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*Corresponding author: E-mail: ibrahimshnawa3@gmail.com; 
 
Cite as: SHNAWA, Ibrahim M S. 2025. “An Inter Mammalian Microbiome-Immune-Axis MIA”. Asian Journal of Immunology 8 
(1):26-34. https://doi.org/10.9734/aji/2025/v8i1157. 
 
 

 
 

Asian Journal of Immunology 
 
Volume 8, Issue 1, Page 26-34, 2025; Article no.AJI.132768 
 

 
 

 

 

An Inter Mammalian Microbiome-
Immune-Axis MIA 

 
Ibrahim M S SHNAWA a,b* 

 
a Department of Medical Biotechnology, College of Biotechnology, AL-Qasim Green University, 

Qasim, Babylon, Iraq. 
b College of Nursing, University of Hilla, Hilla-Babylon, Iraq. 

 

Author’s contribution  
 

The sole author designed, analyzed, interpreted and prepared the manuscript. 
 

Article Information 
 

DOI: https://doi.org/10.9734/aji/2025/v8i1157 
 

Open Peer Review History: 
This journal follows the Advanced Open Peer Review policy. Identity of the Reviewers, Editor(s) and additional Reviewers, peer 

review comments, different versions of the manuscript, comments of the editors, etc are available here: 
https://pr.sdiarticle5.com/review-history/132768 

 
 

 

Received: 18/01/2025 
Published: 25/03/2025 

 
 

ABSTRACT 
 

There is a mutual bidirectional cross-talk between mammalian microbiomes MM and their 
respective immune systems during the host homeostatic and disease states, the microbiome- 
immune axis. The objective of the present opinion paper was to map the current status of the 
microbiome-immune axis updates. Human gut microbiome diversity decreases rapidly after 
autologous stem cell transfer. Myelopoiesis in human is regulated by signals from microbiome 
reaching the bone marrow. Some animal heat treated gut bacterial antigens induces 
proinflammatory cytokines in rabbits ileal and villus cultures while other animal heat treated gut 
bacterial antigens initiated anti-inflammatory cytokines using same test culture systems. Rabbits gut 
microbiome modulates brain development and function with coordinative helping role of the immune 
system. Rabbit models for rhino-sinusitis and cystic fibrosis were found associated with microbiome 
dysbioses in nose and gut microbiomes respectively and simulating that of man. When the 
development of mice microbiome became arrested the immune system undergoes stunting growth 
and development. Obese mice have shown dysbiotic microbiome. Thus, the paradigm of 
microbiome-immune axis MIA have shown that the potentials of the monkeys, rabbit and mice 
microbiomes can be translated to human welfare providing some limitations. 

Opinion Article 

https://doi.org/10.9734/aji/2025/v8i1157
https://pr.sdiarticle5.com/review-history/132768


 
 
 
 

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Keywords: Antigen; axis; bacteria; biosis; dysbiosis; human; immune; mice; rabbit; system. 
 

1. INTRODUCTION  
 

Axis in the functional sense means the presence 
of mutual bidirectional signaling between two 
rather different or inter-related biologic entities. 
As an example, the microbiome-immune axis 
and it is expressed as a crucial relationship 
between microbiome and the immune system. A 
diverse microbiome is essential for maintaining 
balanced and healthy immune systems (Shitara, 
2023). Gut microbiome possess an intensive 
influences on gut associated lymphoid tissue 
GALT.GALT displayed an immune modulatory 
role on gut mucosal responses leading to 
maintain of tolerance to harmless bacteria and 
responding to pathogens. Early exposure to 
beneficial microbiome can enhance immune 
maturation and protect against allergic and 
autoimmune diseases in early life. In the past 
three decades, the change in the composition 
and function of microbiome have shown to be 
associated with obesity, inflammatory bowel 
disease, type II diabetes, liver cirrhosis, drug 
treatment responses (Zeevi et al., 2016). 
Microbiome cross-talk with T cells leading to 
cancer, allergic inflammations and autoimmune 
disease (Shim et al., 2023 Campbell et al., 
2023). The objective of the present opinion paper 
was to map human and representative 
mammalian microbiome-immune axis.  

