Microbial environment, immunity and human health
Sophisticated analytical tools for elucidating genome structure and life of bacteria yielded a new paradigm on our relation to the microbial environment. Formerly, bacteria were seen as jeopardising invaders, and studies on bacterial pathogenesis were the basis for great medical progress in the rest...
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| Опубліковано в: : | Екологічна безпека та природокористування |
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| Дата: | 2008 |
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| Формат: | Стаття |
| Мова: | English |
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Інститут телекомунікацій і глобального інформаційного простору НАН України
2008
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| Назва журналу: | Digital Library of Periodicals of National Academy of Sciences of Ukraine |
| Цитувати: | Microbial environment, immunity and human health / G. Gerber // Екологічна безпека та природокористування: Зб. наук. пр. — К., 2008. — Вип. 2. — С. 5-50. — Бібліогр.: 140 назв. — англ. |
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Gerber, G. 2011-04-27T18:05:36Z 2011-04-27T18:05:36Z 2008 Microbial environment, immunity and human health / G. Gerber // Екологічна безпека та природокористування: Зб. наук. пр. — К., 2008. — Вип. 2. — С. 5-50. — Бібліогр.: 140 назв. — англ. XXXX-0062 https://nasplib.isofts.kiev.ua/handle/123456789/19343 Sophisticated analytical tools for elucidating genome structure and life of bacteria yielded a new paradigm on our relation to the microbial environment. Formerly, bacteria were seen as jeopardising invaders, and studies on bacterial pathogenesis were the basis for great medical progress in the restraint of infections. Now it becomes clear that Homo sapiens is not a single-species organism, but it is to understand as a complex ecosystem assembled of a 10:1 mixture of both environmental microbial and human cells. en Інститут телекомунікацій і глобального інформаційного простору НАН України Екологічна безпека та природокористування Екологічна безпека Microbial environment, immunity and human health Микробиологическая среда, иммунитет и здоровье человека Article published earlier |
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Digital Library of Periodicals of National Academy of Sciences of Ukraine |
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Microbial environment, immunity and human health |
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Microbial environment, immunity and human health Gerber, G. Екологічна безпека |
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Microbial environment, immunity and human health |
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Microbial environment, immunity and human health |
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Microbial environment, immunity and human health |
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Microbial environment, immunity and human health |
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microbial environment, immunity and human health |
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Gerber, G. |
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Gerber, G. |
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Екологічна безпека |
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Екологічна безпека |
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Екологічна безпека та природокористування |
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Інститут телекомунікацій і глобального інформаційного простору НАН України |
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Article |
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Микробиологическая среда, иммунитет и здоровье человека |
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Sophisticated analytical tools for elucidating genome structure and life of bacteria yielded a new paradigm on our relation to the microbial environment. Formerly, bacteria were seen as jeopardising invaders, and studies on bacterial pathogenesis were the basis for great medical progress in the restraint of infections. Now it becomes clear that Homo sapiens is not a single-species organism, but it is to understand as a complex ecosystem assembled of a 10:1 mixture of both environmental microbial and human cells.
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XXXX-0062 |
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https://nasplib.isofts.kiev.ua/handle/123456789/19343 |
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Microbial environment, immunity and human health / G. Gerber // Екологічна безпека та природокористування: Зб. наук. пр. — К., 2008. — Вип. 2. — С. 5-50. — Бібліогр.: 140 назв. — англ. |
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5
Ïðåðîìàíòèçì
Ðîçä³ë 1. Åêîëîã³÷íà áåçïåêà
ÓÄÊ 574/578(031)
MICROBIAL ENVIRONMENT, IMMUNITY
AND HUMAN HEALTH
Gerber G.
(Charité-Universitätsmedizin Berlin,
Humboldt-Universität und Freie Universität Berlin,
Alumni-Club der Charité, Augustenburger Platz 1;
13353 Berlin, Germany)
Sophisticated analytical tools for elucidating genome structure and life of
bacteria yielded a new paradigm on our relation to the microbial environment.
Formerly, bacteria were seen as jeopardising invaders, and studies on bacterial
pathogenesis were the basis for great medical progress in the restraint of
infections. Now it becomes clear that Homo sapiens is not a single-species
organism, but it is to understand as a complex ecosystem assembled of a 10:1
mixture of both environmental microbial and human cells.
The gargantuan diversity of prokaryotic life includes genetic multiplicity,
metabolic endowment, colonised habitats, and response to physical and
chemical stresses. Advances in microbiology, molecular biology, biochemistry
and eukaryotic cell biology have enabled striking discoveries on how
eukaryotic cells cooperate with colonising bacteria. Bacterial life in multi-
species associations and biofilms limits competition, reduces temporal variance
of productivity, enhances performance, and favours positive interactions among
the allied members. Quorum sensing, hypermutable loci in the genome,
horizontal transfer of genes distributed within the population and the enduring
crosstalk with the epithelia and the innate immune system of the host warrant
stability within the microbial community and maintenance of the mutually
beneficial association with the host.
Factors accompanying our current life such as over- and malnutrition,
physical inactivity, excessive use of tobacco, alcohol, drugs and medicine,
Gerber G., 2008
6
Åêîëîã³÷íà áåçïåêà òà ïðèðîäîêîðèñòóâàííÿ
UV-irradiation, incorporation/inhalation of pesticides, toxic gases and heavy
metals and growing-up in a sanitised world disturb the immune balance and
the host-microbiota partnership. Phobia of germs, compulsive hygienic custom
pattern, and the excessive use of antibiotic agents are detaining the immune
system of the microbial information input upon which it is dependent.
This conglomerate of factors and habits conforms to a huge increase of
chronic inflammatory diseases, e.g. atherosclerosis, inflammatory bowel
diseases, diabetes, asthma, rheumatism, neurodermatitis, psoriasis, adipositas,
and cancer. It may be necessary to invent measures of replacing the microbial
input. Food additives with immune modulating (e.g. beta-glucans), prebiotic
(e.g. oligofructosides) or probiotic (e.g. Bifidus, Lactobacillus) features are
anticipated to improve a tilted host-microbiota partnership, immunity and
constitutional performance.
Ñêëàäí³ àíàë³òè÷í³ ï³äõîäè äî âèâ÷åííÿ ñòðóêòóðè ³ æèòòÿ áàêòåð³é
ïîðîäèëè íîâå â³äíîøåííÿ ùî äî ì³êðîáíîãî îòî÷óþ÷îãî ñåðåäîâèùà.
Ðàí³øå ðîçãëÿäàëè áàêòå𳿠ÿê òàê³, ùî ñòâîðþþòü íåáåçïå÷í³ óìîâè
äëÿ ³íøèõ îðãàí³çì³â, ³ äîñë³äæåííÿ ïàòîãåíåçó áàêòåð³àëüíèõ çàõâîðþ-
âàíü áóëè îñíîâîþ äëÿ âåëèêîãî ïðîãðåñó â ìåäèöèí³ ùîäî ñòðèìóâàííÿ
³íôåêö³é. Çàðàç ñòຠçðîçóì³ëèì, ùî Ëþäèíà ðîçóìíà íå îêðåìèé
îðãàí³çì, öå ñêëàäíà åêîñèñòåìà, ÿêà ñêëàäàºòüñÿ ó â³äíîøåíí³ 10:1 ç
ð³çíèõ ì³êðîîðãàí³çì³â òà êë³òèí ëþäèíè.
гçí³ ñåðåäîâèùà ³ñíóâàííÿ êîëîí³çóâàëè âåëè÷åçíå ãåíåòè÷íå ³
ìåòàáîë³÷íå ð³çíîìàí³òòÿ ïðîêàð³îò³â. Äîñÿãíåííÿ ó ì³êðîá³îëî㳿,
ìîëåêóëÿðí³é á³îëî㳿, á³îõ³ì³¿ ³ öèòîëî㳿 åóêàð³îò³â äîçâîëèëè ç�ÿñóâà-
òè, ÿê êë³òèíè åóêàð³îò³â âçàºìîä³þòü ç áàêòåð³ÿìè, ÿê³ êîëîí³çóþòü
îðãàí³çìè.  àñîö³àö³ÿõ ð³çíîìàí³òíèõ áàêòåð³é îáìåæåíà êîíêóðåíö³ÿ,
ñêîðî÷åíà ÷àñîâà ð³çíèöÿ ó â³äòâîðåíí³, âèíèêàþòü ïîçèòèâí³ âçàº-
ìî䳿 ¿õ ÷ëåí³â ³ ñòèìóëþºòüñÿ ðîáîòà. ³ä÷óòòÿ «êâîðóìó», íàÿâí³ñòü
ã³ïåðì³íëèâèõ ì³ñöü ó ãåíîì³, ãîðèçîíòàëüíèé ïåðåíîñ ãåí³â ì³æ áàê-
òåð³ÿìè â ìåæàõ àñîö³àö³¿ òà ñò³éêèé âçàºìîçâ�ÿçîê ç åï³òåë³ÿìè òà
ïðèðîäíîþ ³ìóííîþ ñèñòåìîþ õàçÿ¿íà ãàðàíòóþòü ñòàá³ëüí³ñòü
ì³êðîáíîãî óãðóïóâàííÿ ³ âçàºìíî êîðèñí³ âçàºìî䳿.
Ôàêòîðè, ÿê³ âïëèâàþòü íà íàøå æèòòÿ � ïåðå¿äàííÿ, íåäî¿äàííÿ,
îáìåæåíà ô³çè÷íà àêòèâí³ñòü, íàäì³ðíå âæèâàííÿ òþòþíó, àëêîãîëþ,
íàðêîòèê³â ³ ë³ê³â, óëüòðàô³îëåòîâîãî îïðîì³íåííÿ, ïàë³ííÿ, ä³ÿ êîìï-
ëåêñó ïåñòèöèä³â, îòðóéíèõ ãàç³â ³ âàæêèõ ìåòàë³â, âèõîâàííÿ ä³òåé ó
ñàíîâàíîìó ñâ³ò³ � ïîðóøóþòü ³ìóííèé áàëàíñ ³ âçàºìîä³þ îðãàí³çìó
õàçÿ¿íà ç áàêòåð³ÿìè. Áîÿçíü ì³êðîá³â, ñóâîð³ íàâ�ÿçëèâ³ ã³ã³ºí³÷í³ âèìî-
ãè ³ íàäì³ðíå çàñòîñóâàííÿ àíòèá³îòèê³â çàòðèìóº ðîçâèòîê ³ìóííî¿
ñèñòåìè, òîìó ùî áàãàòî ì³êðîîðãàí³çì³â íå ïîòðàïëÿþòü â îðãàí³çì
ëþäèíè.
