs to be correlated through ongoing clinical evidence.


  Future Directions Top


To explore the literature to find out what connection is lying between PDK-MDK and GM brain. PDK-MDK can be utilized in explaining the clinical validation of BGM, whereas the concept of BGM can help in a better understanding of PDK-MDK pathophysiological connection.


  Conclusion Top


BGM gives us better understanding of pharmacokinetics and pharmacodynamics of medhya rasayan drugs, i.e., mode of action, site of action on PDK, modification or Anupan used to increase the bioavailability of medicine. Diseases related to both the kalas like hetu (viprakrushtha), samprapti, samanya and vishesh poorvarupa, rupa and sadhya-asadhyatva are better related and understood through BGM Axis. The further detailed study of factors affecting both the kala on the basis of factors influencing BGM can be studied. The present study will help understanding the concept of pittadhara kala which is unclear. This can open a passage of near difficult intervention in majja dhatu. Panchakarma esp vaman, virechana, basti is effective as shodhan where medicine comes in contact with the gut. It can be analyzed whether the medicine used in shodhan helps in washing out the microbiota excessively in the gut or it modulates the microbiota to regulate majjadhara kala function by affecting the signaling pathway mechanism.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.





 
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Introduction wit...
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Pittadhara Kala ...
Brain Gut Microb...
Gut Microbiota I...
Brain Influencin...
Clinical Correlation
Brain-Gut Microb...
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