2. AN OLD IS BEING REVISTED AND RE-
CREATED  

 
Pioneer generation microbiologists look to 
normal microbe living in or no human                   
body as commensals and can prevents                    
establishment of pathogens (Parente, 2019).                                                    
In the sixteens notion of the 20th century 
microbiologist was the global realization of 
cultivable/non-cultivable normal human 
microflora. In 19th of the past century, molecular 
genomic studies had led to evolution of 
microbiome concept, Table 1. Commensal 
human mirco-flora have been revisited and 
recreated as microbiota/microbiome (Grice and 
Segre, 2011). 
 

3. MICROBIOME VERSUS MICROBIOTA 
 
Microbiota refers to the profile of the normal 
cultivable microflora. While, microbiome as a 
term   means the profile of cultivable and 
genetically determined uncultivable normal 
microflora inhabiting both in and on                          
various mammalian body sites. So microbiome 
equal to; 
 

Microbiome= Cultivable + in-cultivable 
(normal commensal microflora) 

 
Table 1. Microbiome timeline 

 

Achievements Reference/Date 

1. Five different bacteria of human mouth Leewenhook 1688 
2. Flora and funa within living animals Leidy 1853 

3. Some of human associated micro-organisms 
prove to be pathogenic in same niche 

Nissle 1917 

4. Cultivation of anaerobic microbiota in the 
laboratory 

1940-1950 

5. Realization of the theme for cultivable/non-
cultivable microbiota 

1960s 

6. The theme of commensal microflora in healthy 
body 

Crucishank et al.1974 

7. Genetic and molecular based studies on human 
normal microbiota 

Woese, Pace, Fox and others 1996-
2005 

8. Popularization of microbiome/microbiota research 
theme 

Gordon group 2006 

9. Advisory Microbiome mapping guide ASM 2015 
10. Microbiome strategic plans ASM 2016 
11. National Microbiome data collaboration ASM2019 
12. Microbiome Research Congress ASM 2021 

13. Inclusion of the microbiome in the USA innovation 
act 

ASM 2022 

 



 
 
 
 

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Table 2. Characteristics of human and mammalian microbiomes 
 

Features Human Monkey Rabbit Mice 

First genome MHC MnMHC RMHC MMHC 

Second genome Microbiome 
genes 

Microbiome 
genes 

Microbiome 
genes 

Microbiome 
genes 

Regulation of 
neonate   and 
ageing immune 
system 

Regulate Regulate Regulate Regulate 

Coevolution with 
immune system  

Co-evolved Co-evolved Coevolved Coevolved 

Association with 
homeostasis 

Associated Associated Associated Associated 

Dysbiosis Immune 
mediated 
diseases 

  Immune 
mediated 
diseases 

Translation In applicable Non-tempted till 
now 

 Tempted Tempted 

 
Human microbiome composed of trillion of 
microbial spectra like bacteria, viruses, fungi and 
archea inhabiting various body compartments 
such as; gut skin, genitourinary and respiratory 
tracts. Diverse microbiome is crucial for 
maintaining a balanced and healthy immune 
system. The composition and diversity of these 
microbial communities vary between individuals 
and affected by; diet, genetics and environmental 
factors (Crucishank et al., 1974, Parente, 2019, 
Grice and Segre, 2011, Whiteside et al., 2015, 
Levinson et al., 2018) Table 2. 
 
4. MICROBIOME-IMMUNE AXIS 
 
Axis in the functional sense refers to the 
presence of mutual bidirectional cross-talk 
between two different or inter-related biologic 
entities such as microbiome and that of the 
human cells of the immune system cells (Shitara, 
2023, Zeevi et al., 2016, Shim et al., 2023, 
Campbell et al., 2023). 
 