7
ÏðåðîìàíòèçìÐîçä³ë 1. Åêîëîã³÷íà áåçïåêà
Öåé íàá³ð ôàêòîð³â ³ çâè÷îê â³äïîâ³äຠâåëè÷åçíîìó çá³ëüøåííþ
õðîí³÷íèõ çàõâîðþâàíü, ÿê³ ìàþòü âàæêè íàñë³äêè, íàïðèêëàä, àòåðî-
ñêëåðîçó, õâîðîá øëóíêîâî-êèøêîâîãî òðàêòó, ä³àáåòó, àñòìè, ðåâìà-
òèçìó, íåéðîäåðì³ò³â, ïñîð³àçó, ðàêó. Ìîæëèâî òðåáà çàïðîïîíóâàòè
íîâ³ çàñîáè çàì³íè âïëèâó ì³êðîîðãàí³çì³â , íàïðèêëàä, âèêîðèñòîâóâà-
òè õàð÷îâ³ äîì³øêè, ÿê³ ì³ñòÿòü ³ìóíîìîäóëÿòîðè (íàïðèêëàä, áåòà-
ãë³êàíè); ïðåá³îòèê³ (íàïðèêëàä, îë³ãîôðóêòîçè) àáî ïðîá³îòèê³ (íà-
ïðèêëàä, Áèôiäîáàêòåð³¿, Ëàêòîáàêòåð³¿). ª ñïîä³âàííÿ, ùî ¿õ
çàñòîñóâàííÿ ïîêðàùèòü âçàºìîä³þ ì³êðîîðãàí³çì³â ³ ëþäèíè, ¿¿ ³ìóí³-
òåò ³ ñòàëó ðîáîòó ¿¿ îðãàí³çìó.
Ñëîæíûå àíàëèòè÷åñêèå èíñòðóìåíòû, îáúÿñíÿþùèå ñòðóêòóðó è
æèçíü áàêòåðèé, ïðèâåëè ê íîâîìó îòíîøåíèþ ê ìèêðîáíîé îêðóæàþùåé
ñðåäå. Ïðåæäå áàêòåðèè ðàññìàòðèâàëè êàê òàêèå, êîòîðûå ñîçäàþò
îïàñíûå óñëîâèÿ äëÿ äðóãèõ îðãàíèçìîâ, à èññëåäîâàíèÿ áàêòåðèàëüíîãî
ïàòîãåíåçà áûëè îñíîâàíèåì äëÿ áîëüøîãî ìåäèöèíñêîãî ïðîãðåññà â
ñäåðæèâàíèè èíôåêöèé. Òåïåðü ñòàíîâèòñÿ ÿñíî, ÷òî ×åëîâåê ðàçóìíûé
íå îòäåëüíûé îðãàíèçì, à ñëîæíàÿ ýêîñèñòåìà, ñîñòîÿùàÿ â îòíîøå-
íèè 10:1 èç ðàçíûõ ìèêðîîðãàíèçìîâ è ÷åëîâå÷åñêèõ êëåòîê.
Ðàçíûå ñðåäû îáèòàíèÿ êîëîíèçèðîâàëè ãèãàíòñêîå ãåíåòè÷åñêîå
è ìåòàáîëè÷åñêîå ðàçíîîáðàçèå ïðîêàðèîò. Äîñòèæåíèÿ â ìèêðîáè-
îëîãèè, ìîëåêóëÿðíîé áèîëîãèè, áèîõèìèè è öèòîëîãèè åóêàðèîò ïî-
çâîëèëè ïîêàçàòü êàê êëåòêè åóêàðèîò ñîòðóäíè÷àþò ñ êîëîíèçèðó-
þùèìè îðãàíèçì áàêòåðèÿìè. Â àññîöèàöèÿõ ðàçíîîáðàçíûõ áàêòåðèé
îãðàíè÷åíà êîíêóðåíöèÿ, ñîêðàùåíà âðåìåííàÿ ðàçíèöà âîñïðîèçâîä-
ñòâà, âîçíèêàåò ïîëîæèòåëüíîå âçàèìîäåéñòâèå èõ ÷ëåíîâ è ñòèìó-
ëèðóåòñÿ ðàáîòà. Îùóùåíèå «êâîðóìà», ãèïåðèçìåí÷èâûå ìåñòà â
ãåíîìå, ãîðèçîíòàëüíûé ïåðåíîñ ãåíîâ ìåæäó áàêòåðèÿìè â ïðåäåëàõ
àññîöèàöèè è óñòîé÷èâàÿ ñâÿçü ñ ýïèòåëèÿìè è âðîæäåííîé èììóííîé
ñèñòåìîé õîçÿèíà ãàðàíòèðóåò ñòàáèëüíîñòü ìèêðîáíîãî ñîîáùå-
ñòâà è âçàèìíî ïîëåçíîãî âçàèìîäåéñòâèÿ.
Ôàêòîðû, ñîïðîâîæäàþùèå íàøó òåêóùóþ æèçíü, òàêèå êàê ñâåðõ-
èëè íåäîåäàíèå, ôèçè÷åñêàÿ áåçäåÿòåëüíîñòü, ÷ðåçìåðíîå èñïîëüçîâà-
íèå òàáàêà, àëêîãîëÿ, íàðêîòèêîâ è ëåêàðñòâ, óëüòðàôèîëåòîâîå îáëó-
÷åíèå, äåéñòâèå êîìïëåêñà ïåñòèöèäîâ, ÿäîâèòûõ ãàçîâ è òÿæåëûõ
ìåòàëëîâ è âîñïèòàíèå äåòåé â ñàíèðîâàííîì ìèðå íàðóøàþò èììóí-
íûé áàëàíñ è âçàèìîäåéñòâèå îðãàíèçìà õîçÿèíà ñ áàêòåðèÿìè. Áîÿçíü
ìèêðîáîâ, ñòðîãèå íàâÿç÷èâûå ãèãèåíè÷åñêèå òðåáîâàíèÿ è ÷ðåçìåðíîå
èñïîëüçîâàíèå àíòèáèîòèêîâ çàäåðæèâàåò ðàçâèòèå èììóííîé ñèñòå-
ìû, ò.ê. ìíîãèå ìèêðîîðãàíèçìû íå ïîïàäàþò â îðãàíèçì ÷åëîâåêà.
Ýòîò íàáîð ôàêòîðîâ è ïðèâû÷åê ïîðîæäàåò îãðîìíîå óâåëè÷å-
íèå õðîíè÷åñêèõ áîëåçíåé, êîòîðûå èìåþò òÿæåëûå ïîñëåäñòâèÿ,
8
Åêîëîã³÷íà áåçïåêà òà ïðèðîäîêîðèñòóâàííÿ
íàïðèìåð, àòåðîñêëåðîçà, áîëåçíåé êèøå÷íèêà, äèàáåòà, àñòìû, ðåâ-
ìàòèçìà, íåéðîäåðìèòîâ, ïñîðèàçà, ðàêà. Ìîæåò áûòü íåîáõîäèìî
ïðåäëîæèòü íîâûå ìåòîäû çàìåíû âëèÿíèÿ ìèêðîîðãàíèçìîâ, íàïðè-
ìåð, ïèùåâûìè äîáàâêàìè, ñîäåðæàùèìè èììóíîìîäóëÿòîðû (íàïðè-
ìåð, áåòà-ãëèêàíû), ïðåáèîòèêè (íàïðèìåð, îëèãîôðóêòîçû) èëè ïðî-
áèîòèêè (íàïðèìåð, Áèôèäîáàêòåðèè èëè Ëàêòîáàêòåðèè). Êàê
îæèäàþò, èõ ïðèìåíåíèå óëó÷øèò âçàèìîäåéñòâèå ìèêðîîðãàíèçìîâ
è ÷åëîâåêà, åãî èììóíèòåò è ñòàáèëüíóþ ðàáîòó åãî îðãàíèçìà.
1. Microbial diversity and human activity
Fifteen hundred scientists under the auspices of the United Nations
Environment Programme (UNEP) completed in 1995 the Global
Biodiversity Assessment (Heywood 1995). This appraisal alludes to the
biological diversity at all levels � genes, species, and ecosystems �
and is still extremely uncertain. Of its working figure of 13 million
species, only approximately 1.7 million have been scientifically described
and given Linnaean nomenclature. These living organisms interact
among them and with the non-living environment and comprise the
global ecosystems. The biological multiplicity is pivotally evident for
human society and sustainable development. A reckoned 40 per cent
of the global economy rests upon biological products and processes.
Faced with the rate of species extinctions, which is hundreds or
thousands of times the natural background level, the public begins to
raise attention on the outcome of human activities on biodiversity.
However, the appreciation on how activity of mankind, human health
and biodiversity are intimately connected among one another will only
increase in coming years.
Having a glance in a biology textbook of the 1980s one may realise
that the living matter is subdivided in five kingdoms: Bacteria, Protoctista
(nucleated unicellular organisms), Fungi, Plantae and Animalia. About
5000 species classified by means of traditional bacteriological techniques
were allocated to non-eukaryotic organisms, and thus should contribute
only a minor portion to the overall species variety (Skerman et al.
1989). Just for comparison: more than half a million insect species
have been classified.
Beginning in the 1960s it became feasible to define prokaryotes on
the basis of shared molecular characteristics when Zuckerkandl and
Pauling (1965) expounded the role of nucleic acid as the master
9
ÏðåðîìàíòèçìÐîçä³ë 1. Åêîëîã³÷íà áåçïåêà
candidate of a molecular phylogeny. Obviously, microbial morphology,
motility, metabolism and serological types are too simply or inexplicable
to serve as the basis for a phylogenetically compelling taxonomy.
Sophisticated techniques such as reverse transcription (RT)-PVR, DNA
micro arrays, in vivo expression technology (IVET), fluorescence in situ
hybridisation (FISH), restriction fragment length polymorphism, subtractive
hybridisation, signature-tagged mutagenesis, in situ isotope tracking, and
the sequencing revolution replaced classical phenotypic characteristics by
molecular criteria. This progress culminated in two scientific acmes at
the end of the last century: i) the creation of a new natural system of
organisms dividing life on our planet in three domains (Woese et al.
1990), and ii) the whole-genome random sequencing and assembly of
a free-living microorganism, the ã-proteobacterium Haemophilus influenzae
Rd. (Fleischmann et al. 1995). Comparison of the unique sequences of
nucleobases in the chromosomes has all of a sudden shown that the
three primary domains are: Bacteria, Archaea, and Eukarya. These
domains evolved in parallel along three phylogenetic lineages.