5. FIRST VERSUS SECOND GENOME 
 
The first genome concerned with the 
host/immune system genetic system, while the 
second genome invented to designate the 
collective genomes of the members forming the 
microbiome. Microbiome signals talking to host. 
Host genome signals to cross-talk the 
components of the microbiome. This sort of 
signaling one -another usually followed by 
functional events within the microbiome-immune 
axis (Shitara, 2023, Zeevi et al., 2016, Shim et 
al., 2023, Campbell et al., 2023). 

6. MICROBIOME 
 

6.1 Human Microbiome  
 
Human microbiota is defined as a set of 
microbes inhabiting and interacting with human 
body. These interactions took three main forms 
as commensalism, mutualism and parasitism 
(Grice and Segre, 2011). They form complex and 
solitary ecosystem that adapt to the 
environmental conditions of the host niche. The 
human microbiome is constantly evolving in 
response to the host factors. Human microbiome 
HM consists of an array of; bacteria, archea, 
viruses and eukaryotes.HM colonize various 
sites on or in of the body. Facultative anaerobe 
colonize gastro-intestinal tract while strict 
anaerobe colonize skin, oral cavity and 
respiratory tract.HM impacts human physiology 
and immunology both in health and disease 
(Crucishank et al., 1974, Parente, 2019, Grice 
and Segre, 2011, Whiteside et al., 2015, 
Levinson et al., 2018). 
 

6.2 Mammalian Microbiome  
 
Animals belongs to carnivores, omnivores and 
herbivores groups have shown variable 
compositions of microbiota and maintained 
complexicity and stability which explain the 
difficulty to induce long term change in their 
compositions. They are competing  for the 
essential nutrients and they alter the conditions 
required for growth of bacteria through 
production of bacteriocins that kills the 
competitors and controls pathogens by 



 
 
 
 

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stimulating host immunity and mucosal barrier 
functions .They provide  signals for optimize 
immune functions .Generally speaking 
,mammalian microbiomes are somewhat similar 
one to another in nature  for their members but 
they  are different in proportion quantities, 
composition  and diversity .In healthy animals, 
gram negative Protebacteria , bacteriodetes and 
gram positive firmicutes including Closteridiales 
and Lactobacillales are the major phyla 
inhabiting large and small intestines. All of these 
organisms are adapted to the intra-intestinal 
environment and generally formed stable and 
complex population (Tizard, 2023). Studies onto 
gut/ileal microbiomes of rabbit and pig have 
shown that dominant phyla of pig ileum were 
Firmicutes while the dominant phyla of rabbits 
ileal microbiome was Bacteriodatae (Cui and Xu, 
2016). 
 

6.3 Non-Human Primate Microbiome  
 
Monkey gut microbiome offers an insight into 
primate nutrition, physiology   and immune 
system function (Clayton et al., 2018). 
Geography, genetics, climate, vegetation and 
diet related to microbiome community structure. 
There was more high degree of regional 
specificity in the microbiome composition which 
was associated with; host genetics, available 
plant food which affect diet. Genetic differences, 
drove differences in gut microbiome community 
composition, while, vegetation as a diet drove 
regional gut mircobiome compositional 
differences (Mesquita et al., 2021). Monkey gut 
microbiome adopt characteristic enterotype 
which was compositionally analogous to that of 
human. Such gut microbiome enterotype have 
stable microbial signature over time (Campbell et 
al., 2020, Moeller et al., 2012). 
 

6.4 Rabbits Microbiome  
 
Rabbits are both monogastric and herbivore 
animal with special digestive and physiological 
properties. Their gut microbiome be stable and 
diverse by this it expresses significant resistant 
to intestinal disease (Chen et al., 2017). Different 
rabbit   maternal strains showed different 
microbiome compositions (Biada et al., 2020). 
Rabbits may serve medical and nonmedical 
uses. The non-medical use include; Textile 
production, meat production. While medical uses 
includes; bioreactor to produce polyclonal 
antibodies and as a biomedical model for human 
disease. Whole rabbits body microbiome has 
shown Firmicutes 62.3 %, Proteobacteria 13.44 

% and Bacteriodate 11.84% (Montoro-Dasi et al., 
2022, Hu et al., 2021). Rabbits gut microbiome 
plays a key role in maintaining health and in 
regulation and development of the immune 
system (Kylie, 2016). 

 
6.5 Mice Microbiome  
 
Mice microbiome consists of a number of 
bacteria, viruses, fungi and eukaryotes. Members 
of mouse microbiome distributed to gut, skin, 
respiratory and genitourinary tract. Microbiome 
composition constitutes proportional amounts                
of Firmicuts and Bacteriodaiceae. Mouse 
microbiomes are useful tool impactful in gaining 
a better understanding of human microbiome. 
There are 80 genera of mice similar to that of 
man, these are constituting 15% overall similarity 
of mouse to human microbiome (Maue and 
Lundberg, 2017, Kennedy et al., 2018, Ansaldo 
et al., 2021). 
 

7. MICROBIOME-IMMUNE AXIS 
 

7.1 Human Microbiome-Immune Axis  
 

Human immune system co-evolved with an 
extensive microbiome diversity on the mucosal 
barrier sites. It is evident and clear that microbial 
antigens belong to the microbiome members 
engage in constant dialogue with the immune 
system leading to microbiota specific immune 
responses that occur in the absence of 
inflammation. This constitute a form of immunity 
including B cell, innate like T cell and co-
evolutional T cell helper and T reg cell 
responses. Microbiome induces innate like T cell 
and adaptive immune responses. These 
microbiomes - immune potentials indicate that 
microbiome   involved with cross-talk with the 
immune cells during immune response 
development (Ansaldo et al., 2021). Vital period 
for mammals to be colonized with microbiome is 
in the early life. Such colonization is profoundly 
influence the intestinal immune functions. The 
intestinal immune system is critical for neonates 
in order to resist intestinal infections (Yang et al., 
2022). The initial colonization of an infant gut by 
microbes plays a pivotal role in shaping the 
immune system. Early exposure to probiotics can 
enhances the immune system maturation and 
protects against allergic and autoimmune 
disease (Shitara, 2023). There are a specific 
microbial groups take part in the immune system 
development and have a role in the functional 
changes that occur to the immune cell population 
through ageing (Tibbs et al., 2019). Human 



 
 
 
 

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myelopoiesis in the bone marrow is regulated by 
environmental signals including that of 
microbiome. Microbiota derived signals can be 
sensed directly or indirectly by the hemopoietic 
stem cells and progenitor cells in bone marrow, 
thereby giving rise to myeloid cell lineages at 
steady state and during inflammation. These 
microbial signals affect the myelopoiesis during 
inflammation and infection (Kim and Kamada, 
2023). 
 
The human gut microbiome acts as a signaling 
hub that integrates exposome with genome and 
metabolic pathways Its impacts are wide across 
human body systems including the immune 
system (Institute of Functional Medicine, 2025). 
The gut and skin microbiome both act as a 
barrier between human body and environment 
through sharing similar structure and function 
and allowing for cross-talk between them. Such 
cross-talk is assisted by cytokines and microbial 
metabolites (Owlstone Medical, 2024). Gut 
microbiome diversity decreases rapidly after 
autologous stem cell transplantation. There are 
specific bacterial families and certain immune 
cell subsets in patients receiving autologous 
stem cell transplantation (Becker et al., 2024). 
 

7.2 Mammalian-Immune Axis  
 
Using rabbits ileum and villus culture to elucidate 
the inflammatory response induce by heat killed 
intestinal bacterial antigens of rabbit and pig.it 
has been found that  rabbits intestinal bacterial 
antigen RIBA induced higher expression of 
TLR4,while that of pigs PIBA induced TLR2 and 
TLR3.PIBA and RIBA induced increased 
expression of INFalpha,IL6.PIBA  stimulate INF 
beta and IL10.High appearance of gram negative 
in rabbit ileum do not lead to proinflammatory 
cytokine but high amounts of Lactobacilli in pigs 
ileum was more expressive to anti-inflammatory 
cytokines (Cui and Xu, 2016). 
 