The small unit of ribosomal ribonucleic acid (16S rRNA from
prokaryotic cells and 18S rRNA from eukaryotic cells) proved to be
an elegant taxonomic tool in regard of the following: first, it is present
in all organisms, and secondly, it contains highly conserved as well
as variable nucleotide sequences. Divergence between species or strains
may be evident when comparisons are made of the variable regions,
and comparing highly conserved regions may elucidate divergence at
the higher taxonomic ranks (domain, kingdom). Nowadays, techniques
for high-throughput cultivation of more than 10,000 bacterial and
fungal isolates per environmental sample are available (Zengler et al.
2002). That provides access to the immense reservoir of untapped
microbial diversity by cultivation. Determination the species composition
of a microbial community needs to be followed by establishing the
functions of the community and of each of its members (metabolic
fingerprinting by community level physiological profiling CLPP). After
all, one has to have in mind that there is an ongoing debate on
methods for defining species, mechanisms that lead to speciation and
whether microbial species even exist. Achtman and Wagner (2008)
propose that a method-free species concept based on cohesive evolutionary
forces should direct decisions on the existence of species and procedures
to define them.
10
Åêîëîã³÷íà áåçïåêà òà ïðèðîäîêîðèñòóâàííÿ
From a commonplace of view we recognise only the multicellular
creatures as the denizens of our earth. All are Eukarya, but many single-
cellular belong to this domain, too. Bacteria and Archaea are exclusively
composed of prokaryotic cells and are thus microbial. The major
advances in molecular and cell biology and the application of these
methodologies on microbiology produced cross-fertilisation of these
disciplines and had impacts, which was unimaginable only a generation
ago (Table 1). The gargantuan diversity of prokaryotic life includes
genetic multiplicity, metabolic endowment, colonised habitats, and response
to physical and chemical stresses. Microorganisms are the major life
forms on earth and reside yet in extreme environments like very rocks,
hot springs and submarine grounds. The amount of carbon that is piled
up in prokaryotes matches that in the plant kingdom. In case of nitrogen
and phosphorus the ratio is even ten in favour of the microbes. Since
only less than 1% of species of the microbial world was cultivated and
studied under laboratory conditions, we know nothing of them other
than what can be inferred from their genomic sequence.
The majority of microorganisms lives in microbial dynamic assemblages.
The stability and functions of these consortia are ruled by dependencies
and antagonisms among the members. Life in multi-species associations
and biofilms limits competition and favours positive interactions among
the allied bacteria. A fraction of the microbial universe coexists with
animals in mutually beneficial association. Such microbial communities
have to assert themselves with the vicissitudes of their host (Handelsman
et al. 2005). Microbial symbioses with animals warrant benefits to both
host and bacteria and promote their macro-evolutionary persistency.
Such symbioses have played an essential role in revival of the biosphere
after periodic mass annihilation of major groups of organisms and whole
ecosystems (Hickman 2005). Less than 0.0005 percent of the total
domain Bacteria can cause disease. The relation in fungi is not quiet
different: approximately 300 of the greater than 100,000 classified fungal
species have pathogenic relationships with animals and plants (Steenbergen
and Casadevall 2006). Advances in microbiology, molecular biology and
eukaryotic cell biology have enabled striking discoveries on how eukaryotic
cells cooperate with colonising bacteria and interact with pathogens
during the infectious process. The partnering-up of these related fields
progressed in a novel scientific discipline that has been termed cellular
microbiology (Cossart et al. 1996).
11
ÏðåðîìàíòèçìÐîçä³ë 1. Åêîëîã³÷íà áåçïåêà
Topics Impact References
Diversity of
prokaryotic
life
Genetic diversity highest in the
microbial world, prokaryotes encompass
up to ten million species, wide range of
energy substrates and the availableness
of miscellaneous catabolic and anabolic
pathways, occupying multiple habitats,
multitude of responses to physical and
chemical stresses
Stahl and Tiedje
2002
Torsvik et al. 2002
Ancestry Eukarya, Bacteria and Archaea have
split from a common ancestor 2—3.5
billion years ago
Woese et al. 1990
Doolittle et al. 1996
Biomass 4—6×1030 prokaryotic cells on earth
containing 350—550×109 tons of
carbon, 85—130×109 t nitrogen, 9—
14×109 t phosphorus, cellular production
rate for all prokaryotes on earth is
estimated at 1.7×1030 cells/yr, it is
highest in the open ocean
Whitman et al.
1998
Cultivability 90 to 99.9 % do not grow and replicate
in cultures under laboratory conditions
Henderson et al.
1999 (p.19)
Mode of life Multi-species associations, colonies,
biofilms, quorum sensing systems as
signal amplifiers within a bacteria and as
signal disseminators between bacteria
Palmer et al. 2007
Fuqua et al. 1994
Dunny and Winans
1999
Symbiosis 1000—3000 species (phylotypes)
mutually coexist with man,
specific gene-gene interactions within
the microbiome (genomic plasticity)
Eckburg et al. 2005
Dethlefsen et al.
2007
Ehrlich et al. 2008
Pathogenicity About 50 bacteria cause human diseases Rappuoli 2006
Table 1 � Impact of new analytical tools on cellular microbiology
The current debate on the use and misuse of antibiotics perpetuates
a long history of semantic thoughts on microbes as friend or foe of man.
In the late seventieth century, Antonie van Leeuwenhoek, who ranks first
to had inspected the indiscernible minuscule life, already expressed his
astonishment on the ample colonisation of our body and its environment
by «animalcule» what means «little animals»: «�there are more animals
12
Åêîëîã³÷íà áåçïåêà òà ïðèðîäîêîðèñòóâàííÿ
living in the scum on the teeth in a man´s mouth, than there are men
in the whole kingdom». Bacteriology started two centuries later with the
pioneering work of Robert Koch, Louis Pasteur, Sergei Winogradsky and
other scientific heroes. Koch and Pasteur developed pure culture techniques
to identify causative agents of many diseases that affect humans and
animals. Contrariwise, Sergei Winogradsky � born in Kiev 1856 �
invented a simple columnar device for culturing a large diversity of
bacterial life in natural environments. Among the bacteria within such
a single column there grow members of all four basic life strategies:
phototrophs, chemotrophs, autotrophs, and heterotrophs. The Winogradsky
column evolved, thus, as classic tool for studying the relationships
between different types of microorganisms in mixed communities. In
addition, it is an elegant illustration of how microorganisms occupy
highly specific niches according to their environmental tolerances and
their requirements of energy and carbon.
In the aftermath microbes were dichotomic seen from the viewpoint
of practical purposes (Gutzeit 1918, Duddington 1961). The «good» ones
help in fermentations in the dairy industry, the manufacture of vinegar,
beer, coffee, cocoa, food supplements, and feed for farm animals as well
as in biomining (bioleaching) and sewage treatment. The «bad» ones are
looked upon as pests or can be at least a nuisance in many everyday
situations. According to the widely held opinion, germs should be
eliminated or constrained in their activities. Following such options many
a scientist lumbered in a meander. Ilja Metchnikoff, for example, assumed
«autointoxication» of the human body by the intestinal microflora and
practised surgical ablation of the colon. Later, however, by contemplating
about longevity in Bulgarians he suggested that that may be linked to the
helpful activity of lactic acid bacteria ingested with sour milk.
The elimination of bacterial pathogens appeared to become a reality
when antimicrobial agents were introduced into clinical practice in the
1940s and 1950s. That was one of the most outstanding public health
achievements of the 20th century. In marvelling the unimaginable aid
to legions of infected patients the Western societies lost its fear of
bacterial infection. In 1969 the then United States Surgeon General
presumed to prophesy in his address to Congress «We can close the
book on infectious diseases». One outcome of this misjudgement was
the drop in research into the mechanisms by which bacteria cause
communicable diseases. The other was the assumption on the selective
13
ÏðåðîìàíòèçìÐîçä³ë 1. Åêîëîã³÷íà áåçïåêà
toxicity of a particular antibiotic to a certain bacterial pathogen: due
to fundamental differences to eukaryotic cells the antibiotic therapy
might not threat the host.
Nonetheless, already in the late 1940s strains of Staphylococcus
aureus developed resistance against penicillin. The number increased
steadily and at present MRSA (methicillin-resistant Staphylococcus
aureus) is a menace of hospital settings. Resistance has developed
meanwhile against all available classes of antibiotics (Virk and
Steckelberg 2000, Smith and Coast 2002). Rowe-Magnus and Mazel
(2006) published a survey on the evolution, biochemical mechanisms
of antibiotic resistance and their genetic determinants. Species of the
genus Bacteroides have the highest resistance rates of all anaerobic
pathogens, the multiple mechanisms of which are discussed by Wexler
(2007). In addition, there are alert marks just heralding man-made
tumbling into a new predicament: Resistant Staphylococcus aureus
changed its epidemiology and advanced from being a pathogen primarily
related with nosocomial infection to one that has begun to recurrently
infect individuals outside the hospitals (Chambers 2001). Obviously
the «golden age of antibiotics» turns up jaded after merely two
generations.
By traditional view, the transmission of pathogenic bacteria has been
assumed to take place through ingestion of infected stuff or liquids and
intimate contact with contaminated surfaces. Transmission over short
distances is also possible when the pathogen is enclosed in large
droplets, as in sputum. This route should be rendered more precisely
on the basis of reports on airborne transmission of communicable
diseases (Roy and Milton 2004). Gandara et al. (2006) gave account
on the common appearance of cultivable strains of Staphylococcus
aureus resistant against penicillin, ampicillin and cefaclor in aerosols
sampled within residential homes. The infection of children without
known risk factors with this pathogen has to be regarded as an
exceptionally precarious observation (Gorak et al. 1999). Experiments
on mouse and human cell lines demonstrate the ability of indoor air
bacteria and fungal spores in boosting the production of proinflammatory
mediators (Huttunen et al. 2003). The trends in the epidemiology of
antibiotic-resistant pathogens give persuasive justification for more profound
scientific exploration of both the indoor sources of, and morbid effects
correlated with, indoor residential exposure to airborne pathogens.
14
Åêîëîã³÷íà áåçïåêà òà ïðèðîäîêîðèñòóâàííÿ
Findings emphasise that current concentrated animal feeding operations
(CAFOs) can result among others in the emanation of antibiotic-
resistant bacteria into the general environment (Platz et al. 1995).
Multiresistant strains were detected in the air plume up to 150 m
downwind of a swine confined animal feeding operation (Gibbs et al.
2006). Naïve subjects living in close proximity to such facilities and
employees who work inside suffered from respiratory inflammatory
symptoms (Heederick et al. 2007). The paucity of data in regard of
environmental and community adverse health effects of modern
production of pigs and poultry resulted in a growing controversy in the
public (Cole et al. 2000, Rieger 2001). Intensified cooperation among
animal producers, feed professionals and health officials as well as
forced research in cross-linked human and veterinary health surveillance
systems are indispensable to successfully address these issues. Special
attention should be given to high-risk groups such as children and
asthmatics. A flicker of hope comes from Denmark, where the prevalence
of macrolide-resistant species of Campylobacter dropped subsequently
to the banning of all growth promoters from feeding in livestock.