7.3 Monkey Microbiome-Immune Axis  
 

Short term antibiotic treatment in rhesus 
monkeys induced gut microbiome dysbiosis. 
Such dysbiosis lead to increase in CD3+ T cells, 
CD4+ T cells, and CD16+ NK cells. But, 
decreased the number of T reg cells and CD20 B 
cells in peripheral blood cells (Li et al., 2020). 
 

7.4 Rabbit Microbiome-Immune Axis 
 

Transfer of microbiota during birth fostering 
regulation of the first birth reaction. The maternal 

gamma delta T cells shape the offspring 
pulmonary type2 immunity in a microbiota 
dependent manner .The offsprings of gamma 
delta T cell deficient dams displayed  enhanced 
lung type 2 immunity .TCR delta deficient dams 
displayed deficient both in AMP levels and 
microbiota composition of the skin (Papotto et al., 
2023). Rabbits gut microbiome is important in 
regulating trait and played a key role in immune 
system development. As well as it could be 
related to longevity and resilience (Biada et al., 
2020). Incorporation of probiotic with rabbits diet 
supplementation increased the splenic and 
thymic index, levels of IgM, C3 and C4. 
Hence,probiotics supplement in diet could 
effectively improve immune organ index and 
immune function (Zhang et al., 2020, Salvo-
Romero et al., 2020). Rabbits gut bacteria can 
modulate gut resident immune cells and brain 
resident immune cells Studies on gut-brain axis 
have shown that gut microbiome modulate brain 
development and function in presence of immune 
system cooperation (Li et al., 2020). 

 
7.5 Mice Microbiome-Immune Axis 
 
In an experimental settings mice microbiome 
arrested Such arrestment lead to stunting in the 
immune system maturation with few peripheral 
regulatory T cells and decreased levels of IgA 
and increased susceptibility to Salmonella 
infection (Lubin et al., 2023). Neonatal mouse gut 
is enriched with neuro-transimittors and with 
specific bacteria produce serotonin directly while 
down regulating  mono-amin oxidase A to limit 
the serotonin breakdown .Serotonin inhibit 
mTOR activation to promote  regulatory T cells 
and suppress T cell responses both in ex-vivo 
and in-vivo in the neonatal intestines .Oral 
gavage of serotonin into the neonatal mice lead 
to long term tolerance toward diet antigens and 
commensal bacteria as well as gut microbiome 
dysbiosis (Sanidad et al., 2023, Sanders et al., 
2023). 

 
8. COMPARATIVE VIEW 
 
There were significant co-diversification with ten 
gut bacterial phyla including Firmicutes, 
Actinobacteriota. Strikingly around 44% of co-
diversifying clades detect in African apes were 
absent from microbiome data of man and 54% 
were absent from industrialized human 
population (Salvo-Romero et al., 2020). Gut 
microbial taxa, microbial gene family contents of 
the great ape and human are more related by life 



 
 
 
 

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Table 3. Comparative translation approach in human primate, non-human primate and small 
mammals 

 

Model Microbiome 
homeostasis 

Alteration Matchability 
 to human 

References 

Monkey Gut Dysbiosis Immune 
impairment 

(Li et al., 2020) 

Rabbit/Rhinosinsusitis 
/Cystic fibrosis 

Nasal 
Gut 

Dysbiosis 
Dysbiosis 

Matchable 
Matchable 

(Rowe et al., 2018) 
(Liang et al., 2021) 

Mice/Obesity Gut Dysbiosis Matchable (Maue and Lundberg, 2017) 

 
style than geography (Campbell et al., 2020). 
Human gut microbiome composition and 
potentials are more similar to those of old world 
monkeys, the baboons than African apes. 
Though there were inter-individual variation in 
the functional potentials of gut microbiome with in 
human species. Such variations suggest that 
human gut microbiome may exhibit more 
plasticity in response to environmental variation 
(Amato et al., 2019). Antibiotic treatment of 
rhesus monkey model induced gut microbiome 
dysbiosis and impair the peripheral cellular 
immunity (Li et al., 2020). 
 