2. Man and microbes are companions
Microbes make up a considerable component of the human body.
The external surface � like the skin and its adhering structures � and
the internal surfaces such as the mucosal layers of the gastrointestinal,
respiratory and genito-urinary system and the cavities they enclose,
harbour microbial communities of different complexity. The term
microbiota, or indigenous microflora, or commensal microflora,
respectively, encompasses all of the bacteria, archaea, fungi, proctists,
and viruses. The bacterial component at any body site was chiefly
studied, but little is known about the other types. The microbiota in
the adult has a mass of about 1�2 kg, which corresponds to that of
liver and outruns most other human tissues. Although this represents
only about 2% of the whole body mass, in terms of cell numbers the
total microbial population exceeds our total number of somatic and
germ cells by at least one order of magnitude (Xu and Gordon 2003).
The number of genes in this «microbiome» may overtake the human
genome about 100 times. In conclusion, human sapiens may not be
regarded as a single-species organism, but as a complex ecosystem
15
ÏðåðîìàíòèçìÐîçä³ë 1. Åêîëîã³÷íà áåçïåêà
compiled of a 10:1 mélange of both microbial and human cells
(McVean et al. 2005, Eckburg et al. 2005, Ley et al. 2006). The
microbiome and hosts genome collectively constitute the hologenome
that includes all genes from the host and from all symbionts. It is
flexible and varies with age, health, diet, and environmental factors.
The 6.5 billion humans living on earth represent a microbial reservoir
of 1023�1024 prokaryotic cells. Thus, human intestine and that of other
mammals share a considerable portion of the total microbial mass on
our planet that is estimated to about 4�6×1030 prokaryotic cells. The
human bowel harbours 1011�1012 prokaryotic cells per ml, the highest
observed density for any microbial habitat (Whitman et al. 1998).
During foetal life the human being like all other mammals dwells
in a sterile environment. Birth is the encounter stage in microbial
colonisation of the newborn that discharges into a life-long partnership.
First microbes stem from the mother, members of clinical staff, equipment
and the close environment. Later, germs may attain from more distant
sites of environment and from food. One may wonder in all innocence
what causes the whittling down of a spectrum of more than fifty phyla
of Bacteria and 13 phyla of Archaea staying alive on earth to just four
phyla of Bacteria � the Bacteroidetes, Firmicutes, Actinobacteria, and
Proteobacteria � that overwhelmingly dominate microbial communities
of man. In the colon Bacteroidetes and Firmicutes contribute more than
95% of the microbiota, only one member of Archaea (Methanobrevibacter
smithii) is present? Chlamydiae, Cyanobacteria, Deferribacteres,
Deinococcus-Thermus, Fusobacteria, Verrucomicrobia, and Spirochaetes
establish the minor balance. High levels of strain variation complete this
little dissimilarity in the deep phylogenetic lineages. That type of an
extreme fan-like phylogenetic architecture of the gut microbiota might
have arisen in evolution from the diversification of a distinct limited
primary community into strains (Ley et al. 2006). A more detailed view
of the differences between genomes of human individuals and the
microbiota may foreshadow a deeper comprehension on evolutionary and
biological forces that have made us (Dethlefsen et al. (2007).
Apparently there are stringent requirements for membership in the
microbial community. Whether or not a bacterium affiliates the local
biota depends on the nutritional and physicochemical conditions and
the host defence on site. It obeys two fundamental rules formulated
by Liebig and Shelford. The nutrient present in the lowest concentration
16
Åêîëîã³÷íà áåçïåêà òà ïðèðîäîêîðèñòóâàííÿ
in comparison with the needs of the organism determines the yield
of this organism according to Liebig´s law of minimum. Usually the
host and accompanying microbes are the sources of nutrients, intestinal
microbes utilise in addition ingested foodstuffs. Shelford´s law states
that each of the physicochemical constraints operating on site have to
remain within the tolerance range to make available the survival of a
species within an ecosystem. The effectiveness of these basic laws is
amended by beneficial and antagonistic interactions among the species
present, colonisation history, host characteristics (genotype, age, gender,
life-style, diseases). The dual hegemony of Firmicutes and Bacteroidetes
apparently originates from their particular and complementary metabolic
functions within the microbial community.
The «living-together» is variable with respect to species and topological
distribution of microbes involved and the mode of cooperation with the
host. The biochemical features of binding and identification of molecules
determine the rules of pacing, extent, and pattern of microbial diversity.
Different methodologies employed, variation between individuals, changes
in microbial nomenclature and taxonomy, and so on hamper the
compilation of published data on the distribution of particular fractions
of microbes. Nonetheless, an approach is made to survey the diversity
of indigenous microbiota in various sites of adult humans (Table 2).
Most of the data on the microbiota still have been derived from
culture-based investigations. However, cultivation methods under-represent
the extent of bacterial diversity. For instance, in samples from human
microbiota about 10�50% of bacteria can cultivated, from environments
(soil, lakes, seawater, sediments) less than 1%.
In spite of evident variations in tissue structural and functional
properties of our outer and inner surfaces and environmental determinants,
each microbial community is generally dominated by a limited number
of species. Only five phyla contribute more than 90% and establish
the core set of regional microbiotas. That was shown for the oral cavity,
the distal oesophagus, the stomach, and the colon, where Actinobacteria,
Firmicutes, Proteobacteria, Bacteroidetes and Fusobacteria are dominating.
It holds to be true for skin, too, though Fusobacteria are missing there.
Infrequent taxa compose the remainder of the population and may vary
between times of sampling and among individuals.
The density of sudoriferous (sweat-producing) and sebaceous (sebum-
producing) glands at the particular area principally influence the
17
ÏðåðîìàíòèçìÐîçä³ë 1. Åêîëîã³÷íà áåçïåêà
Body site Number Diversity Bacteria
1 2 3 4
Skin,
hairfollicle
103 -106
per cm2
Stable
scaffold of
small
number of
genera
Actinobacteria, Firmicutes,
Proteobacteria, Corynebacterium,
Staphylococcus, Streptococcus,
Propionibacterium, Micrococcus,
Kocuria, Malassezia, Brevibacterium,
Dermabacter, Acinetobacter,
Methylobacterium
Conjunctiva
of eye
102 - 5x104 Usually not
more than
2 species
CNS (coagulase negative
staphylococci), Propionibacteria,
Corynebacterium, Streptococcus,
Lactobacillus, Sarcina, Bacillus
Oral cavity 108 per ml
saliva
107-109 per
cm2 tongue
High Firmicutes, Bacteriodetes,
Streptococcus, Actinomyces,
Neisseria, Haemophilus, Eubacterium,
Lactobacillus, Fusobacterium,
Abotriophia, Gemella, Veillonella,
Prevotella, Bifidobacterium,
Staphylococcus, Propionibactrium,
Porphyromonas
Plaques: Streptococcus mutans,
Streptococcus viridans, Actinomyces,
Veillonella, Fusobacterium,
Prevotella, Eubacterium, spirochaetes
Porphyromonas gingivalis,
Bacteroides forsythus, and Treponema
denticola
Gastro-
intestinal
tract
1014
1011 – 1012
cells per ml
Upper part:
low
Lower part:
high
Oesophagus: Staphylococci,
lactobacilli, Corynebacterium,
Prevotella, Veillonella.
Stomach: Hel. pylori, acid-tolerant
streptococci, staphylococci and
lactobacilli.
Ileum: Streptococci, enterococci and
coliforms in the lumen; on the mucosa
Bacteroides, Clostridium,
Table 2 � Indigenous microbiota at various sites of human body
18
Åêîëîã³÷íà áåçïåêà òà ïðèðîäîêîðèñòóâàííÿ
Compiled from Paster et al. (2001), Wang et al. (2003), Pei et al. (2004),
Eckburg et al. (2005), de Backer et al. (2007), deFranco et al. (2007),
Dethlefsen et al. (2007), Gao et al. (2007), Wilson (2008).
Body site Number Diversity Bacteria
1 2 3 4
Bifidobacterium.
Cecum: Enterobacteriacea,
lactobacilli, Bacteroidetes,
Clostridium.
Colon: Bacteroides, Eubacterium,
Bifidobacterium, Clostridium; (by
culture-independent methods:
Firmicutes, Bacteroidetes,
Clostridia, Bifidobacterium,
Atopobium)
Respiratory
tract
Upper part:
high
Lower part:
no resident
microflora
Streptococcus, Neisseria,
Haemophilus, CNS,
Corynebacterium,
Propionibacterium,
Prevotella, Veillonella, Mollicutes.
Microbes detectable in the lung,
which are aspirated with microbe-
containing secretions from the
upper respiratory tract
Female
reproductive
system
109 High
<4—8 per
individual
Lactobacilli, CNS, Gram-negative
anaerobic bacilli (GNAB), Gram-
positive anaerobic cocci (GPAC),
Corynebacterium, Bacteroides,
Prevotella, Gardnerella vaginalis,
Atopobium vaginae
composition of cutaneous microbiota. Corynebacterium, Propionibac-
terium, and Staphylococci inhabit at any site, propionibacteria dominate
sebum-rich sites (forehead, scalp), corynebacteria moist areas (axillae,
perineum), and staphylococci are the predominating species in dry
regions such as arms and legs. Microbial communities inhabit nose and
the pharynx, where they adhere to a substratum in order to prevent
19
ÏðåðîìàíòèçìÐîçä³ë 1. Åêîëîã³÷íà áåçïåêà
expulsion by the respiratory flow. This region is a carriage site of a
number of very important human pathogens (Strep. pyogenes, Strep.
pneumoniae, H. influenzae, Staph. aureus, N. meningitides). The
airways in the lungs are sterile to a large extent.
The gastrointestinal tract expanding from the oral cavity until colon
and rectum is highly diverse from anatomical, functional and microbial
points of view. With a surface of 200�300 m2 it is the largest body
surface in contact with the environment. About 700 bacterial phylotypes
have been characterised in the oral cavity with considerable variations
between various sites. Besides of the densely colonised tongue the teeth
are the predominant area in this location. Bacteria on tooth surfaces
live in biofilms that are known as plaques. Adhering to these surfaces
is of pivotal significance for any potential microbial coloniser, since
in this cavity biting, chewing, tongue movements, and salivary flow
generate the highest mechanical forces in the body and the danger of
displacement. «Pioneer colonisers» such as Actinomyces equipped with
adhesins start colonisation of tooth�s surface followed by biofilm-
promoting Streptomyces. «Secondary colonisers», unable either to adhere,
or survive on the bare tooth surface, join expansion to the plaque by
autogenic growth.
The largest assembly of microorganisms undoubtedly inhabit the
intestine. Most are refractory to cultivation. Physicochemical and
nutrient gradients exist along the gut and in the transversal direction
of the lumen. This and the complex microstructure of epithelia and
the mucous layer on their exterior as well as the high rate of cell
renewal make available many niches for microbial existence. So
extreme species diversity (up to 1,000 species), inter-subject variability
and differences between anatomical and microanatomical locations
might be not astonishing (Eckburg et al. 2005). Nevertheless, a few
generally consistent traits appear evident (Table 3).
The part of the body that is beneath the skin and the mucosal
epithelia is devoid of microorganisms. Therefore, one function of
epithelia is to prevent contact of the microbes with the rest of the body.
This is realised in various modes (Fig. 1): Several junctions (tight
junctions, zonula adherence, desmosomes) link epithelial cells with
each other and with the underlying connective tissue matrix to establish
a physical barrier. A coat of keratinised dry and dead horny cells,
which are not accessible for microbes, further protects the skin. Special
20
Åêîëîã³÷íà áåçïåêà òà ïðèðîäîêîðèñòóâàííÿ
Table 3 � Characteristic traits of the intestinal microbiota
Trait Property and function of gut microbiota Reference
Biodiversity Restricted by stringent requirements for
membership in the microbial
community:
- enzymes to utilise available nutrients
- cell-wall accessories to contact the
proper habitat and to conciliate the
supervising immune system,
- evade bacteriophages,
- fast growing to prevent washout,
- mutability to be able to adaptation
- stress resistance in order to leap to
other hosts overcoming an awkward or
toxic environment
Ley et al. 2006
Share of
anaerobes
> 99.9% of the cultivable population in
adults are obligate anaerobes
Moore and
Holdeman 1974
Bifidus spp. Dominating in the preweaning
microbiota, in particular Bifidobac-
terium longum with high activities of
ß-galactosidases to utilise lactose of
mothers milk
Schell et al. 2002
Regional
population
density
Increases from the duodenum
containing 103 cfu/ml (that is 103
organisms per ml luminal contents) to
the colon with 1011 cfu per ml contents.
Thus, it increases by about 8 orders of
magnitude along the gut
Savage 1977
Involvement in
host
metabolism
Microflora operates as a postnatally
acquired, multifunctional
autochthonous organ,
metabolic diversity by far outperforms
that of human tissues,
complements the metabolism of host,
e.g. cracking of indigestible polysac-
charides of plant or microbial origin,
degradation of dietary oxalates, bio-
transformation of conjugated bile acids,
synthesis of vitamins and amino acids
Salmond et al.
1995
21
ÏðåðîìàíòèçìÐîçä³ë 1. Åêîëîã³÷íà áåçïåêà
Trait Property and function of gut microbiota Reference
Immunity Coaching the immune system tolerance
against a wide mix of environmental
and food antigens, decreases number
and extent of allergic responses
Braun-Fahrländer
et al. 2002
Intestinal
epithelia
Maintenance of intestinal epithelial
homeostasis, protecting epithelial cell
layers and stimulating the development
of intestine´s elaborate submucosal
network of interconnected capillaries
Rakoff-Nahoum et
al. 2004,
Stappenbeck et al.
2002
Fat storage in
host
Decreases lipid accumulation in
adipose tissue, increases lipid
mobilisation, prevents adiposity
Ley et al. 2005,
Bäckhed et al.
2007
glycoproteins (mucins) secreted by the epithelium prevent mucosal
surfaces from microbial sticking. One part, the membranous mucins
are fixed to the cells and form the «glycokalyx». Secreted mucins form
large linked polymers that are closely associated with the glycokalyx.
The epithelium secretes microbicidal peptides, and local B cells secrete
IgA. M-cells conduct transport of intact macromolecules from the
lumen to the opposite side by an endocytose mechanism. The most
remote cells on the top of the villus are regularly being expelled and
are thrown out together with mucus and attached microbes.
22
Åêîëîã³÷íà áåçïåêà òà ïðèðîäîêîðèñòóâàííÿ
Figure 1. Physicochemical and immune barriers against microbial invaders.
TJ = Tight junction; ZA = Zonula adherence; DE = Desmosom.
= Immunoglobulin A attacking pathogen microbes
23
ÏðåðîìàíòèçìÐîçä³ë 1. Åêîëîã³÷íà áåçïåêà
3. Stabilisation of the microbiota
The microbiota may maintain sustainable stability by two mechanisms:
firstly, by interactions among the members of the microbial population,
and secondly by interaction with the host.
The general types of interactions between microbial species are
shown in the Table 4. These might be positive or negative for the
members involved that means beneficial for survival or extinction,
respectively. It should be noted that there is some confusion with
respect to the term «symbiosis». Now and then it is used to characterise
an exclusively beneficial cooperation such as synergism or mutualism.
But, strictly speaking, it bears on any long-term relationship between
two populations.
Several mechanisms that may be involved in gut stability are
suggested in the Table 5. From the viewpoint of system biology species
richness insures ecosystems against functional failure since various
species give a better warranty that some will maintain functioning even
if others fail. An understanding of long-term effects of biodiversity on
ecosystem processes may be given by the insurance hypothesis (Yachi
and Lereau, 1999). These authors developed a general stochastic dynamic
model to assess the effects of species richness on the productivity of
the ecosystem, based on individual species� productivity responses to
environmental fluctuations. The model shows two major insurance
effects: i) a buffering effect, i.e., a reduction in the temporal variance
of productivity, and ii) a performance-enhancing effect, i.e., an increase
in the temporal mean of productivity.
This and other models were designed to predict the «pure» effects
of species richness by randomising and averaging across perturbing
environmental factors. Later on Norberg et al. (2001) developed a more
realistic, yet general, model linking diversity and ecosystems functioning
by modelling the means and variances of phenotypes within a group
of species. The presented framework suggests that phenotypic variance
within functional groups is linearly related to their ability to respond
to environmental changes. Most intriguing is the ratio between short-
term productivity with low variance and fixed optimal phenotypes, and
long-term productivity in changing environments with higher phenotypic
variance. The adaptive model had a higher productivity than the model
with a fixed phenotype. The contribution of Norberg et al. is a
24
Åêîëîã³÷íà áåçïåêà òà ïðèðîäîêîðèñòóâàííÿ
Table 4 � Type of interactions between two microbial
populations A and B
A B A B
Commensalism + 0 Supplies vitamins
and amino acids,
degrades polymers
to monomers,
solubilisation of
insoluble
compounds,
neutralisation of
toxic substances
Utilises essential
substances that it is not
able to synthesise,
utilises monomers,
utilises solubilised
compounds,
protects against toxic
substances
Synergism + + Syntrophism (Cross-feeding, food chains, food
webs)
Bacteroides
produces sulphate,
Ent. faecalis
converts arginine
to ornithine and
utilises putrescine
Desulfovibrio utilises
essential sulphate,
E. coli converts ornithine
to putrescine that can be
further utilised by this
species
Mutualism + + A form of synergism in which the relationship
between the two organisms is obligatory
Competition - - Competitve exclusion
E. coli and Clostridium difficile compete on
certain sugars
methanogens and sulphate-reducing bacteria
compete on H2
Amensalism + - Produces toxic
substances:
bactericins,
hydrogen peroxide,
acidic end products
Cessation of growth and
killing in an incompatible
environment (Candida
unable to grow on skin and
vagina owing to low pH)
Parasitism + - Protoctists
Entamoeba
gingivalis in the
oral cavity,
Dientamoeba
fragilis in the
intestine
Bacteria are the major food
for protoctists
25
ÏðåðîìàíòèçìÐîçä³ë 1. Åêîëîã³÷íà áåçïåêà
Table 5 � Mechanisms of maintaining stability
in the intestinal microbiota
persuasive affirmation of linking diversification, abundance and evolution
as bolstered by Darwin in 1859.
There is now expanding belief that microbes of a single species or
a number of different species aggregate to communities of different
complexity in the colon and other sites. That encompasses individual
cells attached to a surface, loosely aggregated microcolonies as well as
biofilms. Four decades ago Guggenheim and Schroeder (1967) observed
aggregation and clumping of Streptococcus mutans a few seconds after
addition of sucrose into the incubation medium. Formation of high-
molecular dextran was surmised to be responsible for this effect, which
was soon confirmed experimentally by Gibbons and Fitzgerald (1969).
Dextran binds receptor molecules on the bacterial surface and links
cells to a network. These findings were conjectured as of clinical
relevance for cariogenic plaque formation and may be seen as the first
report of elucidation of specific macromolecular interactions to the
phenomenon what we now know as biofilm. Probert and Gibson
(2002) allude to experimental research on microbial biofilms already
in 1936. A biofilm is apprehended as a community of surface-adherent
Factor Benefit for population stability
Environment Host provides optimal and stable conditions for life of
microbiota, e.g. supply of nutrients, maintaining temperature
and pH, keeping away perturbing foreign microorganisms
Species
richness
Phenotypic variance insures microbial ecosystems against
functional failure in accord to the insurance hypothesis:
- buffering effect to respond to environmental perturbations
- performance-enhancing effect
Community
formation
More or less tight aggregations of microbial colonies, and
formation of biofilms produce locally optimal conditions and
protection:
- „supergenome” in the population provides momentary
adaptation to changes in the environment
- coordinated population behaviour by quorum sensing
Separation Life within the mucous layer along the epithelium and in
spatial niches offers protection against competitors,
mucous glycoproteins are utilised as food
26
Åêîëîã³÷íà áåçïåêà òà ïðèðîäîêîðèñòóâàííÿ
microorganisms enmeshed within a matrix of extracellular polymeric
substances. The matrix components are usually polysaccharides. Its formation
is a pivotal strategy of bacterial survival in an inhospitable environment.
That makes the affiliates in a way functionally similar to a multicellular
organism. The matrix of the biofilm is produced by the cells constituting
the biofilm, its structural integrity depends essentially on an intact bacterial
metabolism (Il�ina et al. 2004, Branda et al. 2005).
Planktonic bacteria when going to group together in a biofilm
modify specific patterns of protein and gene expression, metabolic
profile and specific physiology. They approach a new state that is
termed «biofilm phenotype» (Whiteley et al. 2001, Sauer et al. 2002).
Biofilm communities tend to be more resistant to antimicrobial
stressors, involving those exerted by host-defence, than bacteria of the
similar species living planktonic. That is apparently the manifestation
of several factors including vitiated penetration of the antibiotic, metabolic
activity and phenotypic variability of biofilm cells.