Results of rabbit microbiome studies can be 
translated to that matching human being as in 
the case of rhinosinusitis accompanied by sinus 
microbiome dysbiosis (Rowe et al., 2018). In 
addition to the young rabbits cystic fibrosis model 
that was associated with gut microbiome 
dysbiosis simulating that of human being cystic 
fibrosis (Liang et al., 2021). 
 
Mouse gut microbiome composition contains 
85% of bacterial genera different from that of 
human gut microbiome. The remaining 15 % of 
the mouse gut bacterial flora were similar to that 
of man. This fraction of mouse gut microbiome 
includes 80 genera shared with human gut 
microbiome. Therefore it is essential for the 
researchers tempting translation of mouse 
experimental results to human being to have a 
clear understanding of the benefits and 
limitations of their model system if they wish to 
translate their finding to man. Mouse obesity and 
IBD are the most models for microbiome studies 
both of which associated with microbiome 
dysbiosis (Maue and Lundberg, 2017), Table 3. 
 

9. HOMEOSTASIS VERSUS DYSBIOSIS 
MICROBIOMES  

 

Homeostasis, is a state of normal functional 
balance of the influence of microbiota on health 
and disease depends onto; quality, quantity, 
proportion of each of microbiota component. 

Homeostasis is in line with functional balance 
between the component of the microbiome. 
Which indicate normal state of each of the 
components. Such balance plays important roles 
in maintenance and development of human 
immune system (Ogunrinol et al., 2020). 
Dysbiosis, is any alteration in human or animal 
microbiota is associated with a disease state. 
Alteration in the microbiota immune axis results 
in immune mediated diseases such as; intestinal 
infection, inflammatory bowel disease, 
autoimmunity, hypersensitivity and cancer 
(Campbell et al., 2023, Ogunrinol et al., 2020). 

 
10. SUGGESTION ONE 
 
"Human gut microbiome and the innate immunity 
levels in neonates, children under five years and 
adolescents". 

 
Elect 50 male and female normal; neonates, 
child under five years and adolescent. Collect 
feces and blood from each group. Test the 
phagocytic activity, acute phase proteins, C3 and 
C4 levels. Fecal sample will be processed for the 
detection of gut microbiome  by the use of either 
DNA or 16SRNA kits. Gut microbiome results 
concerning diversity, composition, similarity, 
enterotype and differences in each group in 
relation to the levels of innate immune 
parameters. 

 
11. SUGGESTION TWO 
 
"Dysbiosis of human gut microbiome in typhoid 
patients". 

 
A plane for gut microbiome dysbiosis in normal 
and typhoid patients will be planed. Normal 
subjects, untreated and treated typhoid patients 
will be the test groups. Fecal samples from each 
group will be collected and processed for gut 
microbiome dysbiosis using either DNA or 16S 
RNA kits. Results analyzed for; composition, 
diversity, and enterotypes for each group. 



 
 
 
 

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12. CONCLUSION 
 
Microbiome is important for human normal 
immune system development from neonates till 
ageing. Human gut microbiome acts as a 
signaling hub that integrate exposome with 
genome and metabolic pathways. Dysbiosis to 
the microbiome is mostly in line with disease 
state. Monkey , rabbit ,and mice  microbiomes 
may simulate but not reach the limits of 
identicality  to human being microbiome ,there 
are advantages and some limitations for each of 
which both in structural and functional aspects 
.Rabbit (Rhinosinusitis, cystic fibrosis) and 
mice(Obesity, IBD) microbiota were tempted for 
translation to human beings .As a suggestion 
monkey microbiome is expected to be more 
similar to human than rabbit and mice but 
apparently no tempts for  translation to human till 
now so far current  information indicated. Two 
suggested programs for human gut microbiome 
studies were made. 
 

DISCLAIMER (ARTIFICIAL INTELLIGENCE) 

    
Author hereby declare that NO generative AI 
technologies such as Lage Language 
Models(ChatGPT ,COPILOT ,etc…) and text to 
image generators have been used during writing 
or editing of this manuscript. 
 

CONSENT AND ETHICAL APPROVAL 
 

It is not applicable. 
 

COMPETING INTERESTS 
 

Author has declared that no competing interests 
exist. 
 

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