Microbes growing in a colony may faster become antibiotic-resistant
due to a greater opportunity of horizontal gene transfer. Such inducible
competence and transformation mechanisms gave the basis of the
«distributed genome hypothesis» or «supergenome hypothesis» (Ehrlich
et al. 2005). It implies the following conceptions (Ehrlich et al. 2008):
a huge phenotypic and genotypic diversity within a microbial species;
an almost universally polyclonal microbial colonisation; and microbiomes
in different hosts are considerably different. A microbial species is thus
classified by a core genome that each member of a species possesses.
It contains in addition distributed genes, which encompass genes that
are not shared by all strains of a species. The species E. coli, for
instance, possesses about 4000 obligate/core genes. In addition, there
are about 2000 facultative genes, of which about 200-1500 genes are
found in each individual strain. The assemblage of facultative genes
codifies additional functions, which are not mandatory for survival.
Rare metabolic routes, resistance against toxins, pathogenic or symbiosis
features or speciation for colonisation of certain niches are such
functions. Thus, the facultative genes are distributed in a gene pool.
Optimised procedures of horizontal gene transfer afford immediate
distribution among all members of the species. New strains can come
up through inducible autocompetence and autotransformation systems.
Contingency genes (hypermutable loci in the genome) are distributed
27
ÏðåðîìàíòèçìÐîçä³ë 1. Åêîëîã³÷íà áåçïåêà
within the population and give the property of changes in phenotype
at a frequency up to 1:100-1000 bacteria per generation. Typically,
activities of genes are affected that interact with the environment. These
mutations are random in time and cause heterogeneity within a
population of replicating bacteria. That is an important mechanism of
momentary adaptation to changes in the environment.
Coordinated population behaviour to gain maximal benefit in a
competitive environment implies intercellular communication. Bacteria
send out and perceive «hormone-like» signal molecules that increase
in concentration as a function of cell density («autoinducer»). The
whole population initiates a concerted action as soon as the population
density and the corresponding signal concentration approach a certain
threshold. Few signal transmitting molecules have been identified: post-
translationally modified peptides (Hardman et al. 1998), diketopiperazines
furanosyl borate diester (Daniels at al. 2004), inorganic polyphosphates
(Brown and Kornberg 2004), acetyl phosphate (Wolfe 2005),
N-acylhomoserine lactones (Swift et al. 2001, Dong and Zang 2005).
Target genes can synchronously be expressed among a local community
and biological activities can be coordinated (Miller and Bassler 2001).
This community genetic regulatory phenomenon was coined «quorum
sensing». Evidence is provided that quorum-sensing signals influence
cellular processes like biofilm association, responses to physicochemical
stresses, organelle biogenesis, cell cycle regulation, phase variation in
stationary-phase planktonic cultures, virulence factor expression, symbiosis,
production of antibiotics, motility, swarming, sporulation, and conjugation.
Bacteria embedded in a biofilm show considerable variability in
metabolic and reproductive activity (Fux et al. 2005). The formation
of the polymer matrix may increase or decrease in dependence on
biofilm evolution (Nadell et al. 2008). Biofilms may contain bacteria
of different species. A curious observation on the «social life» within
a biofilm was reported recently (Diggle et al. 2007). These researchers
showed exploitative behaviour of some individuals. Such bacteria avoid
the expenditure of producing signal molecules and of partaking in
cooperative activities, and thus proliferate faster than the kin relatives.
Salmond et al. (1995) viewed the action of bacterial biofilms as an
example of multi-cellularity in prokaryotic populations. The previous
communications on the fascinating and diverse social life of bacteria
will focus increasing attention into this field.
28
Åêîëîã³÷íà áåçïåêà òà ïðèðîäîêîðèñòóâàííÿ
During the last decades a variety of factors that contribute obviously
to the increased rate of infections by bacteria forming biofilms, e.g.
excessive use of antibiotics, disturbances between intestinal flora and
hosts immune system, failures in nutrition, damage of epithelia by
intracorporeal medical devices with inappropriate coatings and improper
application, failure of diagnostic procedures to recognise bacteria growing
in a biofilm (Matsumoto and Takahashi 1994). Biofilms in water and
its impact in human disease transmission were recently conferred by
Huq et al. (2008). Kaufmann et al. (2008) considered the use of
quorum-sensing blockers for therapeutic purposes. Studies with
Pseudomonas aeruginosa show the role of quorum-sensing and
neuraminidase-dependent biofilm formation for respiratory infection.
Therefore, perturbance of quorum sensing by macrolides and inhibition
of that enzyme may be a novel potential therapeutic perspective to
prevent pneumonia (Otto 2004, Tateda et al. 2004, Raffa et al. 2005,
Rice et al. 2005, Soong 2006).
4. Hosts immunity and microbiota
Generally, each microbe when entering a human tissue may initiate
ruinous outcomes for the host. Physical, chemical and immune barriers
created by the intestinal epithelium and the adjacent lymphatic system
protect the host against such unwelcome intrusion of enteric
microorganisms. Four cell lineages, including enterocytes (form a thin
layer of epithelial cells that separates the gut lumen from the mucosal
immune system; support specific transport functions for nutrients and
give information about the external milieu), hormone-producing entero-
endocrine cells, goblet cells (mucin production), and Paneth cells
(production of antimicrobial peptides and proteins), compose the epithelial
barrier. Intercellular junctional protein complexes such as tight junctions,
adherens junctions, and desmosomes maintain the integrity of the
epithelium. In addition, M cells are specialised epithelial cells belonging
to the follicle-associated epithelium that wraps Peyer�s patches. This
cell type is involved in the communication between intraluminal
microbiota and lymphatic tissue by sampling luminal antigens directly
(see Fig. 1). Peyer�s patches, mesenteric lymph nodes, diffusely scattered
lymphocytes, cryptopatches and great numbers of IgA producing plasma
cells in the intestinal lamina propria and epithelium constitute the
29
ÏðåðîìàíòèçìÐîçä³ë 1. Åêîëîã³÷íà áåçïåêà
GALT (gut-associated lymphoid tissue). It expands along the intestinal
mucosa. One should remember that almost all components of the
immune system are abundant at the end of a full-term pregnancy, but
effective protection of the intestinal mucosa necessitates the microbial
incitement of initial bacterial settling.
It is customarily assumed that the immune system exclusively
provides defence to the host against a multiplicity of bacterial threats
from the environment. However, host immune system and the microbiota
of its most adjacent environment establish a symbiotic, highly redundant
network. It works as a two-way communication system and brings
together the biodiversity of bacteria and the potentially multiple immune
response of the host. In this network the host fulfils its keen rationale
to keep under control the composition of the microbiota. Species-
specific response to suppress or eliminate a particular microbial strain
may be disabled, however, owing to the enormous strain diversity.
Instead, mechanisms evolved to handle whole matching sets of bacteria
with mutual structural and/or functional features. This mission has to
be done for the most part by the innate immune system. It provides
the first frontier of immune defence against infectious agents and on
which the acquired immune system depends for activation and for the
majority of its effector functions.
To live together with numerous bacteria in our gut without any
harmful effects is an outstanding feat by the local epithelium and the
joining lymphoid tissue. The gut microflora, a great variety of antigens
brought along with food, and potential pathogen germs continuously
challenge the gastrointestinal defence. Intruded microbials were held off
by a plethora of sensing and effector functions to initiate proper
immune responses. Intact food antigens have to be excluded, an
arrangement has to be made with commensals, and pathogens have to
be abolished. That is an extremely intricate issue. Obviously a fine
borderline secedes the homeostatic balance upheld in the presence of
the commensal microbiota and the devastating response to invading
bacterial pathogens. For this balance to maintain, a fine-tuned
communication between microbiota, epithelium and the underlying
lymphoid cells is mandatory. This enduring dialogue is coined microbial-
epithelial crosstalk. It ensures tolerance to the normal bacterial flora
and prevents inflammatory derailments and their detrimental clinical
outcomes (Sansonetti 2004).
30
Åêîëîã³÷íà áåçïåêà òà ïðèðîäîêîðèñòóâàííÿ
Microbes present multifaceted surface structures that phagocytes
should identify for immediate killing and triggering the expression of
cytokines and chemokines that orchestrate host antimicrobial defence.
The affiliated epithelium and the immune cells must first of all
recognise present microbes, distinguish them from host cells, and
discriminate pathogens from members of the indigenous microflora.
Surface structures of microbes that both animals and insects are missing
are the basis for this recognition. Janeway suggested this concept in
1989: «� the immune system has evolved specifically to recognize and
respond to infectious microorganisms, and that this involves recognition
not only of specific antigenic determinants, but also of certain
characteristics or patterns common on infectious agents but absent from
the host.» These structures were firstly coined PAMPs, for «pathogen-
associated molecular patterns». Since such structures are also present
in most non-pathogenic species, the term «microbe-associated molecular
patterns» MAMPs should be preferred. The recognising molecules on
host cells are termed pattern recognition receptors (PRR). In the Table
6 are surveyed PRRs, the corresponding ligands, and the microbes to
be recognised by this system as gleaned in the last one decade.
PRR are protein molecules located in outer and inner cell membranes
and in the cytoplasm of immune cells and cells of other tissues. A
collection of soluble pattern recognising molecules, mainly but not
exclusively produced by the liver, circulates in body fluids and contributes
to opsonification and complement activation. Recognition is dependent
on receptor-ligand interaction between pattern recognising protein molecules
on host cells and MAMPs of the microorganism (Medzhitov and
Janeway Jr. 1997). Toll-like receptors (TLR), the ß-glucan-receptor
Dectin 1 and the mannan receptor on the outer cell membrane and
the soluble intracellular proteins NOD1 and NOD2 appertain to cell-
associated PRR. They are germ-line encoded and predominantly expressed
on macrophages/monocytes, neutrophils, fibroblasts, B cells, dendritic
cells, mucosa epithelium cells, endothelial cells, and regulatory T cells
(Treg). Thirteen TLRs have been found in mammals as yet.
Although the recognition mechanism at the molecular level is well
studied, the mechanisms of discrimination and confining potentially
harmful bacteria and allowing indigenous microbiota to remain are far
from being elucidated. That is even more amazing, since the cells make
use of mutual molecular signalling routes. PRRs bound to membranes
31
ÏðåðîìàíòèçìÐîçä³ë 1. Åêîëîã³÷íà áåçïåêà
such as TLRs act as signal-transducer. Binding of the particular MAMP
on the extracellular portion of the corresponding PRR that bears a
motif of leucine-rich repeats initiates dimerisation and/or complexation
with other receptor molecules on the inside of the cell membrane. A
set of adaptor proteins is recruited to amplify the down-stream signalling.
The reaction cascade discharges into activation of transcription factors
(NF-êB, Activator protein1), which enter the cell nucleus and lead to
a distinct array of gene expression products (Fig. 2). These gene
products (cytokines, interleukins) arrange innate immune responses and
direct development of antigen-specific acquired immunity (Medzhitov
and Janeway 1997, Hallman et al. 2001, Akira and Takeda (2004), Oda
and Kitano (2006), deFRanco et al. 2007, Krishnan et al. 2007).
In this framework MyD88 acts as the primary adaptor for microbial
signalling and NF-êB is accepted as the central mediator of the immune
response. Specificity of signalling is approached by collaboration among
TLRs and of TLRs with other receptors, differential utilisation of adaptor
proteins, collaboration among multi-transcription factor binding sites in
the promoter region of a certain gene, interaction with TLR-independent
signalling routes, and so on. Negative and positive feedback loops
preclude rampant inflammation that gives rise to ample tissue damage
and fatal clinical outcomes. In addition to an appropriate response to
a pathogen TLRs play a role in immune cell differentiation and
maturation. Since TLRs are able to recognise endogenous molecules of
the host (e.g. heat shock proteins, fibronectin, RNA, ATP) a function
of these PRR may be anticipated in restraint of immune disorders.
Abbreviations used in the Table 6. Components of antimicrobial
defence
Abbreviations
S = skin
E = eye (tear)
O = oral cavity
G = stomach
R = respiratory tract
F = female genital tract
U = urinary tract
LPS = lipopolysaccharide
SLPI = Secretory leukocyte proteinase inhibitor
SPLA2 = Secretory phospholipase A2
32
Åêîëîã³÷íà áåçïåêà òà ïðèðîäîêîðèñòóâàííÿ
Figure 2. Bow-tie architecture of microbiota-human symbios.
33
ÏðåðîìàíòèçìÐîçä³ë 1. Åêîëîã³÷íà áåçïåêà
T
ab
le
6
�
N
on
-c
el
lu
la
r
co
m
po
ne
nt
s
of
a
nt
im
ic
ro
bi
al
d
ef
en
ce
C
om
po
ne
nt
S
E
O
G
I
R
F
U
T
ar
ge
t o
f a
nt
im
ic
ro
bi
al
a
nd
p
ro
te
ct
iv
e
ac
tiv
iti
es
P
ep
tid
e,
P
ro
te
in
A
ni
o
n
ic
p
e
p
tid
e
+
E
.
co
li,
S
ta
p
h.
a
ur
e
us
,
P
s.
a
e
ru
g.
,
K
.
p
ne
u
m
o
ni
a
e
B
P
I
+
+
+
G
ra
m
-n
e
ga
tiv
e
sp
ec
ie
s,
n
e
ut
ra
lis
es
L
P
S
C
at
he
lic
in
+
+
+
+
+
S
yn
er
gi
c
ac
tiv
ity
w
ith
ly
so
zy
m
e
a
ga
in
st
m
a
n
y
b
ac
te
ria
,
ne
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ra
lis
e
s
LP
S
,
a
ttr
a
ct
s
ne
ut
ro
p
hi
ls
,
m
o
no
cy
te
s
a
nd
T
-
ly
m
p
ho
cy
te
s
(C
D
4
)
C
o
e
ru
lo
p
la
sm
in
+
B
in
d
in
g
o
f c
op
p
e
r
C
o
lle
ct
in
s
+
S
ur
fa
ct
an
t
pr
ot
ei
ns
;
K
le
bs
ie
lla
p
ne
u
m
o
ni
ae
C
o
m
p
le
m
e
n
t
+
M
ic
ro
b
ia
l l
ys
is
a
nd
o
p
so
ni
sa
tio
n,
α-
D
e
fe
ns
in
-5
+
+
C
a
nd
.
a
lb
ic
a
n
s,
E
. c
o
li,
S
ta
p
h.
a
ur
e
u
s,
L
is
.
m
o
no
cy
to
ge
ne
s,
B
a
c.
c
e
re
us
ß
-D
e
fe
ns
in
-1
+
+
+
+
+
+
+
+
G
ra
m
-p
o
s.
/n
e
g.
s
p
e
ci
e
s,
C
a
nd
.
a
lb
ic
a
ns
ß
-D
e
fe
ns
in
-4
+
+
+
E
.
co
li,
S
ta
p
h.
a
ur
e
us
,
P
s.
a
e
ru
g
in
o
sa
,
K
.
p
ne
u
m
o
ni
a
e
,
at
tr
ac
ts
m
o
no
cy
te
s
C
a
lp
ro
te
ct
in
+
+
E
.
co
li,
S
ta
p
h.
a
ur
e
us
,
K
le
b
si
e
lla
,
C
a
nd
.
a
lb
.
D
e
rm
ci
d
in
+
E
.
co
li,
S
ta
p
h.
a
ur
e
us
,
C
a
nd
.
a
lb
.,
E
nt
. f
a
e
ca
lis
E
la
fin
+
+
+
S
ta
p
h.
a
ur
e
us
,
P
s.
a
e
ru
gi
no
sa
,
ne
ut
ra
lis
e
s
LP
S
,
in
hi
b
its
ne
ut
ro
p
hi
l e
la
st
a
se
F
ib
ro
ne
ct
in
+
F
ac
ili
ta
te
s
p
ha
go
cy
to
si
s
G
la
nd
ul
in
+
G
ra
m
-n
e
g.
s
pe
ci
e
s
H
e
m
o
ci
d
in
s
+
E
.
co
li,
S
al
m
o
ne
lla
,
E
n
t.
fa
ea
lis
H
e
p
ci
d
in
+
+
C
a
nd
id
a
a
lb
ic
a
n
s,
E
.
co
li,
S
ta
p
h.
e
p
id
er
m
id
is
H
is
ta
tin
s
+
Y
e
a
st
s,
s
up
pr
e
ss
io
n
o
f c
yt
o
ki
ne
in
d
uc
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n
a
nd
p
la
q
ue
fo
rm
at
io
n,
a
ttr
ac
ts
m
o
no
cy
te
s
34
Åêîëîã³÷íà áåçïåêà òà ïðèðîäîêîðèñòóâàííÿ
C
om
pi
le
d
fr
om
B
ei
ss
w
en
ge
r
an
d
B
al
s
20
05
,
L
ié
vi
n
-L
e
M
oa
l
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d
S
er
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(
20
06
),
M
cA
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ey
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al
.
20
07
,
W
il
so
n
2
00
8.
C
om
po
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nt
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bi
al
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Ig
A
,
Ig
M
+
P
re
ve
nt
m
ic
ro
b
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l a
d
he
si
o
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a
ci
va
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c
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La
ct
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rr
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+
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V
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ac
.
su
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o
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,
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tr
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cc
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H
.
in
flu
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,
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co
li,
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re
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te
lla
,
P
se
ud
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m
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n
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s
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ys
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m
e
+
+
+
+
+
+
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st
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tin
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te
s
G
ra
m
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o
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b
a
ct
e
ri
a
M
uc
in
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+
N
-t
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rm
in
a
l c
le
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ve
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e
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tid
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a
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ic
ro
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ct
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e
P
so
ri
a
si
n
+
E
.
co
li,
c
he
m
o
ki
ne
s
R
e
g
II
Iy
+
Li
st
.
m
o
no
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to
ge
ne
s
a
nd
in
no
cu
a
,
E
n
t.
fa
e
ca
lis
S
ia
lin
+
B
in
d
s
m
ic
ro
b
e
s
S
LP
I
+
+
+
+
+
+
E
.c
o
li,
P
s.
a
e
ru
gi
n.
,
S
ta
p
h.
a
ur
e
us
,
in
h
ib
its
L
P
S
S
P
LA
2
+
+
+
G
ra
m
-p
o
si
tiv
e
sp
ec
ie
s
S
ta
th
e
ri
n
+
+
P
se
ud
o
m
o
na
s
a
e
ru
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ÏðåðîìàíòèçìÐîçä³ë 1. Åêîëîã³÷íà áåçïåêà
This complex immune system and the coexistence with the microbiota
pose numerous questions, such as: Why there is no permanent
inflammation on the mucosal/epithelial surfaces («commensal paradox»)?
There are counteracting mechanisms that bolster or hinder microbial
diversity: Why in vertebrates the microbial diversity is greater than in
invertebrates, although vertebrates possess a stronger immune system,
which may damp diversity? What consequences have bacterial life and
sympatry in micro-niches, resource competition, promoted gene flow
through random mating, and competitive exclusion on species diversity?
How robustness, fragility, resource limitation and performance are
involved in the symbiotic association of microbiota and hosts immunity?
What are the consequences of systemic or local disturbances? Did the
vertebrate immune system evolve under selection pressure to maintain
a diverse and stable microbiota? Systems biological methodology gains
in importance to disentangle the possible logic behind the network and
is beginning to answer such questions (Csete and Doyle 2004, Seymour
2005, Kitano and Oda 2006, Kitano 2007).
In Seymour�s model the host possesses a number of distinct niches,
which harbour generalist and specialist species with varying rates of
growth and reproduction. A low rate of mutation between closely
related species and some migration along routes linking niches are
permitted. The host acts like a predator in an ecological community,
but one with adaptable prey preferences, and uses its immune system
to retard the growth rate of the microbiota. The diversity between
niches increases with the strength of immunity. In the absence of
systematic disturbance a reasonable strong immune response yields
highly diverse communities dominated by several distinct species of
specialists. Stochastic disturbances such as transitory compromises of
immune response constrained diversity of microbiota. Disturbances
having a preference to niches yield competitive dominance by the
generalist members. Seymour supposes that the high diversity with the
relatively even abundance of most species could be related with the
commensal paradox: inflammation demands «above threshold» signals
to trigger the local cytokine network.
A number of investigators attempted to unveil the design principle
and the structural topology of biological networks in relation to their
function by use of mathematical models and computer simulation. For
it, complex biological networks were deconstructed into conceptually
36
Åêîëîã³÷íà áåçïåêà òà ïðèðîäîêîðèñòóâàííÿ
simple entities (modules) that are made up of many species of
interacting molecules (Hartwell et al. 1999, Papin et al. 2004). These
networks have topologies that are principally different to those in
simple randomly linked networks. The choice of bow-tie as a structural
building unit proved to be a concise and smart option for constructing
metabolic and signal transduction networks (Zhao et al. 2006, Kitano
2007).
One of the fundamental characteristics of biological systems is
robustness. It is a «property that allows a system to maintain its
function against internal and external perturbations» (Kitano and Oda
2006, Oda and Kitano 2006). Kitano and co-workers propose that the
intracellular signal transduction pathways and the intercellular signal
processes of both the innate and acquired immune system consist of
a modularised tandem bow-tie pattern (Fig. 2). The MyD88-adapter-
protein complex and NF-êB act as bottlenecks in this topology. This
main bow-tie network has extensive collateral pathways with multiple
positive/negative system controls and crosstalk regulations that may
modulate downstream performance. Such an architecture is characterised
by a great «fan-in» of signals recognised by PRR, and a great «fan-
out» of cytokines, chemokines, and interleukins. In the consequence,
the response of the signalling network to a specific set of stimuli
depends on the activation levels and temporal dynamics of molecules
in this theoretical hyperspace.
That modularised bow-tie design leads to inherent trade-offs among
robustness, fragility, resource limitation, and performance. A modular
signalling network that is nested by many relatively independent and
robust bow-tie units, will give more advantages in generating coordinated
response to various stimuli from environment. Both symbiotic partners
� host�s immune system and a diverse microbiota � coevolved in a
symbiotic relationship to optimise robustness against pathogen challenges
and nutrient perturbations. This concept is in harmony with «conclusions
from a number of studies that these structures result from universal and
fundamental organising principles for efficiency and robustness, rather
than frozen accidents of evolution» (Zhao et al. 2006). There is a
further point of benefit for the host: the enduring homeostasis of
microbiota might be exceptionally important against autoimmune disorders
and other immune derailments which are predicated on the intrinsic
tendency of the immune system toward hyperactivity.
37
ÏðåðîìàíòèçìÐîçä³ë 1. Åêîëîã³÷íà áåçïåêà
5. How to improve a tilted host-microbiota partnership?
Factors accompanying our current life such as over- and malnutrition,
physical inactivity, excessive use of tobacco, alcohol, drugs and medicine,
UV-irradiation, incorporation/inhalation of pesticides, toxic gases and
heavy metals and growing-up in a sanitised world disturb the immune
balance and the host-microbiota partnership with the consequence of
a huge increase of chronic inflammatory diseases, e.g. atherosclerosis,
inflammatory bowel diseases, diabetes, asthma, rheumatism,
neurodermatitis, psoriasis, adipositas, and cancer. The anticipation to
improve the host-microbiota partnership, immunity and constitutional
performance by food additives is based on four aspects: i) using the
recent advance in understanding of the dynamic interplay between host
immune system and microbiota, ii) recognising the established history
of using health-promoting extracts of fungi, algae and herbs in traditional
oriental medicine and in food supplementation, iii) assuring usefulness
and safety of food ingredients for disease prevention and treatment, and
iv) the bioactive molecules to come into question can be given to the
diet, without the prerequisite to cope with phase-I/II/III clinical trials.
Orally administered agent�s come into direct contact with the largest
immune tissue GALT and its microenvironment in the intestine,
which may have an explicit effect on the microbiota and the ensuing
final immune response.
There may be three options to accomplish such an entitlement:
i. Immunomodulating option: Uptake of immune modulating
ingredients to prevent inflammatory lapse or trace back a derailed
immune system into balance.
ii. Prebiotic option: Uptake of non-digestible substrates to feed
health-promoting members of indigenous microbiota, e.g. Bifidus spp.
iii. Probiotic option: Uptake of health-promoting bacteria such as
Lactobacillus spp. and Bifidus spp.
Compounds that can interact with the immune system to upregulate
or downregulate the host response are termed immunomodulator, or
synonymously immunostimulant, immunopotentiator, immune enhancer,
or biological response modifier. The concept of immunomodulation is
to induce the same response as that taking place during the initial
phase in a common infection without producing sustained dangerous
inflammation or harsh side-effects. A particular immune sub-function
38
Åêîëîã³÷íà áåçïåêà òà ïðèðîäîêîðèñòóâàííÿ
has to be increased or suppressed in such a way as to enhance or
complement a desired response. Such a proceeding is promising since
i) it strengthens hosts own defence mechanisms, and ii) it excludes
the use of species-specific antibiotics.
The inflammatory reaction mostly attains a fine balance that
eliminates pathogen microbes and repairs damaged tissues. Strictly
regional low-grade inflammations may occur now and then and should
be understood as a sub-clinical everyday occurrence. However, the fine-
tuned response can go awry and a persistent inflammation arises, often
lacking a recognisable infection. Cytokines, interleukins and chemokines
are local messenger molecules that mediate information between cells.
These mediators have a great impact on cell division, differentiation,
growth and immunity. It makes sense to envisage the cytokines as
constituting a network of inherent agonist and antagonist functions, e.g.
pro-inflammatory and anti-inflammatory reactivity, or growth-promotion
and suppression (Balkwill 2000). At an inflammatory site pro- as well
as anti-inflammatory mediators are consecutively up-regulated followed
by down-regulation. In states of chronic inflammation the equilibrium
is skewed towards the inflammatory arm. The outbalanced cytokine
network induces inflammatory cell recruitment of the tissue(s) concerned,
vitiation of cell functions, and tissue-matrix injury.
Many immunomodulating compounds are polysaccharides or
polysaccharide-protein complexes, such as the zwitterionic polysaccharides,
mannans, protein bound polysaccharides PSK and PSP, and hyaluronan.
One of the best studied is the group of beta-glucans. These polysaccharides
are widely distributed in the biological matter in, for example, yeast,
fungi (excluding zygomycetes), bacteria, and lower and higher plants.
They occur as a primary constituent in the cell wall of fungi and
bacteria. (1→3)-beta-glycosidic bonds link the glucose units in the
backbone. Side chains are formed as (1→4)-linkages or as (1→6)-
linkages. (1→3),(1→6)-beta-D-Glucans are non-toxic, non-immunogenic,
and non-allergenic. beta-Glucans react with PRRs (e.g. Dectin1) on
monocyte/macrophages, natural killer cells, neutrophils, dendritic cells,
vascular endothelial cells, keratinocytes and fibroblasts. The macrophage
has been identified as the master cell in the first line of defence against
most infections as well as in mediating the response of the innate and
acquired immunity. This cell type can be activated as the result of a
common infection process or by products of fungi or bacteria.
39
ÏðåðîìàíòèçìÐîçä³ë 1. Åêîëîã³÷íà áåçïåêà
Binding of beta-glucan to macrophages initiates complexation of the
beta-glucan receptor with TLR2 and TLR6 and activation of signal
transduction pathways involving NF-êB-like transcription factors (Luhm
et al. 2006). It alerts the innate immune system and primes it to
respond immediately and properly to infections. The anti-inflammatory
efficacy has been shown in-vitro and in-vivo (Gerber et al. 2005, Lull
et al. 2005, Dillon et al. 2006, Jung et al. 2007). As an example, the
Figure 3 shows the results of a study on thoroughbred race-horses
performed in springtime. In that period regular hair coat replacement,
environmental changes, intensification of training loads, transportation,
heavy physical exertion and competitive races, and frequent contacts
to other animals bring about an enduring metabolic, immune and
psychological stress. The animals respond with elevation of acute phase
proteins in blood (fibrinogen, haptoglobin, SAA), which are accepted
markers of inflammation. These changes are ameliorated by the immune
modulating activity of yeast beta-glucan.
In 1995 Gibson and Roberfroid inaugurated the prebiotic concept
as part of the functional food strategy. A prebiotic should fulfil the
following criteria: inertness against hydrolytic cleavage and absorption
in the upper part of the gut, acting as selective substrate for one or
few health-promoting colonic bacterial species, and constraining pathogens
via keeping up growth and/or activity of health-promoting species.
Gibson et al. (2004) suggested a definition of prebiotics taking into
account nutritional, biochemical, physiological and microbial areas that
may benefit from a selective targeting of particular micro-organisms:
«A prebiotic is a selectively fermented ingredient that allows specific
changes, both in the composition and/or activity in the gastrointestinal
microflora that confers benefits upon host well-being and health». At
present the only compounds with prebiotic functions are carbohydrates.
The genera commonly targeted are Bifidobacterium and Lactobacillus,
the growth and activity of which should be increased.
Human breast milk may be seen as the prebiotic per se. The bifidus
factor � a glycoprotein � is the specific entity responsible for the
dominance of bifidus bacteria in the colon of newborns fed breast milk.
A range of oligosaccharides has been proven in experimental studies
to exert prebiotic activity, e.g. oligosaccharides of fructose, galactose,
mannose, xylose, and (1→6)-linked glucose, lactulose, isomaltoo-
ligosaccharide, palatinose, and tagatose. However, in food manufacturing
40
Åêîëîã³÷íà áåçïåêà òà ïðèðîäîêîðèñòóâàííÿ
around the globe inulin, fructooligosaccharides, and galacto-
oligosaccharides are the dominating types. There are attempts to
develop a «second generation» of prebiotics with enhanced activity and
desirable attributes such as fine control of microflora modulation,
specific inhibition of pathogen adhesion, varying viscosity, lack of side-
effects, and persistence to distal regions of the colon (Rastall and
Gibson 2002).
The term «probiotic» was coined by Lilly and Stillwell (1965) in
contrast to antibiotic to describe substances secreted by one
microorganism, which stimulates the growth of another. Following
Havenaar and Huis In´t Veld (1992) and Schrezenmeir and de Vrese
M (2001) a probiotic is defined as «A preparation of or a product
containing viable, defined microorganisms in sufficient numbers, which
alter the microflora (by implantation or colonization) in a compartment
of the host and by that exert beneficial health effects in this host».
This definition is applicable independent of the probiotic site of action
and the route of administration. A synbiotic � in the strongest sense
of the term � is a blend of a prebiotic and a probiotic «� in which
Figure 3: Yeast (1?3),(1?6)-beta-D-glucan (Vitagard P) attenuates
the springtime stress-associated increase of the acute phase protein fibrinogen
in blood serum of race-horses.
41
ÏðåðîìàíòèçìÐîçä³ë 1. Åêîëîã³÷íà áåçïåêà
the prebiotic compound selectively favours the probiotic compound»
(Schrezenmeir and de Vrese M, 2001).
The beneficial effects of probiotics and prebiotics on human health
are critically surveyed by Hanske and Blaut (2006). The probiotics
aimed for human use must fulfil a number of criteria: preferentially
from human origin, genetically stable, non-pathogenic and safe, insensitive
to gastric acidity and bile salt, and to remain viable during technological
processing. The comprehension of the mechanisms underlying the
health promoting claim(s) should be verified by a scientifically established
methodology to improve the credibility of the prebiotic and probiotic
conception. Utilisation of advanced molecular methods for monitoring
variations in the particular microbiota are compulsory.
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___________________________
Authors address:
Prof. Dr. sc. med. Gerhard Gerber
Fibona Health Products GmbH
Heinrich-Hertz-Straße 2
65232 Taunusstein
Germany
E-Mail: g.gerber@f-h-p.eu
Îòðèìàíî 15.06. 2008 ð.
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